NEUROGENEZA

Neurogenesis
Neurogenesis (birth of neurons) is the process by which neurons are generated from the neural
stem cells

1
and progenitor cells. Neurogenesis is most active during pre-natal development, and is responsible for
populating the growing brain with neurons. Neurogenesis has been shown to occur in a number of
brain structures, such as the dentate gyrus of the hippocampus, the nucleus accumbens, and in two
parts of the brains of adult mammals: the hippocampus and the subventricular zone. Studies have
indicated that the hormone testosterone in vertebrates, and the prohormone ecdysone in insects, have
an influence on the rate of neurogenesis.

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3
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 Occurrence in adults

Doublecortin expression in the rat dentate gyrus, 21st postnatal day. Oomen et al., 2009.[2]
New neurons are continually born throughout adulthood predominantly in several regions of the
brain>

 The subventricular zone (SVZ) lining the lateral ventricles, where neural stem cells and
progenitor generate new neurons (Neuroblast) that migrate to the olfactory bulb via the rostral
migratory stream. However, recent work has shown these cells migrate to the striatum in humans[3] and
not the olfactory bulb [4]

5
  Striatal interneurons[5]
 The subgranular zone (SGZ), part of the dentate gyrus of hippocampus.[6]
 The nucleus accumbens, specifically medium spiny neurons[7]
Many of the newborn cells die shortly after they are born, [6] but a number of them become
functionally integrated into the surrounding brain tissue. [8][9][10]
Adult neurogenesis is an example of a long-held scientific theory being further studied. Early
neuroanatomists, including Santiago Ramón y Cajal, considered the nervous system fixed and
incapable of regeneration. The first evidence of adult mammalian neurogenesis in the cerebral cortex
was presented by Joseph Altman in 1962,[11] followed by a demonstration of adult neurogenesis in the
dentate gyrus of the hippocampus in 1963. [12] In 1969, Joseph Altman discovered and named the
rostral migratory stream as the source of adult generated granule cell neurons in the olfactory bulb. [13]
Up until the 1980s, the scientific community ignored these findings despite use of the most direct
method of demonstrating cell proliferation in the early studies, i.e. 3H-thymidine autoradiography. By
that time, Shirley Bayer[14][15] (and Michael Kaplan) again showed that adult neurogenesis exists in
mammals (rats), and Nottebohm showed the same phenomenon in birds [16] sparking renewed interest
in the topic. Studies in the 1990s[17][18] finally put research on adult neurogenesis into a mainstream
pursuit. Also in the early 1990s hippocampal neurogenesis was demonstrated in non-human primates
and humans.[19][20] More recently, neurogenesis in the cerebellum of adult rabbits has also been
characterized.[21] Further, some authors (particularly Elizabeth Gould) have suggested that adult
neurogenesis may also occur in regions within the brain not generally associated with neurogenesis
including the neocortex.[22][23][24] However, others[25] have questioned the scientific evidence of these
findings, arguing that the new cells may be of glial origin. Recent research has elucidated the
regulatory effect of GABA on neural stem cells. GABA's well-known inhibitory effects across the
brain also affect the local circuitry that triggers a stem cell to become dormant. They found that
diazepam (Valium) has a similar effect.[26]
Role in learning
The functional relevance of adult neurogenesis is uncertain, [27] but there is some evidence that
hippocampal adult neurogenesis is important for learning and memory.[28] Multiple mechanisms for the
relationship between increased neurogenesis and improved cognition have been suggested, including
computational theories to demonstrate that new neurons increase memory capacity, [29] reduce
interference between memories, [30] or add information about time to memories. [31] Experiments aimed
at ablating neurogenesis have proven inconclusive, but several studies have proposed neurogenic-
dependence in some types of learning, [32] and others seeing no effect. [33] Studies have demonstrated that
the act of learning itself is associated with increased neuronal survival. [34] However, the overall
findings that adult neurogenesis is important for any kind of learning are equivocal.

Alzheimer's disease
Some studies suggest that decreased hippocampal neurogenesis can lead to development of
Alzheimer's disease.[35] Yet, others hypothesize that AD patients have increased neurogenesis in the
CA1 region of Ammon's horn (the principal region of AD hippocampal pathology) in order to
compensate for neuronal loss.[36] While the exact nature of the relationship between neurogenesis and
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Alzheimer's Disease is unknown, Insulin-like growth factor 1-stimulated neurogenesis produces major
changes in hippocampal plasticity and seems to be involved in Alzheimer's pathology. [37]

Allopregnanolone, a neurosteroid, aids the continued neurogenesis in the brain. Levels of

allopregnanolone in the brain decline in old age and Alzheimer's disease.[38] Allopregnanolone has
been shown through reversing impairment of neurogenesis to reverse the cognitive deficits in a mouse
model of Alzheimer's disease.[39] Eph receptors and ephrin signaling have been shown to regulate adult
neurogenesis in the hippocampus and have been studied as potential targets to treat some symptoms of
AD.[40] Molecules associated with the pathology of AD, including ApoE, PS1 and APP, have also been
found to impact adult neurogenesis in the hippocampus.[41]
Role in schizophrenia
Studies suggest that people with schizophrenia have a reduced hippocampus volume, which is
believed to be caused by a reduction of adult neurogenesis. Correspondingly, this phenomenon might
be the underlying cause of many of the symptoms of the disease. Furthermore, several research papers
referred to four genes, dystrobrevin binding protein 1 (DTNBP1), neuregulin 1 (NRG1), disrupted in
schizophrenia 1 (DISC1), and neuregulin 1 receptor (ERBB4), as being possibly responsible for this
deficit in the normal regeneration of neurons. [42] It is important to state that, unlike Alzheimer's
disease, schizophrenia is not characterized by degenerative neural functions, but rather by an abnormal
rate of neurogenesis and an abnormal neuroplasticity. On the other hand, antipsychotics have shown a
significant promise as a reliable way to increase the rates of neurogenesis. [43] Similarities between
depression and schizophrenia suggest a possible biological link between the two diseases. However,
further research must be done in order to clearly demonstrate this relationship. [44]

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 Implications for depression
Many now believe stress to be the most significant factor for the onset of depression, aside from
genetics. As discussed above, hippocampal cells are sensitive to stress which can lead to decreased
neurogenesis. This area is being considered more frequently when examining the causes and
treatments of depression. Studies have shown that removing the adrenal gland in rats caused increased
neurogenesis in the dentate gyrus.[45] The adrenal gland is responsible for producing cortisol in
response to a stressor, a substance that when produced in chronic amounts causes the down regulation
of serotonin receptors and suppresses the birth of neurons. [46] It was shown in the same study that
administration of corticosterone to normal animals suppressed neurogenesis, the opposite effect. [45]

The most typical class of antidepressants administered for this disease are selective serotonin
reuptake inhibitors (SSRIs) [47] and their efficacy may be explained by neurogenesis. In a normal brain,
an increase in serotonin causes suppression of the corticotropin-releasing hormone (CRH) through
9
connection to the hippocampus. It directly acts on the paraventricular nucleus to decrease CRH release
and down regulate norepinephrine functioning in the locus coeruleus.[45] Because CRH is being
repressed, the decrease in neurogenesis that is associated with elevated levels of it is also being
reversed.

This allows for the production of more brain cells, in particular at the 5-HT1a receptor in the
dentate gyrus of the hippocampus which has been shown to improve symptoms of depression. It
normally takes neurons approximately three to six weeks to mature, [48] which is approximately the
same amount of time it takes for SSRIs to take effect.

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 This correlation strengthens the hypothesis that SSRIs act through neurogenesis to decrease the
symptoms of depression.
Effects of stress
Adult-born neurons appear to have a role in the regulation of stress.[49][50] Studies have linked
neurogenesis to the beneficial actions of specific antidepressants, suggesting a connection between
decreased hippocampal neurogenesis and depression.[51][52] In a pioneer study, scientists demonstrated
that the behavioral benefits of antidepressant administration in mice is reversed when neurogenesis is
prevented with x-irradiation techniques.[53] In fact, newborn neurons are more excitable than older
neurons due to a differential expression of GABA receptors.[citation needed] A plausible model, therefore, is
that these neurons augment the role of the hippocampus in the negative feedback mechanism of the
HPA-axis (physiological stress) and perhaps in inhibiting the amygdala (the region of brain
responsible for fearful responses to stimuli). [vague] Indeed, suppression of adult neurogenesis can lead to
an increased HPA-axis stress response in mildly stressful situations. [49] This is consistent with
numerous findings linking stress-relieving activities (learning, exposure to a new yet benign
environment, and exercise) to increased levels of neurogenesis, as well as the observation that animals
exposed to physiological stress (cortisol) or psychological stress (e.g. isolation) show markedly
decreased levels of newborn neurons. Interestingly, under chronic stress conditions, the elevation of
newborn neurons by antidepressants improves the hippocampal-dependent control on the stress
response; without newborn neurons, antidepressants are unable to restore the regulation of the stress
response and recovery becomes impossible. [50]
Some studies have hypothesized that learning and memory are linked to depression, and that
neurogenesis may promote neuroplasticity. One study proposes that mood may be regulated, at a base
level, by plasticity, and thus not chemistry. Accordingly, the effects of antidepressant treatment would
only be secondary to change in plasticity.[54]

However another study has demonstrated an interaction between antidepressants and plasticity;
the antidepressant fluoxetine has been shown to restore plasticity in the adult rat brain. [55]

11
 The results of this study imply that instead of being secondary to changes in plasticity,
antidepressant therapy could promote it.

Effects of sleep reduction

One study has linked lack of sleep to a reduction in rodent hippocampal neurogenesis. The
proposed mechanism for the observed decrease was increased levels of glucocorticoids. It was shown
that two weeks of sleep deprivation acted as a neurogenesis-inhibitor, which was reversed after return
of normal sleep and even shifted to a temporary increase in normal cell proliferation. [56] More
precisely, when levels of corticosterone are elevated, sleep deprivation inhibits this process.
Nonetheless, normal levels of neurogenesis after chronic sleep deprivation return after 2 weeks, with a
temporary increase of neurogenesis. [57] While this is recognized, overlooked is the blood glucose
demand exhibited during temporary diabetic hypoglycemic states. The American Diabetes Association
amongst many documents the pseudosenilia and agitation found during temporary hypoglycemic
states. Much more clinical documentation is needed to competently demonstrate the link between
decreased hematologic glucose and neuronal activity and mood.
Possible use in treating Parkinson's disease
Parkinson's disease is a neurodegenerative disorder characterized by a progressive loss of
dopaminergic neurons in the substantia nigra. Transplantation of fetal dopaminergic precursor cells
has paved the way for the possibility of a cell replacement therapy that could ameliorate clinical
symptoms in affected patients. [58] In recent years, scientists have provided evidence for the existence of
neural stem cells with the potential to produce new neurons, particularly of a dopaminergic phenotype,
in the adult mammalian brain. [59][60][61] Experimental depletion of dopamine in rodents decreases
precursor cell proliferation in both the subependymal zone and the subgranular zone. [62] Proliferation is
restored completely by a selective agonist of D2-like (D2L) receptors. [62] Neural stem cells have been
identified in the neurogenic brain regions, where neurogenesis is constitutively ongoing, but also in the
non-neurogenic zones, such as the midbrain and the striatum, where neurogenesis is not thought to
occur under normal physiological conditions.[58] Newer research has shown that there in fact is
neurogenesis in the striatum. [63] A detailed understanding of the factors governing adult neural stem
cells in vivo may ultimately lead to elegant cell therapies for neurodegenerative disorders such as
Parkinson's disease by mobilizing autologous endogenous neural stem cells to replace degenerated
neurons.[58]
Changes in old age
Neurogenesis is substantially reduced in the hippocampus of aged animals, raising the
possibility that it may be linked to age-related declines in hippocampal function. For example, the rate
of neurogenesis in aged animals is predictive of memory. [64] However, new born cells in aged animals
are functionally integrated.[65] Given that neurogenesis occurs throughout life, it might be expected that
the hippocampus would steadily increase in size during adulthood, and that therefore the number of
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granule cells would be increased in aged animals. However, this is not the case, indicating that
proliferation is balanced by cell death. Thus, it is not the addition of new neurons into the
hippocampus that seems to be linked to hippocampal functions, but rather the rate of turnover of
granule cells.[66]
Effects of exercise
Main article: Neurobiological effects of physical exercise § Neuroplasticity and neurogenesis
Scientists have shown that physical activity in the form of voluntary exercise results in an
increase in the number of newborn neurons in the hippocampus of aging mice. The same study
demonstrates an enhancement in learning of the "runner" (physically active) mice. [67][68] Recent
research has shown that brain-derived neurotrophic factor and insulin-like growth factor 1 are key
mediators of exercise-induced neurogenesis. [69] Exercise increases the uptake of IGF-1 from the
bloodstream into various brain regions, including the hippocampus. In addition, IGF-1 alters c-fos
expression in the hippocampus. When IGF-1 is blocked, exercise no longer induces neurogenesis. [69]
Other research demonstrated that exercising mice that did not produce beta-endorphin, a mood-
elevating hormone, had no change in neurogenesis. Yet, mice that did produce this hormone, along
with exercise, exhibited an increase in newborn cells and their rate of survival. [70] While the
association between exercise-mediated neurogenesis and enhancement of learning remains unclear,
this study could have strong implications in the fields of aging and/or Alzheimer's disease.
Regulation

Summary of the signalling pathways in the neural stem cell microenvironment.

