Behavioural Brain Research 221 (2011) 574–582

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Behavioural Brain Research

journal homepage: www.elsevier.com/locate/bbr

Review

The cholinergic system and depression

Girstautė Dagytė a,b,∗ , Johan A. Den Boer b , Andrea Trentani b
a
Department of Molecular Neurobiology, University of Groningen, The Netherlands
b
Department of Psychiatry, University of Groningen, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: Major depressive disorder is a severe psychiatric condition which forms a substantial burden to
Received 6 January 2010 patients and society. Despite continuous efforts to unravel its etiology and pathophysiology, many ques-
Accepted 10 February 2010 tions remain. The majority of neurobiological research and classical pharmacotherapy regimens have
Available online 16 February 2010
approached this illness as the consequence of a failing monoaminergic neurotransmitter system. In
the last decades, involvement of adult hippocampal neurogenesis in the pathogenesis and treatment
Keywords:
of depressive disorder has gained an enormous interest. Numerous neurobiological systems and circuits
Acetylcholine
thus appear to underlie this complex multi-factorial disease. One of them is the cholinergic system, which
Affective disorders
Antidepressants
plays a major role in the regulation of various CNS functions, such as arousal, attention, cognition and
Basolateral amygdala memory. Cognitive impairments are often observed in depression, next to low mood, anhedonia and other
Hippocampus clinical symptoms. Cholinergic dysfunctions may account for the development of cognitive symptoms
Prefrontal cortex during the course of depression. Changes in hippocampal neurogenesis, often associated with chronic
SCN stress in animal models, may be in part mediated by cholinergic dysfunction, which in turn could underlie
the cognitive disturbances observed in depression. Here, we discuss the involvement of the cholinergic
system in depressive disorder, with particular focus on its role in associated cognitive impairment. Since
such deficits are often modified by cholinergic drugs, application of these neuropharmacological findings
may provide a new therapeutic niche while yielding valuable insight into the pathophysiology of this
complex illness.
© 2010 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
2. The cholinergic hypothesis of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575
3. Altered cholinergic function in depression: involvement in cognitive rather than affective symptoms? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576
3.1. Neuropharmacological evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576
3.2. Cholinergic changes in depression and stress: contribution to cognitive dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
3.3. Relationship between the cholinergic system and hippocampal neurogenesis: implication in depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
3.4. Involvement of the cholinergic system in depression: beyond the hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578
4. Conclusion and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579

1. Introduction cesses, including sleep, appetite and libido [1]. Depression has
been described since antiquity but it is still conceptualized as
Major depressive disorder is a multidimensional syndrome a common and complex disease of unknown etiology. Research
which involves disruption of mood, cognition and other pro- attempts to elucidate the mechanisms responsible for develop-
ment and treatment of depression have yielded valuable insight,
but its puzzling nature persists. For half a century, the majority
∗ Corresponding author at: Department of Molecular Neurobiology, University of
of neurobiological research and classical pharmacotherapy regi-
Groningen, P.O. Box 14, 9750 AA Haren, The Netherlands. Tel.: +31 50 363 2339;
mens have explained this illness with the monoamine hypothesis of
fax: +31 50 363 2331. depression, which proposes that low levels of brain monoamines,
E-mail address: G.Dagyte@rug.nl (G.. Dagytė). such as serotonin, noradrenaline and dopamine, are responsible

0166-4328/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbr.2010.02.023
 G.. Dagytė et al. / Behavioural Brain Research 221 (2011) 574–582
for the development of depressive symptoms. In contrast, many
currently used antidepressant drugs, such as selective serotonin
reuptake inhibitors (SSRI), noradrenaline reuptake inhibitors (NRI),
serotonin and noradrenaline reuptake inhibitors (SNRI), tricyclics
and monoamine oxidase inhibitors (MAOI) potentiate the brain’s
monoaminergic system and elevate the monoamine levels [2].
Despite their acute effects on the monoaminergic system, how-
ever, the mood-alleviating properties of all these medications
take at least several weeks to become manifest [3]. Therefore,
although considerably advancing the way depression was viewed
and treated, the monoamine hypothesis has failed to fully explain
the nature of this disorder [4]. The discovery of adult hippocampal
neurogenesis seemed again to revolutionize the understanding of
the neurobiological mechanisms governing depression and antide-
pressant therapies as it proved to be affected by stress, yet restored
by antidepressants [5]. Despite contradictions in literature, the
possibility that hippocampal neurogenesis may be oppositely regu-
lated by depression and antidepressants, gained enormous interest
among researchers and great enthusiasm among clinicians. Nev-
ertheless, although initially promising, this phenomenon has lost
some of its appeal due to difficulties providing functional mech-
anism for the etiology of depression. Not surprisingly, failure of
one neurobiological system is not sufficient to explain the nature
of such a complex disorder as depression. Numerous brain systems
and neuronal networks act in concert to maintain normal function-
ing; likewise, in depression many of them may get dysregulated.
One of those is the cholinergic system, responsible for a number of
CNS functions, including arousal, attention, learning and memory.
Cognitive impairments are often observed in depression, in
addition to mood disturbances and other motoric, autonomic,
endocrine and sleep-wake abnormalities. This spectrum of symp-
toms is thought to arise from the complex interaction between
multiple genetic and environmental factors [6]. It has been hypoth-
esized that different neurotransmitter-mediated dysfunctions may
subserve specific symptom domains. Depression-associated anx-
iety is thought to arise from abnormal serotonergic function