Many factors may affect the rate of hippocampal neurogenesis. Exercise and an enriched
environment have been shown to promote the survival of neurons and the successful integration of
newborn cells into the existing hippocampus. [67][71][72][73] Another factor is central nervous system injury
since neurogenesis occurs after cerebral ischemia,[74] epileptic seizures,[75] and bacterial meningitis.[76]
On the other hand, conditions such as chronic stress and aging can result in a decreased neuronal
proliferation.[77][78][79] Circulating factors within the blood may reduce neurogenesis. In healthy aging
humans, the plasma and cerebrospinal fluid levels of certain chemokines are elevated. In a mouse
model, plasma levels of these chemokines correlate with reduced neurogenesis, suggesting that
neurogenesis may be modulated by certain global age-dependent systemic changes. These chemokines
include CCL11, CCL2 and CCL12, which are highly localized on mouse and human chromosomes,
implicating a genetic locus in aging.[28]
Epigenetic regulation also plays a large role in neurogenesis. DNA methylation is critical in the
fate-determination of adult neural stem cells in the subventricular zone for post-natal neurogenesis
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through the regulation of neuronic genes such as Dlx2, Neurog2, and Sp8. Many microRNAs such as
miR-124 and miR-9 have been shown to influence cortical size and layering during development. [80]
Adult neural stem cells
Neural stem cells (NSCs) are the self-renewing, multipotent cells that generate the main phenotypes of
the nervous system.
Neural stem cells (NSCs) are self-renewing, multipotent cells that generate the main phenotype of the
nervous system. Stem cells are characterized by their capability to differentiate into multiple cell types via
exogenous stimuli from their environment.[1] They undergo asymmetric cell division into two daughter
cells, one non-specialized and one specialized. NSCs primarily differentiate into neurons, astrocytes, and
oligodendrocytes.[2]
History
In 1989, Sally Temple described multipotent, self-renewing progenitor and stem cells in the
subventricular zone (SVZ) of the mouse brain. [3] In 1992, Brent A. Reynolds and Samuel Weiss were the
first to isolate neural progenitor and stem cells from the adult striatal tissue, including the SVZ — one of
the neurogenic areas — of adult mice brain tissue.[4] In the same year the team of Constance Cepko and
Evan Y. Snyder were the first to isolate multipotent cells from the mouse cerebellum and stably
transfected them with the oncogene v-myc.[5] Interestingly, this molecule is one of the genes widely used
now to reprogram adult non-stem cells into pluripotent stem cells. Since then, neural progenitor and stem
cells have been isolated from various areas of the adult brain, including non-neurogenic areas, such as the
spinal cord, and from various species including humans.[6][7]
Aging and development
In vivo origin
There are two basic types of stem cell: adult stem cells, which are limited in their ability to differentiate,
and embryonic stem cells (ESCs), which are pluripotent. ESCs are not limited to a particular cell fate;
rather they have the capability to differentiate into any cell type. [1] ESCs are derived from the inner cell
mass of the blastocyst with the potential to self-replicate.[2]
NSCs are considered adult stem cells because they are limited in their capability to differentiate. NSCs
are generated throughout an adult's life via the process of neurogenesis.[8] Since neurons do not divide
within the central nervous system (CNS), NSCs can be differentiated to replace lost or injured neurons or
in many cases even glial cells.[2] NSCs are differentiated into new neurons within the SVZ of lateral
ventricles, a remnant of the embryonic germinal neuroepithelium, as well as the dentate gyrus of the
hippocampus.[8]
In vitro origin
Adult NSCs were first isolated from mouse striatum in the early 1990s. They are capable of forming
multipotent neurospheres when cultured in vitro. Neurospheres can produce self-renewing and
proliferating specialized cells. These neurospheres can differentiate to form the specified neurons, glial
cells, and oligodendrocytes.[2][8] In previous studies, cultured neurospheres have been transplanted into the
brains of immunodeficient neonatal mice and have shown engraftment, proliferation, and neural
differentiation.[8]
NSC communication and migration
NSCs are stimulated to begin differentiation via exogenous cues from the microenvironment, or stem cell
niche. This capability of the NSCs to replace lost or damaged neural cells is called neurogenesis.[2] Some
neural cells are migrated from the SVZ along the rostral migratory stream which contains a marrow-like
structure with ependymal cells and astrocytes when stimulated. The ependymal cells and astrocytes form
glial tubes used by migrating neuroblasts. The astrocytes in the tubes provide support for the migrating
cells as well as insulation from electrical and chemical signals released from surrounding cells. The
astrocytes are the primary precursors for rapid cell amplification. The neuroblasts form tight chains and
migrate towards the specified site of cell damage to repair or replace neural cells. One example is a
neuroblast migrating towards the olfactory bulb to differentiate into periglomercular or granule[disambiguation
needed]
neurons which have a radial migration pattern rather than a tangential one.[9]
On the other hand, the dentate gyrus neural stem cells produce excitatory granule neurons which are
involved in learning and memory. One example of learning and memory is pattern separation, a cognitive
process used to distinguish similar inputs.[2]
Aging
Neural stem cell proliferation declines as a consequence of aging.[10] Various approaches have been taken
to counteract this age-related decline. [11] Because FOXO proteins regulate neural stem cell homeostasis,[12]
FOXO proteins have been used to protect neural stem cells by inhibiting Wnt signaling.[13]
Functions of NSCs during differentiation and disease

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Epidermal growth factor (EGF) and fibroblast growth factor (FGF) are mitogens that promote neural
progenitor and stem cell growth in vitro, though other factors synthesized by the neural progenitor and
stem cell populations are also required for optimal growth. [14] It is hypothesized that neurogenesis in the
adult brain originates from NSCs. The origin and identity of NSCs in the adult brain remain to be defined.
Function of NSCs during differentiation
The most widely accepted model of an adult NSC is a radial, astrocytes-like, GFAP-positive cell.
Quiescent stem cells are Type B that are able to remain in the quiescent state due to the renewable tissue
provided by the specific niches composed of blood vessels, astrocytes, microglia, ependymal cells, and
extracellular matrix present within the brain. These niches provide nourishment, structural support, and
protection for the stem cells until they are activated by external stimuli. Once activated, the Type B cells
develop into Type C cells, active proliferating intermediate cells, which then divide into neuroblasts
consisting of Type A cells. The undifferentiated neuroblasts form chains that migrate and develop into
mature neurons. In the olfactory bulb, they mature into GABAergic granule neurons, while in the
hippocampus they mature into dentate granule cells.[15]
Function of NSCs during disease
NSCs have an important role during development producing the enormous diversity of neurons,
astrocytes and oligodendrocytes in the developing CNS. They also have important role in adult animals,
for instance in learning and hippocampal plasticity in the adult mice in addition to supplying neurons to
the olfactory bulb in mice.[8]
Notably the role of NSCs during diseases is now being elucidated by several research groups around the
world. The responses during stroke, multiple sclerosis, and Parkinson's disease in animal models and
humans is part of the current investigation. The results of this ongoing investigation may have future
applications to treat human neurological diseases.[8]
Neural stem cells have been shown to engage in migration and replacement of dying neurons in classical
experiments performed by Sanjay Magavi and Jeffrey Macklis.[16] Using a laser-induced damage of
cortical layers, Magavi showed that SVZ neural progenitors expressing Doublecortin, a critical molecule
for migration of neuroblasts, migrated long distances to the area of damage and differentiated into mature
neurons expressing NeuN marker. In addition Masato Nakafuku's group from Japan showed for the first
time the role of hippocampal stem cells during stroke in mice. [17] These results demonstrated that NSCs
can engage in the adult brain as a result of injury. Furthermore, in 2004 Evan Y. Snyder's group showed
that NSCs migrate to brain tumors in a directed fashion. Jaime Imitola, M.D and colleagues from Harvard
demonstrated for the first time, a molecular mechanism for the responses of NSCs to injury. They showed
that chemokines released during injury such as SDF-1a were responsible for the directed migration of
human and mouse NSCs to areas of injury in mice. [18] Since then other molecules have been found to
participate in the responses of NSCs to injury. All these results have been widely reproduced and
expanded by other investigators joining the classical work of Richard L. Sidman in Autoradiography to
visualize neurogenesis during development, and neurogenesis in the adult by Joseph Altman in 1960's, as
evidence of the responses of adult NSCs activities and neurogenesis during homeostasis and injury.
The search for additional mechanisms that operate in the injury environment and how they influence the
responses of NSCs during acute and chronic disease is matter of intense research. [19]
Potential clinical applications
Regenerative therapy of the CNS
Cell death is a characteristic of acute CNS disorders as well as neurodegenerative disease. The loss of
cells is amplified by the lack of regenerative abilities for cell replacement and repair in the CNS. One way
to circumvent this is to use cell replacement therapy via regenerative NSCs. NSCs can be cultured in
vitro as neurospheres. These neurospheres are composed of neural stem cells and progenitors (NSPCs)
with growth factors such as EGF and FGF. The withdrawal of these growth factors activate differentiation
into neurons, astrocytes, or oligodendrocytes which can be transplanted within the brain at the site of
injury. The benefits of this therapeutic approach have been examined in Parkinson's disease, Huntington's
disease, and multiple sclerosis. NSPCs induce neural repair via intrinsic properties of neuroprotection and
immunomodulation. Some possible routes of transplantation include intracerebral transplantation and
xenotransplantation.[20][21]
An alternative therapeutic approach to the transplantation of NSPCs is the pharmacological activation of
endogenous NSPCs (eNSPCs). Activated eNSPCs produce neurotrophic factors,several treatments that
activate a pathway that involves the phosphorylation of STAT3 on the serine residue and subsequent
elevation of Hes3 expression (STAT3-Ser/Hes3 Signaling Axis) oppose neuronal death and disease
progression in models of neurological disorder.[22][23]
Basic laboratory studies
Generation of 3D in vitro models of the human CNS

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Human midbrain-derived neural progenitor cells (hmNPCs) have the ability to differentiate down
multiple neural cell lineages that lead to neurospheres as well as multiple neural phenotypes. The hmNPC
can be used to develop a 3D in vitro model of the human CNS. There are two ways to culture the
hmNPCs, the adherent monolayer and the neurosphere culture systems. The neurosphere culture system
has previously been used to isolate and expand CNS stem cells by its ability to aggregate and proliferate
hmNPCs under serum-free media conditions as well as with the presence of epidermal growth factor
(EGF) and fibroblast growth factor-2 (FGF2). Initially, the hmNPCs were isolated and expanded before
performing a 2D differentiation which was used to produce a single-cell suspension. This single-cell
suspension helped achieve a homogenous 3D structure of uniform aggregate size. The 3D aggregation
formed neurospheres which was used to form an in vitro 3D CNS model.[24]
Neural stem cells and bioactive scaffolds as traumatic brain injury treatment
Traumatic Brain Injury (TBI) can deform the brain tissue, leading to necrosis primary damage which can
then cascade and activate secondary damage such as excitotoxicity, inflammation, ischemia, and the
breakdown of the blood-brain-barrier. Damage can escalate and eventually lead to apoptosis or cell death.
Current treatments focus on preventing further damage by stabilizing bleeding, decreasing intracranial
pressure and inflammation, and inhibiting pro-apoptoic cascades. In order to repair TBI damage, an
upcoming therapeutic option involves the use of NSCs derived from the embryonic
periventricular[disambiguation needed] region. Stem cells can be cultured in a favorable 3-dimensional, low
cytotoxic environment, a hydrogel, that will increase NSC survival when injected into TBI patients. The
intracerebrally injected, primed NSCs were seen to migrate to damaged tissue and differentiate into
oligodendrocytes or neuronal cells that secreted neuroprotective factors.[25][26]
Galectin-1 in neural stem cells
Galectin-1 is expressed in adult NSCs and has been shown to have a physiological role in the treatment of
neurological disorders in animal models. There are two approaches to using NSCs as a therapeutic
treatment: (1) stimulate intrinsic NSCs to promote proliferation in order to replace injured tissue, and (2)
transplant NSCs into the damaged brain area in order to allow the NSCs to restore the tissue. Lentivirus
vectors were used to infect human NSCs (hNSCs) with Galectin-1 which were later transplanted into the
damaged tissue. The hGal-1-hNSCs induced better and faster brain recovery of the injured tissue as well
as a reduction in motor and sensory deficits as compared to only hNSC transplantation. [9]

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Assays
Neural stem cells are routinely studied in vitro using a method referred to as the Neurosphere Assay (or
Neurosphere culture system), first developed by Reynolds and Weiss. [4] Neurospheres are intrinsically
heterogeneous cellular entities almost entirely formed by a small fraction (1 to 5%) of slowly dividing
neural stem cells and by their progeny, a population of fast-dividing nestin-positive progenitor cells.[4][27]
[28]
The total number of these progenitors determines the size of a neurosphere and, as a result, disparities
in sphere size within different neurosphere populations may reflect alterations in the proliferation,
survival and/or differentiation status of their neural progenitors. Indeed, it has been reported that loss of
β1-integrin in a neurosphere culture does not significantly affect the capacity of β1-integrin deficient stem
cells to form new neurospheres, but it influences the size of the neurosphere: β1-integrin deficient
neurospheres were overall smaller due to increased cell death and reduced proliferation. [29]
While the Neurosphere Assay has been the method of choice for isolation, expansion and even the
enumeration of neural stem and progenitor cells, several recent publications have highlighted some of the
limitations of the neurosphere culture system as a method for determining neural stem cell frequencies. [30]
In collaboration with Reynolds, STEMCELL Technologies has developed a collagen-based assay, called
the Neural Colony-Forming Cell (NCFC) Assay, for the quantification of neural stem cells. Importantly,
this assay allows discrimination between neural stem and progenitor cells.[31]
Neural Stem Cell Institute
The damaged CNS tissue has very limited regenerative and repair capacity so that loss of neurological
function is often chronic and progressive. Cell replacement from stem cells is being actively pursued as a

17
 therapeutic option. In 2009, a research institute dedicated solely to translating neural stem research into
therapies for patients was created outside of Albany, New York, The Neural Stem Cell Institute.
A single stem cell capable of extended self-renewal (indicated by the arrow that loops around
the top of the cell), gives rise to progenitor cells that then generate neuroblasts (neuronal precursors)
or glioblasts (glia precursors). These precursors give rise to different types of neurons and glia. Factors
that influence cells at particular stage of differentiation as well as epigenetic and genetic means of
propagation (Snyder's study) have been indicated.
Effects of cannabinoids
Some studies have shown that the stimulation of the cannabinoids results in the growth of new
nerve cells in the hippocampus from both embryonic and adult stem cells. In 2005 a clinical study of
rats at the University of Saskatchewan showed regeneration of nerve cells in the hippocampus. [81]
Studies have shown that a synthetic drug resembling THC, the main psychoactive ingredient in
marijuana, provides some protection against brain inflammation, which might result in better memory
at an older age. This is due to receptors in the system that can also influence the production of new
neurons.[82] Nonetheless, a study directed at Rutgers University demonstrated how synchronization of
action potentials in the hippocampus of rats was altered after THC administration. Lack of
synchronization corresponded with impaired performance in a standard test of memory. [83] Recent
studies indicate that a natural cannabinoid of cannabis, cannabidiol (CBD), increases adult
neurogenesis while having no effect on learning. THC however impaired learning and had no effect on
neurogenesis.[84] A greater CBD to THC ratio in hair analyses of cannabis users correlates with
protection against gray matter reduction in the right hippocampus. [85] CBD has also been observed to
attenuate the deficits in prose recall and visuo-spatial associative memory of those currently under the
influence of cannabis,[86][87] implying neuroprotective effects against heavy THC exposure.
Neurogenesis might play a role in its neuroprotective effects, but further research is required.
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 Rolls, E.T & Treves, A. (1998). Neural Networks and Brain Function. Oxford: OUP. ISBN 0-
19-852432-3.
 Santarelli L, Saxe M, Gross C, et al. (August 2003). "Requirement of hippocampal
neurogenesis for the behavioral effects of antidepressants". Science 301 (5634): 805–9.
Bibcode:2003Sci...301..805S. doi:10.1126/science.1083328. PMID 12907793.
 Schloesser RJ, Manji HK, Martinowich K (April 2009). "Suppression of adult neurogenesis
leads to an increased hypothalamo-pituitary-adrenal axis response.". NeuroReport 20 (6):
553–7. doi:10.1097/WNR.0b013e3283293e59. PMC 2693911. PMID 19322118.
 Shankle, WR, Rafii, MS, Landing, BH, and Fallon, JH (1999) Approximate doubling of the
numbers of neurons in the postnatal human cortex and in 35 specific cytoarchitectonic areas
from birth to 72 months. Pediatric and Developmental Pathology 2:244-259.
23
  Zhao M, Momma S, Delfani K, et al. (June 2003). "Evidence for neurogenesis in the adult
mammalian substantia nigra". Proc. Natl. Acad. Sci. U.S.A. 100 (13): 7925–30.
Bibcode:2003PNAS..100.7925Z. doi:10.1073/pnas.1131955100. PMC 164689.
PMID 12792021.
 Dedicated issue of Philosophical Transactions B on Stem Cells and Brain Repair. Some
articles are freely available.
External links
 Concise introduction to neurogenesis from Wellesley College
 Comprehensive website on neurogenesis from Lafayette College
 Early literature on adult neurogenesis
 Neurogenesis in adult brain - Fred H. Gage and Henriette van Praag
 "Neurogenesis and Parkinson´s disease"
 Scholarpedia Article on Adult Neurogenesis
 "TRENDS in Neurosciences, 10 October 2001 (Michael S. Kaplan MD, PhD)
 New York Times: Studies Find Brains Grow New Cells
 Michael Specter: Rethinking the Brain - How the songs of canaries upset a fundamental
principle of science
 The Neurogenesis Experiment - Article series on adult human neurogenesis
 Seed magazine: The Reinvention of the Self - A historical background on the field of
neurogenesis and implications of this research
 BBC Radio 4: The Memory Experience - Use it or Lose it
 PBS: Changing Your Mind - Grow Your Own Brain
 Lobes of Steel: Aerobic exercise appears to promote neurogenesis , New York Times, 19
August 2007.

NEUROBIOLOGICAL EFFECTS
OF PHYSICAL EXERCISE

The neurobiological effects of physical exercise are numerous and involve a wide range of
interrelated neuropsychological changes. A large body of research in humans has demonstrated that
consistent aerobic exercise (e.g., 30 minutes every day) induces persistent beneficial behavioral and
neural plasticity as well as healthy alterations in gene expression in the brain; some of these long-term
effects include: increased neuron growth, increased neurological activity (c-Fos and BDNF signaling),
improved stress coping, enhanced cognitive control over behavior, improved declarative and working
memory, and structural and functional improvements in brain structures and pathways associated with
cognitive control and memory. The effects of exercise on cognition have important implications for
improving academic performance in children and college students, improving adult productivity,
preserving cognitive function in old age, preventing or treating certain neurological disorders, and
improving overall quality of life.
People who regularly participate in aerobic exercise have greater scores on neuropsychological
function and performance tests. Examples of aerobic exercise that produce these changes are running,
jogging, brisk walking, swimming, and cycling. Exercise intensity and duration are positively
correlated with the release of neurotrophic factors and the magnitude of nearly all forms of exercise-
induced behavioral and neural plasticity; consequently, more pronounced improvements in measures
of neuropsychological performance are observed in endurance athletes as compared with recreational
athletes or sedentary individuals. Aerobic exercise is also a potent long-term antidepressant and a
short-term euphoriant; consequently, consistent exercise has also been shown to produce general
improvements in mood and self-esteem in all individuals.
Long-term effects
24
Neuroplasticity and neurogenesis
Neuroplasticity is essentially the ability of neurons in the brain to adapt over time, and most often
occurs in response to repeated exposure to stimuli; [1] whereas neurogenesis is the postnatal (after-birth)
growth of new neurons, a beneficial form of neuroplasticity. [1] Aerobic exercise promotes neurogenesis
by increasing the production of neurotrophic factors (compounds which promote the growth or
survival of neurons), such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1
(IGF-1), and vascular endothelial growth factor (VEGF).[2][3][4] Consistent aerobic exercise over a
period of several months induces marked clinically significant improvements in executive function
(i.e., the "cognitive control" of behavior) and increased gray matter volume in multiple brain regions,
particularly those which give rise to cognitive control. [4][5][6][7] The brain structures that show the
greatest improvements in gray matter volume in response to aerobic exercise are the prefrontal cortex
and hippocampus;[4][5][8] moderate improvements seen in the anterior cingulate cortex, parietal cortex,
cerebellum, caudate nucleus, and nucleus accumbens.[4][5][8] The prefrontal cortex, caudate nucleus, and
anterior cingulate cortex are among the most significant brain structures in the dopamine and
norepinephrine systems that give rise to cognitive control. [5][9] Exercise-induced neurogenesis (i.e., the
increases in gray matter volume) in the hippocampus is associated with measurable improvements in
spatial memory.[5][8][10][11] Higher physical fitness scores (measured by VO2 max) are associated with
better executive function, faster processing speed, and greater volume of the hippocampus, caudate
nucleus, and nucleus accumbens. [5] Long-term aerobic exercise is also associated with persistent
beneficial epigenetic changes that result in improved stress coping, improved cognitive function, and
increased neuronal activity (c-Fos and BDNF signaling).[12][13]
BDNF signaling
See also: Brain-derived neurotrophic factor
One of the most significant effects of exercise on the brain is the increased synthesis and expression of
BDNF, a neuropeptide hormone, in the brain and periphery, resulting in increased signaling through
its tyrosine kinase receptor, tropomyosin receptor kinase B (TrkB).[12][14][15] Since BDNF is capable of
crossing the blood–brain barrier, higher peripheral BDNF synthesis also increases BDNF signaling in
the brain.[2] Exercise-induced increases in brain BDNF signaling are associated with beneficial
epigenetic changes, improved cognitive function, improved mood, and improved memory. [3][8][12][14]
Furthermore, research has provided a great deal of support for the role of BDNF in hippocampal
neurogenesis, synaptic plasticity, and neural repair. [4][14] Engaging in moderate-high intensity aerobic
exercise such as running, swimming and cycling, increases BDNF biosynthesis through myokine
signaling, resulting in up to a threefold increase in blood plasma and brain BDNF levels;[12][14][15]
exercise intensity affects the magnitude of increased BDNF synthesis and expression. [12][14][15] A meta-
analysis of studies involving the effect of exercise on BDNF levels found that consistent exercise
modestly increases resting BDNF levels as well. [3]
Antidepressant effect
A number of medical reviews have indicated that exercise has a marked and persistent antidepressant
effect in humans,[4][16][17][18][19][20] an effect believed to be mediated through enhanced BDNF signaling in
the brain.[8][17] Several systematic reviews have analyzed the potential for physical exercise in the
treatment of depressive disorders. The 2013 Cochrane Collaboration review on physical exercise for
depression noted that, based upon limited evidence, it is more effective than a control intervention and
comparable to psychological or antidepressant drug therapies. [16] Three subsequent 2014 systematic
reviews that included the Cochrane review in their analysis concluded with similar findings: one
indicated that that physical exercise is effective as an adjunct treatment (i.e., treatments that are used
together) with antidepressant medication; [17] the other two indicated that physical exercise has marked
antidepressant effects and recommended the inclusion of physical activity as an adjunct treatment for
mild–moderate depression[18] and mental illness in general. [19] One review asserted that evidence from
clinical trials supports the efficacy of physical exercise as a treatment for depression over 2–4 months.
[4]

IGF-1 signaling
See also: Insulin-like growth factor 1
IGF-1 is a peptide that mediates some of the effects of growth hormone and acts through the IGF-1
receptor to control body growth and tissue remodeling. [21] In the brain, IGF-1 functions as a
neurotrophic factor that, like BDNF, plays a significant role in cognition, neurogenesis, and neuronal
25
survival.[14][22][23] Physical activity is associated with increased levels of serum IGF-1, which is known
to contribute to neuroplasticity along with locally produced IGF-1 in the brain due to its capacity to
cross the blood–brain barrier in the capillary bed and blood–cerebrospinal fluid barrier;[4][14][21][22]
consequently one review noted that IGF-1 is a key mediator of exercise-induced adult neurogenesis,
while a second review characterized it as a factor which links "body fitness" with "brain fitness". [21][22]
The amount of IGF-1 released during exercise is positively correlated with exercise intensity and
duration.[24]
VEGF signaling
See also: Vascular endothelial growth factor
VEGF is a neurotrophic and angiogenic (i.e., blood vessel growth promoting) signaling protein that
binds to two receptor tyrosine kinases, VEGFR1 and VEGFR2, which are expressed in neurons and
glial cells the brain.[23] Hypoxia, or inadequate cellular oxygen supply, strongly upregulates VEGF
expression and VEGF exerts a neuroprotective effect in hypoxic neurons. [23] Like BDNF and IGF-1,
aerobic exercise has been shown to increase VEGF biosynthesis in peripheral tissue which
subsequently crosses the blood–brain barrier and promotes neurogenesis and blood vessel formation
the central nervous system.[2][25][26] Exercise-induced increases in VEGF signaling have been shown to
improve cerebral blood volume and contribute to exercise-induced neurogenesis in the hippocampus. [4]
[25][26]

ΔFosB and addiction

Part of this section is transcluded from FOSB. (edit | history)
Similar to other natural rewards and addictive drugs, consistent aerobic exercise increases gene
expression of the gene transcription factor that causes and maintains addiction, ΔFosB, in the nucleus
accumbens;[27][28] however, exercise also increases c-Fos expression as well, thereby opposing the long-
term accumulation of ΔFosB.[12][29][30] Clinical and preclinical evidence indicate that consistent aerobic
exercise, especially endurance exercise (e.g., marathon running), actually prevents the development of
certain drug addictions and is an effective adjunct treatment for drug addiction, and for
psychostimulant addiction in particular. [28][31][32] Consistent aerobic exercise magnitude-dependently
(i.e., by duration and intensity) reduces drug addiction risk, which appears to occur through the
reversal of drug induced addiction-related neuroplasticity. [28][31] In particular, aerobic exercise
decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-
seeking, and induces opposite effects on striatal dopamine receptor D2 (DRD2) signaling (increased
DRD2 density) to those induced by pathological stimulant use (decreased DRD2 density). [28][31]
Consequently, consistent aerobic exercise leads to better treatment outcomes when used as an adjunct
treatment for addiction.[31][32]
SUMMARY OF ADDICTION-RELATED PLASTICITY
Type of reinforcer
Form of neural
Physical
or behavioral Psycho- High fat or Sexual Environmental Sources
Opiates exercise
plasticity stimulants sugar food reward enrichment
(aerobic)
ΔFosB expression
in
[28]
nucleus ↑ ↑ ↑ ↑ ↑ ↑
accumbens D1-
type MSNs
Behavioral plasticity
Escalation of [28]
Yes Yes Yes
intake
Psychostimulant Not [28]
Yes Yes Yes Attenuated Attenuated
cross-sensitization applicable
Psychostimulant [28]
↑ ↑ ↓ ↓ ↓
self-administration

26
Psychostimulant
[28]
conditioned place ↑ ↑ ↓ ↑ ↓ ↑
preference
Reinstatement of
[28]
drug-seeking ↑ ↑ ↓ ↓
behavior
Neurochemical plasticity
CREB
phosphorylation [28]
↓ ↓ ↓ ↓ ↓
in the nucleus
accumbens
Sensitized
dopamine
[28]
response No Yes No Yes
in the nucleus
accumbens
Altered striatal ↑DRD1, ↑DRD1,
↓DRD2, [28]
dopamine ↓DRD2, ↓DRD2, ↑DRD2 ↑DRD2
↑DRD3
signaling ↑DRD3 ↑DRD3
↑μ-opioid
↑μ-
Altered striatal ↑μ-opioid receptors ↑μ-opioid [28]
opioid No change No change
opioid signaling receptors ↑κ-opioid receptors
receptors
receptors
Changes in striatal [28]
↑dynorphin ↑dynorphin ↓enkephalin ↑dynorphin ↑dynorphin
opioid peptides
Mesocorticolimbic synaptic plasticity
Number of
dendrites in the [28]
↓ ↑ ↑
nucleus
accumbens
Dendritic spine
density in [28]
↓ ↑ ↑
the nucleus
accumbens

Structural growth

Reviews of neuroimaging studies indicate that consistent aerobic exercise increases gray matter
volume in several brain regions associated with memory, cognitive control, motor function, and
reward processing;[4][5][8] the most prominent gains are seen in the prefrontal cortex and hippocampus,
which are primarily associated with cognitive control and memory processing respectively. [5][7][8]
Moreover, the left and right halves of the prefrontal cortex, which is divided by the medial
longitudinal fissure, appear to become more interconnected in response to consistent aerobic exercise.
[6]
Two reviews indicate that marked improvements in prefrontal and hippocampal gray matter volume
occur in healthy adults that engage in medium intensity exercise for several months. [5][33] Other regions
of the brain that demonstrate moderate or less significant gains in gray matter volume during
neuroimaging include the anterior cingulate cortex, parietal cortex, cerebellum, caudate nucleus, and
nucleus accumbens.[4][5][8][34]

Regular exercise has been shown to counter the shrinking of the hippocampus and memory
impairment that naturally occurs in late adulthood. [4][5][8] Sedentary adults over age 55 show a 1–
2% decline in hippocampal volume annually. [8][35] A neuroimaging study with a sample of 120 adults
revealed that participating in regular aerobic exercise increased the volume of the left hippocampus by
27
2.12% and the right hippocampus by 1.97% over a one-year period. [8][35] Subjects in the low intensity
stretching group who had higher fitness levels at baseline showed less hippocampal volume loss,
providing evidence for exercise being protective against age-related cognitive decline. [35] In general,
individuals that exercise more over a given period have greater hippocampal volumes and better
memory function.[4][8] Aerobic exercise has also been shown to induce growth in the white matter tracts
in the anterior corpus callosum, which normally shrink with age.[4][33]

The various functions of the brain structures that show exercise-induced increases in gray matter
volume include:

 Prefrontal and anterior cingulate cortices – required for the cognitive control of behavior,
particularly: working memory, attentional control, decision-making, cognitive flexibility,
social cognition, and inhibitory control of behavior;[36][37] implicated in attention deficit
hyperactivity disorder (ADHD) and addiction[36]
 Nucleus accumbens – responsible for reward perception, motivation, and positive
reinforcement; implicated in addiction[38]

 Hippocampus – responsible for storage and consolidation of declarative memory and spatial
memory;[5][39] implicated in depression[8]

 Cerebellum – responsible for motor coordination and motor learning[40]

 Caudate nucleus – responsible for stimulus-response learning and inhibitory control;

implicated in Parkinson's disease, Huntington's disease and ADHD[36][39]

 Parietal cortex – responsible for sensory perception, working memory, and attention[36][41]

Cognitive control and memory

See also: Executive functions

Concordant with the functional roles of the brain structures that exhibit increased gray matter volumes,
exercise has been shown to improve numerous aspects of cognitive control and memory function. [4][6][7]
[42][43]
In particular, consistent aerobic exercise has been shown to improve attentional control,[note 1]
attention span, information processing speed, cognitive flexibility (e.g., task switching), inhibitory
control,[note 2] working memory updating and capacity,[note 3] declarative memory,[note 4] and spatial
memory.[4][5][6][7][42][43] Individuals who have a sedentary lifestyle tend to have impaired cognitive
control relative to other more physically active non-exercisers. [7][42] A reciprocal relationship between
exercise and cognitive control has also been noted: improvements in control processes, such as
attentional control and inhibitory control, increase an individual's tendency to exercise. [7] A systematic
review of studies conducted on children suggests that some of the exercise-induced improvements in
executive function are apparent after single bouts of exercise, while other aspects (e.g., attentional
control) only improve following consistent exercise on a regular basis. [43]

ADHD is a developmental neuropsychiatric disorder in which there are deficits in certain aspects of
cognitive control, particularly attentional control and inhibitory control. [36] Regular physical exercise,
particularly aerobic exercise, is an effective adjunct treatment for ADHD, although the best type and
intensity is not currently known. [45][46] In non-randomized trials, physical exercise has been shown to
result in better behavior and motor abilities without causing any side effects in ADHD populations. [45]
[46]

Short-term effects

28
 Diagram of the hypothalamic–pituitary–adrenal axis

Psychological stress and cortisol

The "stress hormone", cortisol, is a glucocorticoid that binds to glucocorticoid receptors.[47][48][49]
Psychological stress induces the release of cortisol from the adrenal gland by activating the
hypothalamic–pituitary–adrenal axis (HPA axis).[47][48][49] Short-term increases in cortisol levels are
associated with adaptive cognitive improvements, such as enhanced inhibitory control; [25][48][49]
however, excessively high exposure or prolonged exposure to high levels of cortisol causes
impairments in cognitive control and has neurotoxic effects in the human brain. [25][42][49] For example,
chronic psychological stress decreases BDNF expression which has detrimental effects on
hippocampal volume and can lead to depression.[25][47]
As a physical stressor, aerobic exercise stimulates cortisol secretion in an intensity-dependent manner;
[48]
however, it does not result in long-term increases in cortisol production since this exercise-induced
effect on cortisol is a response to transient negative energy balance.[note 5][48] Individuals who have
recently exercised exhibit improvements in stress coping behaviors. [12][13][25] Aerobic exercise increases
physical fitness and lowers neuroendocrine (i.e., HPA axis) reactivity and therefore reduces the
biological response to psychological stress in humans (e.g., reduced cortisol release and attenuated
heart rate response).[25][50] Exercise also reverses stress-induced decreases in BDNF expression and
signaling in the brain, thereby acting as a buffer against stress-related diseases like depression. [25][47][50]
Euphoria
Continuous exercise can produce short-term euphoria, an affective state associated with feelings of
profound contentment, elation, and well-being, which is colloquially known as a "runner's high" in
distance running or a "rower's high" in crew.[51][52] Current medical reviews indicate that several
endogenous euphoriants are responsible for producing exercise-related euphoria, specifically
phenethylamine (a stimulant), β-endorphin (an opioid), and anandamide (a cannabinoid).[53][54][55][56][57]
Neurotransmitters, neuromodulators, and neuropeptides
β-Phenylethylamine
See also: Phenethylamine § Pharmacology
β-Phenylethylamine, commonly referred to as phenethylamine, is a potent endogenous trace amine
neuromodulator which has the same biomolecular targets as amphetamine;[58][59] consequently, both
compounds interact with monoamine neurons in the central nervous system in an identical manner.
Thirty minutes of moderate to high intensity physical exercise has been shown to induce an enormous
increase in urinary β-phenylacetic acid, the primary metabolite of phenethylamine. [53][54][55] Two
reviews noted a study where the mean 24 hour urinary β-phenylacetic acid concentration following
just 30 minutes of intense exercise rose 77% above its base level; [53][54][55] the reviews suggest that
phenethylamine synthesis sharply increases during physical exercise during which it is rapidly
metabolized due to its short half-life of roughly 30 seconds.[53][54][55][60] In a resting state,

29
phenethylamine is synthesized in catecholamine neurons from L-phenylalanine by aromatic amino
acid decarboxylase at approximately the same rate at which dopamine is produced. [60]
In light of this observation, the original paper and both reviews suggest that phenethylamine plays a
prominent role in mediating the mood-enhancing euphoric effects of a runner's high, as both
phenethylamine and amphetamine are potent euphoriants.[53][54][55]
β-Endorphin
β-Endorphins (contracted from "endogenous morphine") are endogenous opioid neuropeptides that
bind to μ-opioid receptors, in turn producing euphoria and pain relief.[56] A meta-analytic review found
that exercise significantly increases the secretion of β-endorphins and that this secretion is correlated
with improved mood states.[56] Moderate intensity exercise produces the greatest increase in β-
endorphin synthesis, while higher and lower intensity forms of exercise are associated with smaller
increases in β-endorphin synthesis.[56]
A review on β-endorphins and exercise noted that an individual's mood improves for the remainder of
the day following physical exercise and that one's mood is positively correlated with overall daily
physical activity level.[56] Exercise-induced improvements in mood occur in sedentary individuals,
recreational exercisers, and marathoner runners, but recreational athletes and marathon runners
experience more pronounced mood-lifting effects from exercising. [56]
Anandamide
Anandamide is an endogenous cannabinoid neurotransmitter that binds to cannabinoid receptors.[57] It
has been shown that aerobic exercise causes an increase in plasma anandamide levels, where the
magnitude of this increase is highest at moderate exercise intensity (i.e., exercising at ~70–
80% maximum heart rate).[57] Increases in plasma anandamide levels are associated with psychoactive
effects because anandamide is able to cross the blood–brain barrier and act within the central nervous
system.[57] Thus, because anandamide is a euphoriant and aerobic exercise is associated with euphoric
effects, it has been proposed that anandamide partly mediates the short-term mood-lifting effects of
exercise (e.g., the euphoria of a runner's high) via exercise-induced increases in its synthesis. [51][57]
Classical monoamines

Glutamate
Glutamate, one of the most common neurochemicals in the brain, is an excitatory neurotransmitter
involved in many aspects of brain function, including learning and memory. [61] Glutamate regulates
certain exercise-related memory processes primarily via cotransmission with dopamine in the
dopaminergic projections from the ventral tegmental area;[62][63] in particular, exercise has been shown
to modulate (normalize) glutamatergic cotransmission in the mesocorticolimbic dopamine pathway.[31]
Children

Education and learning implications

Physical activity has contributed to reducing childhood obesity and the incidences of cardiovascular
disease, colon & breast cancer, and depression & anxiety across the adult lifespan. [64] The connection
between physical activity and cognitive performance has been investigated in a number of studies,
many of which observed a positive correlation between the two. Sibley and Etnier (2003) performed a
meta-analysis that looked at the relationship in children. They reported a beneficial relationship in the
categories of perceptual skills, intelligence quotient, achievement, verbal tests, mathematic tests,
developmental level/academic readiness and other, with the exception of memory, that was found to
be unrelated to physical activity.[65] The correlation was strongest for the age ranges of 4–7 and 11–13
years.[65] On the other hand, Chaddock and colleagues (2011) found results that contrasted Sibley and
Etnier's meta-analysis. In their study, the hypothesis was that lower-fit children would perform poorly
in executive control of memory and have smaller hippocampal volumes compared to higher-fit
children.[66] Instead of physical activity being unrelated to memory in children between 4 and 18 years
of age, it may be that preadolescents of higher fitness have larger hippocampal volumes, than
preadolescents of lower fitness. According to a previous study done by Chaddock and colleagues
(Chaddock et al. 2010), a larger hippocampal volume would result in better executive control of
memory.[67] They concluded that hippocampal volume was positively associated with performance on
relational memory tasks.[67] Their findings are the first to indicate that aerobic fitness may relate to the

30
structure and function of the preadolescent human brain. [67] In Best’s (2010) meta-analysis of the effect
of activity on children’s executive function, there are two distinct experimental designs used to assess
aerobic exercise on cognition. The first is chronic exercise, in which children are randomly assigned to
a schedule of aerobic exercise over several weeks and later assessed at the end. [68] The second is acute
exercise, which examines the immediate changes in cognitive functioning after each session. [68] The
results of both suggest that aerobic exercise may briefly aid children’s executive function and also
influence more lasting improvements to executive function. [68] Other studies have suggested that
exercise is unrelated to academic performance, perhaps due to the parameters used to determine
exactly what academic achievement is. [64] This area of study has been a focus for education boards that
make decisions on whether physical education should be implemented in the school curriculum, how
much time should be dedicated to physical education, and its impact on other academic subjects. [65]
Animal studies have also shown that exercise can impact brain development early on in life. Mice that
had access to running wheels and other such exercise equipment had better neuronal growth in the
neural systems involved in learning and memory. [64] Neuroimaging of the human brain has yielded
similar results, where exercise leads to changes in brain structure and function. [64] Some investigations
have linked low levels of aerobic fitness in children with impaired executive function in older adults,
but there is mounting evidence it may also be associated with a lack of selective attention, response
inhibition, and interference control.[66]
Elderly and neurodegenerative disorders

Signs of cognitive decline become more evident with age. Cross-sectional studies have shown a
positive link between exercise and general cognitive function in older individuals. [69] Fitness is
associated with better cognitive performance in individuals with cardiovascular disease, [70] which is
associated with an increased rate of cognitive decline during aging. The protective effects of fitness
may be relevant to the prevention of cognitive decline due to neurodegenerative disorders.
Summarized below are the effects that physical activity is thought to have on three neurodegenerative
conditions that usually manifest in mid-to-late adulthood causing cognitive symptoms (Alzheimer's
disease, Huntington's disease and Parkinson's disease).
Alzheimer's disease
Alzheimer's Disease is a cortical neurodegenerative disorder and the most prevalent form of dementia,
representing approximately 65% of all cases of dementia; it is characterized by impaired cognitive
function, behavioral abnormalities, and a reduced capacity to perform basic activities of daily life.[71][72]
Two meta-analytic systematic reviews of randomized controlled trials with durations of 3–12 months
have examined the effects of physical exercise on the aforementioned characteristics of Alzheimer's
disease.[71][72] The reviews found beneficial effects of physical exercise on cognitive function, the rate
of cognitive decline, and the ability to perform activities of daily living in individuals with Alzheimer's
disease.[71][72] One review suggested that, based upon transgenic mouse models, the cognitive effects of
exercise on Alzheimer's disease may result from a reduction in the quantity of amyloid plaque.[71][73]
The Caerphilly Prospective study followed 2,375 male subjects over 30 years and examined the
association between healthy lifestyles and dementia, among other factors. [74] Analyses of the
Caerphilly study data have found that exercise is associated with a lower incidence of dementia and a
reduction in cognitive impairment.[74][75] A subsequent systematic review of longitudinal studies also
found higher levels of physical activity to be associated with a reduction in the risk of dementia and
cognitive decline;[76] this review further asserted that increased physical activity appears to be causally
related with these reduced risks.[76]
Huntington's disease
Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder leading to a decline
in motor skills, chorea, subcortical dementia, and other psychiatric symptoms. [77]
Physical therapy can be sought to help improve the motor impairments of the disease. The conclusions
about the effects of exercise on cognitive function in HD patients have varied across the literature.
Pang and colleagues (2006) studied R6/1 transgenic mice models of HD, with results that showed
exercise delayed the onset of symptoms and slowed cognitive decline. [77] On the other hand, another
study by Kohl and colleagues (2007) used the R6/2 transgenic mouse model of HDstrain to see if
physical activity could stimulate hippocampal neurogenesis from neural stem cells.[78] Their study

31
found that physical exercise did stimulate cell proliferation and survival in normal healthy mice, but
did not enhance hippocampal neurogenesis in the transgenic mice. [78] They speculated that this result
may be due to an effect the mutated Huntingtin gene, and by extension the mutated Huntingtin protein,
has on the mechanisms needed for successful hippocampal neurogenesis in HD patients. [78]
Parkinson's disease
Parkinson's disease (PD) is a movement disorder that produces symptoms such as bradykinesia,
rigidity, shaking, and impaired gait.[79]
A review by Kramer and colleagues (2006) found that some neurotransmitter systems are affected by
exercise in a positive way. [80] A few studies reported seeing an improvement in brain health and
cognitive function due to exercise. [80] One particular study by Kramer and colleagues (1999) found that
aerobic training improved executive control processes supported by frontal and prefrontal regions of
the brain.[81] These regions are responsible for the cognitive deficits in PD patients, however there was
speculation that the difference in the neurochemical environment in the frontal lobes of PD patients
may inhibit the benefit of aerobic exercise. [82] Nocera and colleagues (2010) performed a case study
based on this literature where they gave participants with early-to mid-staged PD, and the control
group cognitive/language assessments with exercise regimens. Individuals performed 20 minutes of
aerobic exercise three times a week for 8 weeks on a stationary exercise cycle. It was found that
aerobic exercise improved several measures of cognitive function, [82] providing evidence that such
exercise regimens may be beneficial to patients with PD.
Notes
 Attentional control allows an individual to focus their attention on a specific source and ignore other stimuli
that compete for one's attention,[9] such as in the cocktail party effect.
  Inhibitory control is the process of altering one's learned behavioral responses, sometimes called "prepotent
responses", in a way that makes it easier to complete a particular goal. [36][44] Inhibitory control allows individuals
to control their impulses and habits when necessary or desired,[36][42][44] e.g., to overcome procrastination.
  Working memory is the form of memory used by an individual at any given moment for active information
processing,[9] such as when reading or writing an encyclopedia article. Working memory has a limited capacity
and functions as an information buffer, analogous to a computer's data buffer, that permits the manipulation of
information for comprehension, decision-making, and guidance of behavior.[36]
  Declarative memory, also known as explicit memory, is the form of memory that pertains to facts and
events.[39]  In healthy individuals, this energy deficit resolves simply from eating and drinking a sufficient
amount of food and beverage after exercising.
References

 Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY, ed. Molecular Neuropharmacology: A
Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 5, 351.
ISBN 9780071481274. The clinical actions of fluoxetine, like those of many neuropharmacologic agents, reflect
drug-induced neural plasticity, which is the process by which neurons adapt over time in response to chronic
disturbance. ... For example, evidence indicates that prolonged increases in cortisol may be damaging to
hippocampal neurons and can suppress hippocampal neurogenesis (the generation of new neurons postnatally).
  Tarumi T, Zhang R (January 2014). "Cerebral hemodynamics of the aging brain: risk of Alzheimer disease
and benefit of aerobic exercise". Front Physiol 5: 6. doi:10.3389/fphys.2014.00006. PMC 3896879.
PMID 24478719. Exercise-related improvements in brain function and structure may be conferred by the
concurrent adaptations in vascular function and structure. Aerobic exercise increases the peripheral levels of
growth factors (e.g., BDNF, IFG-1, and VEGF) which cross the blood-brain barrier (BBB) and stimulate
neurogenesis and angiogenesis (Trejo et al., 2001; Lee et al., 2002; Fabel et al., 2003; Lopez-Lopez et al.,
2004).
  Szuhany KL, Bugatti M, Otto MW (October 2014). "A meta-analytic review of the effects of exercise on
brain-derived neurotrophic factor". J Psychiatr Res 60C: 56–64. doi:10.1016/j.jpsychires.2014.10.003.
PMC 4314337. PMID 25455510. Consistent evidence indicates that exercise improves cognition and mood,
with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects.
The aim of the current meta-analysis was to provide an estimate of the strength of the association between
exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-
analysis of 29 studies (N = 1111 participants) examining the effect of exercise on BDNF levels in three exercise
paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise,
and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also
examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of
32
exercise (Hedges' g = 0.46, p < 0.001). Further, regular exercise intensified the effect of a session of exercise on
BDNF levels (Hedges' g = 0.59, p = 0.02). Finally, results indicated a small effect of regular exercise on resting
BDNF levels (Hedges' g = 0.27, p = 0.005). ... Effect size analysis supports the role of exercise as a strategy for
enhancing BDNF activity in humans
  Gomez-Pinilla F, Hillman C (January 2013). "The influence of exercise on cognitive abilities". Compr
Physiol 3 (1): 403–428. doi:10.1002/cphy.c110063. PMC 3951958. PMID 23720292. A second recent meta-
analysis (162) corroborated Colcombe and Kramer’s (30) findings, in that aerobic exercise was related to
attention, processing speed, memory, and cognitive control. ... Normal aging results in the loss of brain tissue
(31), with markedly larger tissue loss evidenced in the frontal, temporal, and parietal cortices (16, 58, 149). As
such, cognitive functions subserved by these brain regions (such as those involved in cognitive control and
memory) are expected to decay more dramatically than other aspects of cognition. Specifically, age-related
decreases in gray matter volume have been associated with decrements in a variety of cognitive control
processes. ... Decreases in gray matter volume may result from several factors including loss in the number of
neurons, neuronal shrinkage, reduction in dendritic arborization, and alterations in glia (158). Further,
decreases in white matter (brain tissue composed primarily of myelinated nerve fibers) volume, which represent
changes in connectivity between neurons, also occur as a result of aging. Loss of white matter volume further
relates to performance decrements on a host of cognitive tasks ... aerobic fitness relates to larger hippocampal
volume (23) and better relational memory performance (24), during preadolescent childhood. ... Specifically,
those assigned to the aerobic training group demonstrated increases in gray matter in the frontal lobes,
including the dorsal anterior cingulate cortex (ACC), supplementary motor area, middle frontal gyrus,
dorsolateral region of the right inferior frontal gyrus, and the left superior temporal lobe (32). White matter
volume changes were also evidenced for the aerobic fitness group with increases in white matter tracts within
the anterior third of the corpus callosum (32). ... In addition, aerobic fitness has been shown to promote better
functioning of brain, especially in neural networks involved in cognitive control of inhibition and attention
(33). ... In addition to BDNF, the actions of IGF-1 and vascular endothelial growth factor (VEGF) (54) are
considered essential for the angiogenic and neurogenic effects of exercise in the brain. ... Randomized and
crossover clinical trials demonstrate the efficacy of aerobic or resistance training exercise (2–4 months) as a
treatment for depression in both young and older individuals. ... exercise seems to have both preventative and
therapeutic effects on the course of depression
  Erickson KI, Leckie RL, Weinstein AM (September 2014). "Physical activity, fitness, and gray matter
volume". Neurobiol. Aging. 35 Suppl 2: S20–528. doi:10.1016/j.neurobiolaging.2014.03.034. PMC 4094356.
PMID 24952993. Retrieved 9 December 2014. We conclude that higher cardiorespiratory fitness levels are
routinely associated with greater gray matter volume in the prefrontal cortex and hippocampus and less
consistently in other regions. We also conclude that physical activity is associated with greater gray matter
volume in the same regions that are associated with cardiorespiratory fitness including the prefrontal cortex and
hippocampus. ... Meta-analyses (Colcombe and Kramer, 2003; Smith et al., 2010) suggest that the effects of
exercise on the brain might not be uniform across all regions and that some brain areas, specifically those areas
supporting executive functions, might be more influenced by participation in exercise than areas not as critically
involved in executive functions. ... The effects appear to be general in the sense that many different cognitive
domains are improved after several months of aerobic exercise, but specific in the sense that executive functions
are improved more than other cognitive domains. ... physical activity and exercise may reduce the risk for AD
(Barnes and Yaffe, 2011; Podewils et al., 2005; Sofi et al., 2011) ... Erickson et al. (2010) reported that greater
amounts of physical activity were associated with greater gray matter volume 9-years later in the prefrontal
cortex, anterior cingulate, parietal cortex, cerebellum, and hippocampus. ... higher fitness levels (VO2max)
were associated with larger hippocampal volumes, better executive function, and faster processing speed. ...
Verstynen et al. (2012) examined the association between cardiorespiratory fitness levels (VO2max) and the size
of the basal ganglia ... Verstynen et al. (2012) found that higher fitness levels were associated with greater
volume of the caudate nucleus and nucleus accumbens, and in turn, greater volumes were associated with better
performance on a task-switching paradigm. ... That is, higher physical activity levels mitigated the detrimental
effects of lifetime stress on the size of the hippocampus. ... The few randomized interventions published thus far
have found results highly overlapping with the cross-sectional studies and suggest that the prefrontal cortex and
hippocampus remain pliable in late life and that moderate intensity exercise for 6 months–1 year is sufficient for
changing the size of these areas.
  Guiney H, Machado L (February 2013). "Benefits of regular aerobic exercise for executive functioning in
healthy populations". Psychon Bull Rev 20 (1): 73–86. doi:10.3758/s13423-012-0345-4. PMID 23229442.
Executive functions are strategic in nature and depend on higher-order cognitive processes that underpin
planning, sustained attention, selective attention, resistance to interference, volitional inhibition, working
memory, and mental flexibility ... Data to date from studies of aging provide strong evidence of exercise-linked
benefits related to task switching, selective attention, inhibition of prepotent responses, and working memory
capacity; furthermore, cross-sectional fitness data suggest that working memory updating could potentially
33
benefit as well. In young adults, working memory updating is the main executive function shown to benefit from
regular exercise, but cross-sectional data further suggest that task-switching and post-error performance may
also benefit. In children, working memory capacity has been shown to benefit, and cross-sectional data suggest
potential benefits for selective attention and inhibitory control. ... Support for the idea that higher levels of
aerobic activity may be associated with superior brain structure has been gained through cross-sectional studies
in older adults and children (for a recent review, see Voss, Nagamatsu, et al., 2011). ... only those in the aerobic
exercise group exhibited improved connectivity between the left and right prefrontal cortices, two areas that are
crucial to the effective functioning of the fronto-executive network. ... Together, these studies provide evidence
that regular aerobic exercise benefits control over responses during selective attention in older adults. ...
aerobic fitness is a good predictor of performance on tasks that rely relatively heavily on inhibitory control over
prepotent responses (e.g., Colcombe et al., 2004, Study 1; Prakash et al., 2011) and also that regular aerobic
exercise improves performance on such tasks ... Overall, the results from the span and Sternberg tasks suggest
that regular exercise can also confer benefits for the volume of information that children and older adults can
hold in mind at one time.
  Buckley J, Cohen JD, Kramer AF, McAuley E, Mullen SP (2014). "Cognitive control in the self-regulation
of physical activity and sedentary behavior". Front Hum Neurosci 8: 747. doi:10.3389/fnhum.2014.00747.
PMC 4179677. PMID 25324754. Recent theory (e.g., Temporal Self-Regulation Theory; Hall and Fong, 2007,
2010, 2013) and evidence suggest that the relation between physical activity and cognitive control is reciprocal
(Daly et al., 2013). Most research has focused on the beneficial effects of regular physical activity on executive
functions-the set of neural processes that define cognitive control. Considerable evidence shows that regular
physical activity is associated with enhanced cognitive functions, including attention, processing speed, task
switching, inhibition of prepotent responses and declarative memory (for reviews see Colcombe and Kramer,
2003; Smith et al., 2010; Guiney and Machado, 2013; McAuley et al., 2013). Recent research demonstrates a
dose-response relationship between fitness and spatial memory (Erickson et al., 2011) ... The effects of physical
activity on cognitive control appear to be underpinned by a variety of brain processes including: increased
hippocampal volume, increased gray matter density in the prefrontal cortex (PFC), upregulation of
neurotrophins and greater microvascular density ... Together, this research suggests that an improvement in
control processes, such as attention and inhibition or interference control, is associated with an improvement in
self-regulation of physical activity. ... Hoang et al. (2013) found that young adults who initially exhibited low
levels of physical activity and remained relatively inactive for 25 years had nearly twofold greater odds of
impaired executive function compared with those who exhibited higher activity levels; very-low physical activity
patterns were associated with even more pronounced declines in executive functioning. … sedentary behavior
indirectly led to poor executive function through depressive symptoms (Vance et al., 2005). … sedentary
individuals display less capacity to quickly and accurately switch between tasks.
  Erickson KI, Miller DL, Roecklein KA (2012). "The aging hippocampus: interactions between exercise,
depression, and BDNF". Neuroscientist 18 (1): 82–97. doi:10.1177/1073858410397054. PMC 3575139.
PMID 21531985. Late adulthood is associated with increased hippocampal atrophy and dysfunction.  ...
However, there is strong evidence that decreased BDNF is associated with age-related hippocampal
dysfunction, memory impairment, and increased risk for depression, whereas increasing BDNF by aerobic
exercise appears to ameliorate hippocampal atrophy, improve memory function, and reduce depression. ... For
example, longitudinal studies have reported between 1% and 2% annual hippocampal atrophy in adults older
than 55 years without dementia ... Over a nine-year period, greater amounts of physical activity in the form of
walking are associated with greater gray matter volume in several regions including prefrontal, temporal, and
hippocampal areas. ... The prefrontal cortex and hippocampus deteriorate in late adulthood, preceding and
leading to deficits in executive and memory function. We examined in this review the evidence that age-related
changes in BDNF might at least partially explain hippocampal atrophy and increased risk for memory
impairment. We can conclude that 1) decreases in BDNF protein expression are associated with poorer
hippocampal function and increased rates of geriatric depression and AD. ... 3) Aerobic exercise enhances
executive and memory function and reduces hippocampal atrophy in late adulthood, and this may be partially
mediated through a BDNF pathway.
  Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines,
Acetylcholine, and Orexin". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical
Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 147–148, 154–157. ISBN 9780071481274.
Neurons from the SNc densely innervate the dorsal striatum where they play a critical role in the learning and
execution of motor programs. Neurons from the VTA innervate the ventral striatum (nucleus accumbens),
olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cingulate cortex. VTA DA
neurons play a critical role in motivation, reward-related behavior, attention, and multiple forms of memory.  ...
Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself
or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this
new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and
34
hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus
accumbens core region and dorsal striatum). ... DA has multiple actions in the prefrontal cortex. It promotes the
"cognitive control" of behavior: the selection and successful monitoring of behavior to facilitate attainment of
chosen goals. Aspects of cognitive control in which DA plays a role include working memory, the ability to hold
information "on line" in order to guide actions, suppression of prepotent behaviors that compete with goal-
directed actions, and control of attention and thus the ability to overcome distractions. ... Noradrenergic
projections from the LC thus interact with dopaminergic projections from the VTA to regulate cognitive
control. ...
  Lees C, Hopkins J (2013). "Effect of aerobic exercise on cognition, academic achievement, and
psychosocial function in children: a systematic review of randomized control trials". Prev Chronic Dis 10:
E174. doi:10.5888/pcd10.130010. PMC 3809922. PMID 24157077. This omission is relevant, given the
evidence that aerobic-based physical activity generates structural changes in the brain, such as neurogenesis,
angiogenesis, increased hippocampal volume, and connectivity (12,13). In children, a positive relationship
between aerobic fitness, hippocampal volume, and memory has been found (12,13). ... Mental health outcomes
included reduced depression and increased self-esteem, although no change was found in anxiety levels (18). ...
This systematic review of the literature found that APA is positively associated with cognition, academic
achievement, behavior, and psychosocial functioning outcomes. Importantly, Shephard also showed that
curriculum time reassigned to APA still results in a measurable, albeit small, improvement in academic
performance (24).  ... The actual aerobic-based activity does not appear to be a major factor; interventions used
many different types of APA and found similar associations. In positive association studies, intensity of the
aerobic activity was moderate to vigorous. The amount of time spent in APA varied significantly between
studies; however, even as little as 45 minutes per week appeared to have a benefit.
  Carvalho A, Rea IM, Parimon T, Cusack BJ (2014). "Physical activity and cognitive function in individuals
over 60 years of age: a systematic review". Clin Interv Aging 9: 661–682. doi:10.2147/CIA.S55520.
PMC 3990369. PMID 24748784.
  Denham J, Marques FZ, O'Brien BJ, Charchar FJ (February 2014). "Exercise: putting action into our
epigenome". Sports Med 44 (2): 189–209. doi:10.1007/s40279-013-0114-1. PMID 24163284. Aerobic physical
exercise produces numerous health benefits in the brain. Regular engagement in physical exercise enhances
cognitive functioning, increases brain neurotrophic proteins, such as brain-derived neurotrophic factor
(BDNF), and prevents cognitive diseases [76–78]. Recent findings highlight a role for aerobic exercise in
modulating chromatin remodelers [21, 79–82]. ... These results were the first to demonstrate that acute and
relatively short aerobic exercise modulates epigenetic modifications. The transient epigenetic modifications
observed due to chronic running training have also been associated with improved learning and stress-coping
strategies, epigenetic changes and increased c-Fos-positive neurons ... Nonetheless, these studies demonstrate
the existence of epigenetic changes after acute and chronic exercise and show they are associated with improved
cognitive function and elevated markers of neurotrophic factors and neuronal activity (BDNF and c-Fos).  ...
The aerobic exercise training-induced changes to miRNA profile in the brain seem to be intensity-dependent
[164]. These few studies provide a basis for further exploration into potential miRNAs involved in brain and
neuronal development and recovery via aerobic exercise.
  Ehlert T, Simon P, Moser DA (February 2013). "Epigenetics in sports". Sports Med 43 (2): 93–110.
doi:10.1007/s40279-012-0012-y. PMID 23329609. Alterations in epigenetic modification patterns have been
demonstrated to be dependent on exercise and growth hormone (GH), insulin-like growth factor 1 (IGF-1), and
steroid administration. ... the authors observed improved stress coping in exercised subjects. Investigating the
dentate gyrus, a brain region which is involved in learning and coping with stressful and traumatic events, they
could show that this effect is mediated by increased phosphorylation of serine 10 combined with H3K14
acetylation, which is associated with local opening of condensed chromatin. Consequently, they found increased
immediate early gene expression as shown for c-FOS (FBJ murine osteosarcoma viral oncogene homologue).
  Phillips C, Baktir MA, Srivatsan M, Salehi A (2014). "Neuroprotective effects of physical activity on the
brain: a closer look at trophic factor signaling". Front Cell Neurosci 8: 170. doi:10.3389/fncel.2014.00170.
PMC 4064707. PMID 24999318. Moreover, recent evidence suggests that myokines released by exercising
muscles affect the expression of brain-derived neurotrophic factor synthesis in the dentate gyrus of the
hippocampus, a finding that could lead to the identification of new and therapeutically important mediating
factors. ... Studies have demonstrated the intensity of exercise training is positively correlated with BDNF
plasma levels in young, healthy individuals (Ferris et al., 2007). Resistance exercise has also been shown to
elevate serum BDNF levels in young individuals (Yarrow et al., 2010). Moreover, it has been shown that
moderate levels of physical activity in people with AD significantly increased plasma levels of BDNF (Coelho et
al., 2014). ... In humans, it has been shown that 4 h of rowing activity leads to increased levels of plasma BDNF
from the internal jugular (an indicator of central release from the brain) and radial artery (an indicator of
peripheral release; Rasmussen et al., 2009). Seifert et al. (2010) reported that basal release of BDNF increases
following 3 months endurance training in young and healthy individuals, as measured from the jugular vein.
35
These trends are augmented by rodent studies showing that endurance training leads to increased synthesis of
BDNF in the hippocampal formation (Neeper et al., 1995, 1996). ... Both BDNF and IGF-1 play a significant
role in cognition and motor function in humans. ... Multiple large-scale studies in humans have shown that
serum levels of IGF-1 are correlated with fitness and as well as body mass indices (Poehlman and Copeland,
1990). Furthermore, animal studies have shown that exercise in rats is associated with increased amounts of
IGF-1 in the CSF.
  Heinonen I, Kalliokoski KK, Hannukainen JC, Duncker DJ, Nuutila P, Knuuti J (November 2014). "Organ-
Specific Physiological Responses to Acute Physical Exercise and Long-Term Training in Humans". Physiology
(Bethesda) 29 (6): 421–436. doi:10.1152/physiol.00067.2013. PMID 25362636. The Effects of Acute Exercise
Studies in humans and animals have shown that brain blood flow remains largely unchanged in response to
acute exercise[,] ... does not increase with increasing exercise intensity[, and] ... increased metabolic demands
of active brain parts are mostly met by redistributing oxygen supply, although changes in oxygen extraction may
also contribute. During exercise, blood flow is directed to the areas controlling locomotor, vestibular,
cardiorespiratory, and visual functions (8, 91), facilitated by direct communication of neurons and vascular
cells (94, 134). ... with increasing exercise intensity, brain glucose uptake decreases (75) as the uptake and
utilization of lactate is enhanced (65, 139, 182). Regional differences in brain glucose uptake are also evident,
which is furthermore influenced by the level of physical fitness. Thus the decrease in glucose uptake in the
dorsal part of the anterior cingulate cortex during exercise is significantly more pronounced in subjects with
higher exercise capacity (75) ...
The Effects of Long-Term Exercise Training
[A] physically active lifestyle has been shown to lead to higher cognitive performance and delayed or prevented
neurological conditions in humans (71, 101, 143, 191). ... The production of brain-derived neurotrophic factor
(BDNF), a key protein regulating maintenance and growth of neurons, is known to be stimulated by acute
exercise (145), which may contribute to learning and memory. BDNF is released from brain already at rest but
increases two- to threefold during exercise, which contributes 70–80% of circulating BDNF (145).
  Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE (2013).
"Exercise for depression". Cochrane Database Syst Rev 9: CD004366. doi:10.1002/14651858.CD004366.pub6.
PMID 24026850. Exercise is moderately more effective than a control intervention for reducing symptoms of
depression, but analysis of methodologically robust trials only shows a smaller effect in favour of exercise.
When compared to psychological or pharmacological therapies, exercise appears to be no more effective,
though this conclusion is based on a few small trials.
  Mura G, Moro MF, Patten SB, Carta MG (2014). "Exercise as an add-on strategy for the treatment of
major depressive disorder: a systematic review". CNS Spectr 19 (6): 496–508.
doi:10.1017/S1092852913000953. PMID 24589012. Considered overall, the studies included in the present
review showed a strong effectiveness of exercise combined with antidepressants. ... Conclusions
This is the first review to have focused on exercise as an add-on strategy in the treatment of MDD. Our findings
corroborate some previous observations that were based on few studies and which were difficult to
generalize.41,51,73,92,93 Given the results of the present article, it seems that exercise might be an effective strategy
to enhance the antidepressant effect of medication treatments. Moreover, we hypothesize that the main role of
exercise on treatment-resistant depression is in inducing neurogenesis by increasing BDNF expression, as was
demonstrated by several recent studies.
  Josefsson T, Lindwall M, Archer T (2014). "Physical exercise intervention in depressive disorders: meta-
analysis and systematic review". Scand J Med Sci Sports 24 (2): 259–272. doi:10.1111/sms.12050.
PMID 23362828. Physical activity has also become increasingly and firmly associated with improvements in
mental health and psychological well-being (Mutrie, 2000; Landers & Arent, 2007). In particular, exercise is
believed to be effective in preventing depression and also to significantly reduce depressive symptoms in clinical
as well as in nonclinical populations (O’Neal et al., 2000; Landers & Arent, 2007). Several correlational studies
show that exercise is negatively related to depressive symptoms (e.g., Galper et al., 2006; Hassmén et al., 2000).
Moreover, a considerably large number of intervention studies have by now investigated the effect of various
exercise programs on depression and the vast majority of them indicate that exercise significantly reduces
depression (e.g., Blumenthal et al., 2007; Martinsen et al., 1985; Singh et al., 1997). ... To date, it is not possible
to determine exactly how effective exercise is in reducing depression symptoms in clinical and nonclinical
depressed populations, respectively. However, the results from the present meta-analysis as well as from seven
earlier meta-analyses (North et al., 1990; Craft & Landers, 1998; Lawlor & Hopker, 2001; Stathopoulou et al.,
2006; Mead et al., 2009; Rethorst et al., 2009; Krogh et al., 2011) indicate that exercise has a moderate to large
antidepressant effect. Some meta-analytic results (e.g., Rethorst et al., 2009) suggest that exercise may be even
more efficacious for clinically depressed people. ... In short, our final conclusion is that exercise may well be
recommended for people with mild and moderate depression who are willing, motivated, and physically healthy
enough to engage in such a program.

36
  Rosenbaum S, Tiedemann A, Sherrington C, Curtis J, Ward PB (2014). "Physical activity interventions for
people with mental illness: a systematic review and meta-analysis". J Clin Psychiatry 75 (9): 964–974.
doi:10.4088/JCP.13r08765. PMID 24813261. This systematic review and meta-analysis found that physical
activity reduced depressive symptoms among people with a psychiatric illness. The current meta-analysis differs
from previous studies, as it included participants with depressive symptoms with a variety of psychiatric
diagnoses (except dysthymia and eating disorders). ... This review provides strong evidence for the
antidepressant effect of physical activity; however, the optimal exercise modality, volume, and intensity remain
to be determined. ... Conclusion
Few interventions exist whereby patients can hope to achieve improvements in both psychiatric symptoms and
physical health simultaneously without significant risks of adverse effects. Physical activity offers substantial
promise for improving outcomes for people living with mental illness, and the inclusion of physical activity and
exercise programs within treatment facilities is warranted given the results of this review.
  Brené S, Bjørnebekk A, Aberg E, Mathé AA, Olson L, Werme M (2007). "Running is rewarding and
antidepressive". Physiol. Behav. 92 (1–2): 136–140. doi:10.1016/j.physbeh.2007.05.015. PMC 2040025.
PMID 17561174.
  Torres-Aleman I (2010). "Toward a comprehensive neurobiology of IGF-I". Dev Neurobiol 70 (5): 384–96.
doi:10.1002/dneu.20778. PMID 20186710. However, the adult brain appears to have an external input from
serum IGF-I, where this anabolic peptide is abundant. Thus, serum IGF-I has been proven to be an important
modulator of brain activity, including higher functions such as cognition. Many of these functions can be
ascribed to its tissue-remodeling activity as IGF-I modulates adult neurogenesis and angiogenesis. Other
activities are cytoprotective; indeed, IGF-I can be considered a key neuroprotective peptide. Still others pertain
to the functional characteristics of brain cells, such as cell excitability. Through modulation of membrane
channels and neurotransmission, IGF-I impinges directly on neuronal plasticity, the cellular substrate of
cognition. However, to fully understand the role of IGF-I in the brain, we have to sum the actions of locally
produced IGF-I to those of serum IGF-I ... An operational approach to overcome this limitation would be to
consider IGF-I as a signal coupling environmental influences on body metabolism with brain function. Or in a
more colloquial way, we may say that IGF-I links body "fitness" with brain fitness
  Aberg D (2010). "Role of the growth hormone/insulin-like growth factor 1 axis in neurogenesis". Endocr
Dev 17: 63–76. doi:10.1159/000262529. PMID 19955757. The growth hormone/insulin-like growth factor 1
(GH/IGF-1) axis is not only involved in brain growth, development and myelination, but also in brain plasticity
as indexed by neurogenesis. This may have links to various cognitive effects of GH and IGF-1. GH and IGF-1
affect the genesis of neurons, astrocytes, endothelial cells and oligodendrocytes. Specifically, IGF-1 increases
progenitor cell proliferation and numbers of new neurons, oligodendrocytes, and blood vessels in the dentate
gyrus of the hippocampus. In the adult cerebral cortex IGF-1 only affects oligodendrogenesis. ... Altogether,
data suggest that both exogenous and endogenous GH and/or IGF-1 may be used as agents to enhance cell
genesis and neurogenesis in the adult brain.  ... GH and IGF-1 have been shown to affect a multitude of
mechanisms, including neurogenesis, oligodendrogenesis, angiogenesis, glutamate receptor activation,
cholinergic system, dopaminergic reward system, monoamine abundance, dendritic arborization, astrocyte
communication via connexin 43, and opioid receptor abundance ... IGF-1 also reaches the brain via both the
capillary bed BBB and via the blood-CSF barrier. It appears that IGF-1 uptake is mediated by a specific carrier
both in the capillary bed BBB [40] and in the blood-CSF barrier [41, 42]. Moreover, IGF-1 transport across the
BBB can be either increased, such as by exercise [43] ... Thus, although not fully characterized, there appear to
be mechanisms for transport of both GH and IGF-1 across the BBB. ... Interestingly, exercise is a factor known
to enhance cell genesis in the brain, and it appears that IGF-1 is a key mediator of the effect of exercise in terms
of cell genesis in the adult brain [52, 53]. ... IGF-1 treatment enhances neurogenesis [52, 53, 55],
oligodendrogenesis [56, 58] and angiogenesis [59]. ... As physical exercise has positive effects in many diseases
as well as in normal health, it is of interest that circulating IGF-1 as been shown to be one of the mediators of
enhanced neurogenesis in the hippocampus.
  Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY, ed. Molecular Neuropharmacology: A
Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 221, 412.
ISBN 9780071481274. BDNF, CNTF, insulin-like growth factor-1 (IGF-1), and VEGF have been proven to
support motor neuron survival in vitro and in vivo. ... VEGF exerts its effects through two receptor tyrosine
kinases, VEGFR1 (also known as flt-1) and VEGFR2 (or flk-1). VEGF and its receptors are expressed in
neurons and glia, and this expression is highly up-regulated by hypoxia. The neurotrophic properties of VEGF
were first identified when mutations in the VEGF promoter of mice resulted in ALS-like symptoms. Subsequently,
VEGF was found to rescue hypoxia-induced motor neuron death both in vivo and in vitro. Recently, a
polymorphism in the VEGF promoter sequence was identified in a subset of ALS patients. It is thought that low
VEGF levels may underlie motor neuron degeneration in at least one group of patients, but measurement of
VEGF in ALS patients has proven difficult. VEGF may also be important for response to stroke and other forms
of neural injury. ... One of the prototypical triggers for apoptosis, at least in vitro, is the withdrawal of
37
neurotrophic factors. Neurotrophic factor receptors, such as the TrkA receptor for NGF or the IGF-I receptor
for insulin-like growth factor, activate prosurvival signaling cascades
  Gatti R, De Palo EF, Antonelli G, Spinella P (2012). "IGF-I/IGFBP system: metabolism outline and
physical exercise". J. Endocrinol. Invest. 35 (7): 699–707. doi:10.3275/8456. PMID 22714057.
  Silverman MN, Deuster PA (October 2014). "Biological mechanisms underlying the role of physical fitness
in health and resilience". Interface Focus 4 (5): 20140040. doi:10.1098/rsfs.2014.0040. PMID 25285199.
Physical fitness, achieved through regular exercise and/or spontaneous physical activity, can protect against the
development of chronic stress- and inflammatory-related disease by optimizing physiological and
neuroendocrine stress responsivity, promoting an anti-inflammatory state, and enhancing neuroplasticity and
growth factor expression. stress responsive systems are adaptive when activated and terminated in a timely
manner, prolonged (or insufficient) activation of these systems can cause a variety of maladaptive responses. ...
For example, Rimelle et al. [123] documented significantly lower cortisol and heart rate responses to
psychosocial stress (Trier social stress test) in trained men compared with untrained men. Moreover,
significantly greater calmness and better mood, and a trend towards lower state anxiety, were noted in these
trained men during the stress protocol. ... Whereas hippocampal and/or serum/plasma BDNF levels are
downregulated by chronic psychosocial stress and inflammation [138,180,201], central and peripheral BDNF
levels can be upregulated by acute exercise [33,198,202,203]. ... Exercise-induced increases in brain
monoamines (norepinephrine and serotonin) may also contribute to increased expression of hippocampal BDNF
[194]. In addition, other growth factors—insulin-like growth factor-1 (IGF-1) and vascular endothelial growth
factor—have been shown to play an important role in BDNF-induced effects on neuroplasticity
[33,172,190,192], as well as exerting neuroprotective effects of their own [33,214,215], thereby contributing to
the beneficial effects of exercise on brain health. Like BDNF, increases in circulating IGF-1 levels in response
to acute exercise are only transient and possibly time-dependent as it relates to chronic training (i.e. increases
seen after 12 weeks of training) [216]. ... Whereas reduced HPA axis reactivity to a given stressor has
repeatedly been reported in physically fit individuals, the finding of reduced sympathetic reactivity is less
consistent.
  Bouchard J, Villeda SA (2015). "Aging and brain rejuvenation as systemic events". J. Neurochem. 132 (1):
5–19. doi:10.1111/jnc.12969. PMC 4301186. PMID 25327899. The beneficial effects of exercise extend beyond
peripheral tissues to also include the brain. ... Because of the blood–brain barrier, it was traditionally thought
that the beneficial effects of exercise on the CNS were not orchestrated through systemic changes in the
periphery. However, recent studies suggest that the effects of exercise are, in part, mediated by changes in the
systemic environment. Investigations looking at magnetic resonance imaging (MRI) measurements of cerebral
blood volume in the hippocampus have demonstrated that exercise selectively increased the cerebral blood
volume of the dentate gyrus, correlating with post-mortem increase in neurogenesis (Pereira et al. 2007). From
a molecular perspective, elevated systemic levels of circulating growth factors such as vascular endothelial
growth factor and insulin-like growth factor 1 (IGF-1) in blood elicited by increased exercise have been shown
to mediate, in part, enhancements in neurogenesis (Trejo et al. 2001; Fabel et al. 2003). Coincidently,
circulating levels of IGF-1 decrease with age and the restoration to levels resembling a younger systemic
environment up-regulate neurogenesis and improve learning and memory (Lichtenwalner et al. 2001;
Darnaudery et al. 2006).
  Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat.
Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been
linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD,
a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional
activity, in the NAc or OFC blocks these key effects of drug exposure 14,22–24. This indicates that ΔFosB is both
necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also
induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat
food, sex, wheel running, where it promotes that consumption 14,26–30. This implicates ΔFosB in the regulation of
natural rewards under normal conditions and perhaps during pathological addictive-like states.
  Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions".
Neuropharmacology 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704.
PMID 21459101. Similar to environmental enrichment, studies have found that exercise reduces self-
administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some
evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal
symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery
program has seen success in participants that train for and compete in a marathon as part of the program
(Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently
been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking
dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive)

38
engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader,
2008).
  Zlebnik NE, Hedges VL, Carroll ME, Meisel RL (2014). "Chronic wheel running affects cocaine-induced c-
Fos expression in brain reward areas in rats". Behav. Brain Res. 261: 71–78. doi:10.1016/j.bbr.2013.12.012.
PMID 24342748.
  Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB".
Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 363 (1507): 3245–
3255. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB
also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived
Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug
exposure—cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos
expression is complex and is covered below. ...
Examples of validated targets for ΔFosB in nucleus accumbens ... GluR2 ... dynorphin ... Cdk5 ... NFκB ... c-
Fos
Table 3
  Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013). "Exercise as a novel treatment for
drug addiction: a neurobiological and stage-dependent hypothesis". Neurosci Biobehav Rev 37 (8): 1622–44.
doi:10.1016/j.neubiorev.2013.06.011. PMC 3788047. PMID 23806439. [exercise] efficacy may be related to its
ability to normalize glutamatergic and dopaminergic signaling and reverse drug-induced changes in chromatin
via epigenetic interactions with brain-derived neurotrophic factor (BDNF) in the reward pathway. ... these data
show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to
modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an
individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced
treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also
stimulant-induced increases in dopamine release in the NAc (Chen et al., 2008) and striatum (Marques et al.,
2008). ... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent
individuals ... wheel running [reduces] methamphetamine self-administration under extended access conditions
(Engelmann et al., 2013) ... These findings suggest that exercise may "magnitude"-dependently prevent the
development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes
that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for
drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated
the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a
reduction in drug craving and better treatment outcomes (see Table 4). ... Taken together, these data suggest
that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be
mediated via chromatin remodeling and possibly lead to greater treatment outcomes.
  Linke SE, Ussher M (2015). "Exercise-based treatments for substance use disorders: evidence, theory, and
practicality". Am J Drug Alcohol Abuse 41 (1): 7–15. doi:10.3109/00952990.2014.976708. PMID 25397661.
The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In
contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and
practical reasons supporting the investigation of this topic has been published. ... numerous theoretical and
practical reasons support exercise-based treatments for SUDs, including psychological, behavioral,
neurobiological, nearly universal safety profile, and overall positive health effects.
  Valkanova V, Eguia Rodriguez R, Ebmeier KP (June 2014). "Mind over matter—what do we know about
neuroplasticity in adults?". Int Psychogeriatr 26 (6): 891–909. doi:10.1017/S1041610213002482.
PMID 24382194. Control group: Active
Intervention: Aerobic exercise
[Increased GMV in:] Lobes (dorsal anterior cingulate cortex, supplementary motor area, middle frontal gyrus
bilaterally); R inferior frontal gyrus, middle frontal gyrus and L superior temporal lobe; increase in the volume
of anterior white matter tracts ... ↑GMV anterior hippocampus
  Ruscheweyh R, Willemer C, Krüger K, Duning T, Warnecke T, Sommer J, Völker K, Ho HV, Mooren F,
Knecht S, Flöel A (July 2011). "Physical activity and memory functions: an interventional study". Neurobiol.
Aging 32 (7): 1304–19. doi:10.1016/j.neurobiolaging.2009.08.001. PMID 19716631.
  Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM,
Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF (February 2011).
"Exercise training increases size of hippocampus and improves memory". Proc. Natl. Acad. Sci. U.S.A. 108 (7):
3017–22. doi:10.1073/pnas.1015950108. PMC 3041121. PMID 21282661.
  Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral
Control". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd
ed.). New York: McGraw-Hill Medical. pp. 313–321. ISBN 9780071481274.  • Executive function, the cognitive
control of behavior, depends on the prefrontal cortex, which is highly developed in higher primates and
39
especially humans.
 • Working memory is a short-term, capacity-limited cognitive buffer that stores information and permits its
manipulation to guide decision-making and behavior. ...
These diverse inputs and back projections to both cortical and subcortical structures put the prefrontal cortex in
a position to exert what is often called “top-down” control or cognitive control of behavior.  ... The prefrontal
cortex receives inputs not only from other cortical regions, including association cortex, but also, via the
thalamus, inputs from subcortical structures subserving emotion and motivation, such as the amygdala (Chapter
14) and ventral striatum (or nucleus accumbens; Chapter 15). ...
In conditions in which prepotent responses tend to dominate behavior, such as in drug addiction, where drug
cues can elicit drug seeking (Chapter 15), or in attention deficit hyperactivity disorder (ADHD; described
below), significant negative consequences can result. ... ADHD can be conceptualized as a disorder of executive
function; specifically, ADHD is characterized by reduced ability to exert and maintain cognitive control of
behavior. Compared with healthy individuals, those with ADHD have diminished ability to suppress
inappropriate prepotent responses to stimuli (impaired response inhibition) and diminished ability to inhibit
responses to irrelevant stimuli (impaired interference suppression). ... Functional neuroimaging in humans
demonstrates activation of the prefrontal cortex and caudate nucleus (part of the striatum) in tasks that demand
inhibitory control of behavior. ... Early results with structural MRI show thinning of the cerebral cortex in
ADHD subjects compared with age-matched controls in prefrontal cortex and posterior parietal cortex, areas
involved in working memory and attention.
  Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral
Control". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd
ed.). New York: McGraw-Hill Medical. p. 315. ISBN 9780071481274. However, damage to the prefrontal
cortex has a significant deleterious effect on social behavior, decision making, and adaptive responding to the
changing circumstances of life. ... Several subregions of the prefrontal cortex have been implicated in partly
distinct aspects of cognitive control, although these distinctions remain somewhat vaguely defined. The anterior
cingulate cortex is involved in processes that require correct decision-making, as seen in conflict resolution (eg,
the Stroop test, see in Chapter 16), or cortical inhibition (eg, stopping one task and switching to another). The
medial prefrontal cortex is involved in supervisory attentional functions (eg, action-outcome rules) and
behavioral flexibility (the ability to switch strategies). The dorsolateral prefrontal cortex, the last brain area to
undergo myelination during development in late adolescence, is implicated in matching sensory inputs with
planned motor responses. The ventromedial prefrontal cortex seems to regulate social cognition, including
empathy. The orbitofrontal cortex is involved in social decision making and in representing the valuations
assigned to different experiences.
  Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY, ed. Molecular Neuropharmacology: A
Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 147, 266, 376.
ISBN 9780071481274. VTA DA neurons play a critical role in motivation, reward-related behavior (Chapter
15), attention, and multiple forms of memory. This organization of the DA system, wide projection from a limited
number of cell bodies, permits coordinated responses to potent new rewards. Thus, acting in diverse terminal
fields, dopamine confers motivational salience (“wanting”) on the reward itself or associated cues (nucleus
accumbens shell region) ... Dopamine acts in the nucleus accumbens to attach motivational significance to
stimuli associated with reward. ... The NAc and VTA are central components of the circuitry underlying reward
and memory of reward. As previously mentioned, the activity of dopaminergic neurons in the VTA appears to be
linked to reward prediction. The NAc is involved in learning associated with reinforcement ... The shell of the
NAc appears to be particularly important to initial drug actions within reward circuitry; addictive drugs appear
to have a greater effect on dopamine release in the shell than in the core of the NAc.
  Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY, ed. Molecular Neuropharmacology: A
Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 148, 324–328, 438.
ISBN 9780071481274. [dopamine] helps consolidate multiple forms of memory (amygdala and hippocampus) ...
the specific crucial structures underlying the ability to store declarative memories are the hippocampus, the
subicular complex, and the entorhinal cortex ... These findings strongly suggest that LTP in the hippocampus is
required for at least some forms of learning and memory known to be dependent on this brain region. ...
Evidence that the caudate nucleus and putamen influence stimulus-response learning comes from lesion studies
in rodents and primates and from neuroimaging studies in humans and from studies of human disease. In
Parkinson disease, the dopaminergic innervation of the caudate and putamen is severely compromised by the
death of dopamine neurons in the substantia nigra pars compacta (Chapter 17). Patients with Parkinson disease
have normal declarative memory ... However, they have marked impairments of stimulus-response learning.
Patients with Parkinson disease or other basal ganglia disorders such as Huntington disease (in which caudate
neurons themselves are damaged) have deficits in other procedural learning tasks, such as the acquisition of
new motor programs. ... Huntington disease is associated with degenerative changes that are most apparent in
the caudate nucleus and putamen.
40
  Grimaldi G, Argyropoulos GP, Bastian A, Cortes M, Davis NJ, Edwards DJ, Ferrucci R, Fregni F, Galea
JM, Hamada M, Manto M, Miall RC, Morales-Quezada L, Pope PA, Priori A, Rothwell J, Tomlinson SP, Celnik
P (2014). "Cerebellar Transcranial Direct Current Stimulation (ctDCS): A Novel Approach to Understanding
Cerebellar Function in Health and Disease". Neuroscientist. doi:10.1177/1073858414559409.
PMID 25406224.
  Sereno MI, Huang RS (2014). "Multisensory maps in parietal cortex". Curr. Opin. Neurobiol. 24 (1): 39–
46. doi:10.1016/j.conb.2013.08.014. PMC 3969294. PMID 24492077.
  Diamond A (2013). "Executive functions". Annu Rev Psychol 64: 135–168. doi:10.1146/annurev-psych-
113011-143750. PMC 4084861. PMID 23020641. Core EFs are inhibition [response inhibition (self-control—
resisting temptations and resisting acting impulsively) and interference control (selective attention and cognitive
inhibition)], working memory, and cognitive flexibility (including creatively thinking “outside the box,” seeing
anything from different perspectives, and quickly and flexibly adapting to changed circumstances). ... EFs and
prefrontal cortex are the first to suffer, and suffer disproportionately, if something is not right in your life. They
suffer first, and most, if you are stressed (Arnsten 1998, Liston et al. 2009, Oaten & Cheng 2005), sad (Hirt et
al. 2008, von Hecker & Meiser 2005), lonely (Baumeister et al. 2002, Cacioppo & Patrick 2008, Campbell et al.
2006, Tun et al. 2012), sleep deprived (Barnes et al. 2012, Huang et al. 2007), or not physically fit (Best 2010,
Chaddock et al. 2011, Hillman et al. 2008). Any of these can cause you to appear to have a disorder of EFs,
such as ADHD, when you do not. You can see the deleterious effects of stress, sadness, loneliness, and lack of
physical health or fitness at the physiological and neuroanatomical level in prefrontal cortex and at the
behavioral level in worse EFs (poorer reasoning and problem solving, forgetting things, and impaired ability to
exercise discipline and self-control). ...
EFs can be improved (Diamond & Lee 2011, Klingberg 2010). ... At any age across the life cycle EFs can be
improved, including in the elderly and in infants. There has been much work with excellent results on improving
EFs in the elderly by improving physical fitness (Erickson & Kramer 2009, Voss et al. 2011) ... Inhibitory
control (one of the core EFs) involves being able to control one’s attention, behavior, thoughts, and/or emotions
to override a strong internal predisposition or external lure, and instead do what’s more appropriate or needed.
Without inhibitory control we would be at the mercy of impulses, old habits of thought or action (conditioned
responses), and/or stimuli in the environment that pull us this way or that. Thus, inhibitory control makes it
possible for us to change and for us to choose how we react and how we behave rather than being unthinking
creatures of habit. It doesn’t make it easy. Indeed, we usually are creatures of habit and our behavior is under
the control of environmental stimuli far more than we usually realize, but having the ability to exercise
inhibitory control creates the possibility of change and choice.
  Janssen M, Toussaint HM, van Mechelen W, Verhagen EA (2014). "Effects of acute bouts of physical
activity on children's attention: a systematic review of the literature". Springerplus 3: 410. doi:10.1186/2193-
1801-3-410. PMC 4132441. PMID 25133092. There is weak evidence for the effect of acute bouts of physical
activity on attention. ... Fortunately, the literature-base on the acute effect of PA on the underlying cognitive
processes of academic performance is growing. Hillman et al. (2011) found in their review a positive effect of
acute PA on brain health and cognition in children, but concluded it was complicated to compare the different
studies due to the different outcome measures (e.g. memory, response time and accuracy, attention, and
comprehension). Therefore, this review focuses on the sole outcome measure ‘attention’ as a mediator for
cognition and achievement.
  Ilieva IP, Hook CJ, Farah MJ (2015). "Prescription Stimulants' Effects on Healthy Inhibitory Control,
Working Memory, and Episodic Memory: A Meta-analysis". J Cogn Neurosci: 1–21.
doi:10.1162/jocn_a_00776. PMID 25591060.
  Kamp CF, Sperlich B, Holmberg HC (July 2014). "Exercise reduces the symptoms of attention-
deficit/hyperactivity disorder and improves social behaviour, motor skills, strength and neuropsychological
parameters". Acta Paediatr. 103 (7): 709–14. doi:10.1111/apa.12628. PMID 24612421. Retrieved 14 March
2015. The present review summarises the impact of exercise interventions (1–10 weeks in duration with at least
two sessions each week) on parameters related to ADHD in 7-to 13-year-old children. We may conclude that all
different types of exercise (here yoga, active games with and without the involvement of balls, walking and
athletic training) attenuate the characteristic symptoms of ADHD and improve social behaviour, motor skills,
strength and neuropsychological parameters without any undesirable side effects. Available reports do not
reveal which type, intensity, duration and frequency of exercise is most effective in this respect and future
research focusing on this question with randomised and controlled long-term interventions is warranted.
  Rommel AS, Halperin JM, Mill J, Asherson P, Kuntsi J (September 2013). "Protection from genetic
diathesis in attention-deficit/hyperactivity disorder: possible complementary roles of exercise". J Am Acad Child
Adolesc Psychiatry 52 (9): 900–10. doi:10.1016/j.jaac.2013.05.018. PMID 23972692. As exercise has been
found to enhance neural growth and development, and improve cognitive and behavioural functioning in
[healthy] individuals and animal studies, we reviewed the literature on the effects of exercise in children and
adolescents with ADHD and animal models of ADHD behaviours.
41
A limited number of undersized non-randomized, retrospective and cross-sectional studies have investigated the
impact of exercise on ADHD and the emotional, behavioural and neuropsychological problems associated with
the disorder. The findings from these studies provide some support for the notion that exercise has the potential
to act as a protective factor for ADHD.  ... Although it remains unclear which role, if any, BDNF plays in the
pathophysiology of ADHD, enhanced neural functioning has been suggested to be associated with the reduction
of remission of ADHD symptoms.49,50,72 As exercise can elicit gene expression changes mediated by alterations in
DNA methylation38, the possibility emerges that some of the positive effects of exercise could be caused by
epigenetic mechanisms, which may set off a cascade of processes instigated by altered gene expression that
could ultimately link to a change in brain function.
  Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 14: Mood and Emotion". In Sydor A, Brown RY.
Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill
Medical. pp. 350–359. ISBN 9780071481274. The excessive release of stress hormones, such as cortisol, which
occurs in many individuals with mood disorders, may result from hyperfunctioning of the PVN of the
hypothalamus, hyperfunctioning of the amygdala (which activates the PVN), or hypofunctioning of the
hippocampus (which exerts a potent inhibitory influence on the PVN). ... Chronic stress decreases the
expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, which in turn may contribute to
the atrophy of CA3 neurons and their increased vulnerability to a variety of neuronal insults. Chronic elevation
of glucocorticoid levels is also known to decrease the survival of these neurons. Such activity may increase the
dendritic arborizations and survival of the neurons, or help repair or protect the neurons from further
damage. ... Stress and glucocorticoids inhibit, and a wide variety of antidepressant drugs, exercise, and
enriched environments activate hippocampal neurogenesis.
  Fuqua JS, Rogol AD (July 2013). "Neuroendocrine alterations in the exercising human: implications for
energy homeostasis". Metab. Clin. Exp. 62 (7): 911–921. doi:10.1016/j.metabol.2013.01.016. PMID 23415825.
Cortisol has wide-ranging effects, including alterations of carbohydrate, protein, and lipid metabolism;
catabolic effects on skin, muscle, connective tissue, and bone; immunomodulatory effects; blood pressure and
circulatory system regulation; and effects on mood and central nervous system function. In the short term,
activation of the HPA axis in response to stress is adaptive. However, long-term stress promoting chronic
exposure of tissues to high cortisol concentrations becomes maladaptive. ... Exercise, particularly sustained
aerobic activity, is a potent stimulus of cortisol secretion. The circulating concentrations of cortisol are directly
proportional to the intensity of exercise as measured by oxygen uptake. As is the case for the GH/IGF-1 and
HPG axes, the HPA axis also receives many other inputs, including the light/dark cycle, feeding schedules,
immune regulation, and many neurotransmitters that mediate the effects of exercise and physical and psychic
stress [52]. ... The HPA is activated by stress, whether physical (exercise) or psychological. ... Thus, a negative
net energy balance leads to activation of the HPA axis and the circulating concomitants of the catabolic state in
an attempt to keep core processes functional, realizing that the stress of exercise has no effect on cortisol and
circulating metabolic substrates beyond the impact of the exercise energy expenditure on energy availability
[60]. Thuma et al. [61] had already made the important observation that the reported differences in cortisol
levels pre- and post-exercise depended on whether this difference was measured from a single pre-test level or
from the physiologic circadian baseline as determined in an independent session in the resting state. By this
analytical technique, these investigators showed that increasing energy expenditure led to significant cortisol
release. This release was apparent if they subtracted the physiologic circadian baseline from the post-exercise
value.
  Ebner NC, Kamin H, Diaz V, Cohen RA, MacDonald K (January 2015). "Hormones as "difference makers"
in cognitive and socioemotional aging processes". Front Psychol 5: 1595. doi:10.3389/fpsyg.2014.01595.
PMC 4302708. PMID 25657633. It is known that chronically elevated levels of the stress hormone cortisol
exert neurotoxic effects on the aging brain with negative impacts on cognition and socioemotional
functioning. ... Cortisol is a steroid hormone released by the HPA axis in response to challenging situations. As
the primary effector of the biological stress response in humans, it is implicated in a diverse array of
physiologic, metabolic, immunologic, and psychological processes directed toward successful coping (Sapolsky
et al., 2000; Kassel and Herrlich, 2007). Cortisol receptors are well-represented in limbic structures involved in
affective response (i.e., hippocampus, hypothalamus, amygdala) and in regions central to executive function
such as the prefrontal cortex and anterior cingulate cortex (Dedovic et al., 2009; Joëls and Baram, 2009). As a
result, the effects of cortisol extend beyond the stress and threat response system to impact mood, attention, and
memory (Lupien and McEwen, 1997; Sapolsky et al., 2000; de Kloet et al., 2005). ... In contrast, evidence
indicated positive associations between cortisol levels that were acutely elevated by stress or hydrocortisone
administration and inhibitory control (Schlosser et al., 2013) as well as spatial learning (Meyer et al., 2013).
Regarding cortisol’s effect on memory, the evidence is currently mixed (Schwabe et al., 2012; van Ast et al.,
2013). ... There also is evidence that effects of cortisol on cognition vary in a dose-dependent fashion. In
particular, there is evidence of cognitive improvements under conditions of moderate, time-limited cortisol
elevation but evidence of cognitive impairments when cortisol concentrations are persistent or excessively high
42
(Lupien et al., 1999; Abercrombie et al., 2003; Hupbach and Fieman, 2012; Schilling et al., 2013; Moriarty et
al., 2014).
  Zschucke E, Gaudlitz K, Ströhle A (January 2013). "Exercise and physical activity in mental disorders:
clinical and experimental evidence". J Prev Med Public Health. 46 Suppl 1: S12–521.
doi:10.3961/jpmph.2013.46.S.S12. PMC 3567313. PMID 23412549. In psychiatric patients, different
mechanisms of action for PA and EX have been discussed: On a neurochemical and physiological level, a
number of acute changes occur during and following bouts of EX, and several long-term adaptations are related
to regular EX training. For instance, EX has been found to normalize reduced levels of brain-derived
neurotrophic factor (BDNF) and therefore has neuroprotective or even neurotrophic effects [7–9]. Animal
studies found EX-induced changes in different neurotransmitters such as serotonin and endorphins [10,11],
which relate to mood, and positive effects of EX on stress reactivity (e.g., the hypothalamus-pituitary-adrenal
axis [12,13]). Finally, anxiolytic effects of EX mediated by atrial natriuretic peptide have been reported [14].
Potential psychological mechanisms of action include learning and extinction, changes in body scheme and
health attitudes/behaviors, social reinforcement, experience of mastery, shift of external to more internal locus
of control, improved coping strategies, or simple distraction [15,16].
  Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A (2012). "Wired to run: exercise-induced
endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high'". J. Exp.
Biol. 215 (Pt 8): 1331–6. doi:10.1242/jeb.063677. PMID 22442371. Humans report a wide range of
neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the 'runner's
high', which may function to encourage habitual aerobic exercise. ... Thus, a neurobiological reward for
endurance exercise may explain why humans and other cursorial mammals habitually engage in aerobic
exercise despite the higher associated energy costs and injury risks
  Cohen EE, Ejsmond-Frey R, Knight N, Dunbar RI (2010). "Rowers' high: behavioural synchrony is
correlated with elevated pain thresholds". Biol. Lett. 6 (1): 106–8. doi:10.1098/rsbl.2009.0670. PMC 2817271.
PMID 19755532.
  Szabo A, Billett E, Turner J (2001). "Phenylethylamine, a possible link to the antidepressant effects of
exercise?". Br J Sports Med 35 (5): 342–343. doi:10.1136/bjsm.35.5.342. PMC 1724404. PMID 11579070. The
24 hour mean urinary concentration of phenylacetic acid was increased by 77% after exercise. ... These results
show substantial increases in urinary phenylacetic acid levels 24 hours after moderate to high intensity aerobic
exercise. As phenylacetic acid reflects phenylethylamine levels 3 , and the latter has antidepressant effects, the
antidepressant effects of exercise appear to be linked to increased phenylethylamine concentrations.
Furthermore, considering the structural and pharmacological analogy between amphetamines and
phenylethylamine, it is conceivable that phenylethylamine plays a role in the commonly reported "runners high"
thought to be linked to cerebral β-endorphin activity. The substantial increase in phenylacetic acid excretion in
this study implies that phenylethylamine levels are affected by exercise. ... A 30 minute bout of moderate to high
intensity aerobic exercise increases phenylacetic acid levels in healthy regularly exercising men. The findings
may be linked to the antidepressant effects of exercise.
  Lindemann L, Hoener MC (2005). "A renaissance in trace amines inspired by a novel GPCR family".
Trends Pharmacol. Sci. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID 15860375. The pharmacology
of TAs might also contribute to a molecular understanding of the well-recognized antidepressant effect of
physical exercise [51]. In addition to the various beneficial effects for brain function mainly attributed to an
upregulation of peptide growth factors [52,53], exercise induces a rapidly enhanced excretion of the main β-
PEA metabolite β-phenylacetic acid (b-PAA) by on average 77%, compared with resting control subjects [54],
which mirrors increased β-PEA synthesis in view of its limited endogenous pool half-life of ~30 s [18,55].
  Berry MD (2007). "The potential of trace amines and their receptors for treating neurological and
psychiatric diseases". Rev Recent Clin Trials 2 (1): 3–19. doi:10.2174/157488707779318107. PMID 18473983.
It has also been suggested that the antidepressant effects of exercise are due to an exercise-induced elevation of
PE [151].
  Dinas PC, Koutedakis Y, Flouris AD (2011). "Effects of exercise and physical activity on depression". Ir J
Med Sci 180 (2): 319–325. doi:10.1007/s11845-010-0633-9. PMID 21076975. According to the 'endorphins
hypothesis', exercise augments the secretion of endogenous opioid peptides in the brain, reducing pain and
causing general euphoria. ... Based upon a large effect size, the results confirmed the endorphins hypothesis
demonstrating that exercise leads to an increased secretion of endorphins which, in turn, improved mood states.
β-Endorphin, an endogenous μ-opioid receptor selective ligand, has received much attention in the literature
linking endorphins and depression or mood states. ... exercise of sufficient intensity and duration can increase
circulating β-endorphin levels. ... Moreover, a recent study demonstrated that exercise and physical activity
increased β-endorphin levels in plasma with positive effects on mood. Interestingly, the researchers reported
that, independently of sex and age, dynamic anaerobic exercises increased β-endorphin, while resistance and
aerobic exercises seem to only have small effects on β-endorphins. ... The results showed that mood tends to be
higher in a day an individual exercises as well as that daily activity and exercise overall are strongly linked with
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mood states. In line with these findings, a recent study showed that exercise significantly improved mood states
in non-exercises, recreational exercisers, as well as marathon runners. More importantly, the effects of exercise
on mood were twofold in recreational exercisers and marathon runners.
  Tantimonaco M, Ceci R, Sabatini S, Catani MV, Rossi A, Gasperi V, Maccarrone M (2014). "Physical
activity and the endocannabinoid system: an overview". Cell. Mol. Life Sci. 71 (14): 2681–2698.
doi:10.1007/s00018-014-1575-6. PMID 24526057. The traditional view that PA engages the monoaminergic
and endorphinergic systems has been challenged by the discovery of the endocannabinoid system (ECS),
composed of endogenous lipids, their target receptors, and metabolic enzymes. Indeed, direct and indirect
evidence suggests that the ECS might mediate some of the PA-triggered effects throughout the body. ... the
evidence that PA induces some of the psychotropic effects elicited by the Cannabis sativa active ingredient Δ9-
tetrahydrocannabinol (Δ9-THC, Fig. 1), like bliss, euphoria, and peacefulness, strengthened the hypothesis that
endocannabinoids (eCBs) might mediate, at least in part, the central and peripheral effects of exercise [14]. ...
To our knowledge, the first experimental study aimed at investigating the influence of PA on ECS in humans was
carried out in 2003 by Sparling and coworkers [63], who showed increased plasma AEA content after 45 min of
moderate intensity exercise on a treadmill or cycle ergometer. Since then, other human studies have shown
increased blood concentrations of AEA ... A dependence of the increase of AEA concentration on exercise
intensity has also been documented. Plasma levels of AEA significantly increased upon 30 min of moderate
exercise (heart rate of 72 and 83 %), but not at lower and significantly higher exercise intensities, where the
age-adjusted maximal heart rate was 44 and 92 %, respectively ... Several experimental data support the
hypothesis that ECS might, at least in part, explain PA effects on brain functions, because: (1) CB1 is the most
abundant GPCR in the brain participating in neuronal plasticity [18]; (2) eCBs are involved in several brain
responses that greatly overlap with the positive effects of exercise; (3) eCBs are able to cross the blood–brain
barrier [95]; and (4) exercise increases eCB plasma levels [64–67].
  "β-phenylethylamine: Biological activity". Guide to Pharmacology. The International Union of Basic and
Clinical Pharmacology. Retrieved 10 February 2015.
  "Dexamfetamine: Biological activity". Guide to Pharmacology. The International Union of Basic and
Clinical Pharmacology. Retrieved 10 February 2015.
  Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther.
125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186. Trace amines are metabolized in
the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2) ... It deaminates primary
and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the
sympathetic neurone ... Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for
MAO-B which is not found in the gut ...
Brain levels of endogenous trace amines are several hundred-fold below those for the classical
neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of
noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular
tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations
arise because of their very short half-life ...
  Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 5: Excitatory and Inhibitory Amino Acids". In Sydor
A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York:
McGraw-Hill Medical. pp. 117–130. ISBN 9780071481274.  • The major excitatory neurotransmitter in the
brain is glutamate; the major inhibitory neurotransmitter is GABA. ...
 • The most extensively studied form of synaptic plasticity is long-term potentiation (LTP) in the hippocampus,
which is triggered by strong activation of NMDA receptors and the consequent large rise in postsynaptic
calcium concentration.
 • Long-term depression (LTD), a long-lasting decrease in synaptic strength, also occurs at most excitatory and
some inhibitory synapses in the brain. ... The bidirectional control of synaptic strength by LTP and LTD is
believed to underlie some forms of learning and memory in the mammalian brain.
  Broussard JI (2012). "Co-transmission of dopamine and glutamate". J. Gen. Physiol. 139 (1): 93–6.
doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950. Coincident and convergent input often induces
plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from
basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain
dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For
example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing
PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates
PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of
midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to
test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed
behavior.

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  Descarries L, Bérubé-Carrière N, Riad M, Bo GD, Mendez JA, Trudeau LE (2008). "Glutamate in
dopamine neurons: synaptic versus diffuse transmission". Brain Res Rev 58 (2): 290–302.
doi:10.1016/j.brainresrev.2007.10.005. PMID 18042492. Moreover, all TH varicosities which co-localize
VGluT2 are synaptic, as if there was a link between the potential of DA axon terminals to release glutamate and
their establishment of synaptic junctions. Together with the RT-PCR and in situ hybridization data
demonstrating the co-localization of TH and VGluT2 mRNA in mesencephalic neurons of the VTA, these
observations raise a number of fundamental questions regarding the functioning of the meso-telencephalic DA
system in healthy or diseased brain.
  Hillman, C.H., Erickson, K.I., and Kramer, A.F. 2008. Be smart, exercise your heart: exercise effects on
brain and cognition. Nature Reviews Neuroscience. 9:58–65.
  Sibley, B. A. and Etnier, J. L. 2003. The Relationship Between Physical Activity and Cognition in Children:
A Meta-Analysis. Pediatric Exercise Science. 15(3):243–256.
  Chaddock, L., Hillman, C. H., Buck, S. M. and Cohen, N. J. 2011. Aerobic Fitness and Executive Control
of Relational Memory in Preadolescent Children. Medicine & Science in Sports & Exercise. 43(2):344–349.
  Chaddock, I., Erickson, K. I., Prakash, R. S., Kim, J. S., Voss, M. A., VanPatter, M. et al.. 2010. A
neuroimaging investigation of the association between aerobic fitness, hippocampal volume, and memory
performance in preadolescent children. Brain Research. 1358:172–183.
  Best, J. R. 2010. Effects of physical activity on children’s executive function: Contributions of experimental
research on aerobic exercise. Developmental Review. 30(4):331–351. doi: 10.1016/j.brainres.2010.08.049
  Dik, M. G., Deeg, D. J. H., Visser, M. and Jonker, C. 2003. Early Life Physical Activity and Cognition at
Old Age. Journal of Clinical and Experimental Neuropsychology. 25(5):643–653.
  Swardfager W, Herrmann N, Marzolini S, Saleem M, Kiss A, Shammi P, Oh PI and Lanctôt KL, 2010.
Cardiopulmonary fitness is associated with cognitive performance in patients with coronary artery disease. J.
Amer. Geriatrics. Soc. 58(8):1519–25.
  Farina N, Rusted J, Tabet N (January 2014). "The effect of exercise interventions on cognitive outcome in
Alzheimer's disease: a systematic review". Int Psychogeriatr 26 (1): 9–18. doi:10.1017/S1041610213001385.
PMID 23962667. Six RCTs were identified that exclusively considered the effect of exercise in AD patients.
Exercise generally had a positive effect on rate of cognitive decline in AD. A meta-analysis found that exercise
interventions have a positive effect on global cognitive function, 0.75 (95% CI = 0.32–1.17). ... The most
prevalent subtype of dementia is Alzheimer’s disease (AD), accounting for up to 65.0% of all dementia cases  ...
Cognitive decline in AD is attributable at least in part to the buildup of amyloid and tau proteins, which promote
neuronal dysfunction and death (Hardy and Selkoe, 2002; Karran et al., 2011). Evidence in transgenic mouse
models of AD, in which the mice have artificially elevated amyloid load, suggests that exercise programs are
able to improve cognitive function (Adlard et al., 2005; Nichol et al., 2007). Adlard and colleagues also
determined that the improvement in cognitive performance occurred in conjunction with a reduced amyloid
load. Research that includes direct indices of change in such biomarkers will help to determine the mechanisms
by which exercise may act on cognition in AD.
  Rao AK, Chou A, Bursley B, Smulofsky J, Jezequel J (January 2014). "Systematic review of the effects of
exercise on activities of daily living in people with Alzheimer's disease". Am J Occup Ther 68 (1): 50–56.
doi:10.5014/ajot.2014.009035. PMID 24367955. Alzheimer’s disease (AD) is a progressive neurological
disorder characterized by loss in cognitive function, abnormal behavior, and decreased ability to perform basic
activities of daily living [(ADLs)] ... All studies included people with AD who completed an exercise program
consisting of aerobic, strength, or balance training or any combination of the three. The length of the exercise
programs varied from 12 weeks to 12 months. ... Six studies involving 446 participants tested the effect of
exercise on ADL performance ... exercise had a large and significant effect on ADL performance (z = 4.07, p < .
0001; average effect size = 0.80). ... These positive effects were apparent with programs ranging in length from
12 wk (Santana-Sosa et al., 2008; Teri et al., 2003) and intermediate length of 16 wk (Roach et al., 2011;
Vreugdenhil et al., 2012) to 6 mo (Venturelli et al., 2011) and 12 mo (Rolland et al., 2007). Furthermore, the
positive effects of a 3-mo intervention lasted 24 mo (Teri et al., 2003). ... No adverse effects of exercise on ADL
performance were noted. ... The study with the largest effect size implemented a walking and aerobic program of
only 30 min four times a week (Venturelli et al., 2011).
  Adlard PA, Perreau VM, Pop V, Cotman CW (2005). "Voluntary exercise decreases amyloid load in a
transgenic model of Alzheimer's disease". J. Neurosci. 25 (17): 4217–21. doi:10.1523/JNEUROSCI.0496-
05.2005. PMID 15858047.
  Elwood P, Galante J, Pickering J, Palmer S, Bayer A, Ben-Shlomo Y, Longley M, Gallacher J (December
2013). "Healthy lifestyles reduce the incidence of chronic diseases and dementia: evidence from the Caerphilly
cohort study". PLoS ONE 8 (12): e81877. doi:10.1371/journal.pone.0081877. PMC 3857242. PMID 24349147.
  Morgan GS, Gallacher J, Bayer A, Fish M, Ebrahim S, Ben-Shlomo Y (2012). "Physical activity in middle-
age and dementia in later life: findings from a prospective cohort of men in Caerphilly, South Wales and a meta-
analysis". J. Alzheimers Dis. 31 (3): 569–80. doi:10.3233/JAD-2012-112171. PMID 22647258.
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  Blondell SJ, Hammersley-Mather R, Veerman JL (May 2014). "Does physical activity prevent cognitive
decline and dementia?: A systematic review and meta-analysis of longitudinal studies". BMC Public Health 14:
510. doi:10.1186/1471-2458-14-510. PMC 4064273. PMID 24885250. Longitudinal observational studies show
an association between higher levels of physical activity and a reduced risk of cognitive decline and dementia. A
case can be made for a causal interpretation. Future research should use objective measures of physical
activity, adjust for the full range of confounders and have adequate follow-up length. Ideally, randomised
controlled trials will be conducted. ... On the whole the results do, however, lend support to the notion of a
causal relationship between physical activity, cognitive decline and dementia, according to the established
criteria for causal inference.
  Pang, T.Y.C., Stam, N. C., Nithianantharajah, J., Howard, M. L., and Hannan, A. J. 2006. Differential
effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in
Huntington's disease transgenic mice. Neuroscience. 141:569–584.
  Kohl, Z., Kandasamy, M., Winner, B., Aigner, R., Gross, C., Couillard-Despres et al.. 2007. Physical
activity fails to rescue hippocampal neurogenesis deficits in the R6/2 mouse model of Huntington's disease.
Trends in Cognitive Sciences. 11(8):342–348.
  Baatile, J., Langbein, W.E., Weaver, F., Maloney, C., and Jost, M.B. 2000. Effect of exercise on perceived
quality of life of individuals with Parkinson's Disease. Journal of Rehabilitation Research and Development.
37(5):529–534.
  Kramer, A. F., Erickson, K. I. And Colcombe, S. J. 2006. Exercise, cognition, and the aging brain. Journal
of Applied Physiology. 101(4):1237–1242.
  Kramer, A. F., Hahn, S., Cohen, N. J., Banich, M. T., McAuley, Harrison, C. R. et al. 1999. Ageing, fitness
and neurocognitive function. Nature. 400:418–419.
 Nocera, J. R., Altman, L. J. P., Sapienza, C., Okun, M. S. and Hass, C. J. 2010. Can exercise improve
language and cognition in Parkinson's disease? A case report. Neurocase: The Neural Basis of Cognition.
16(4):301–

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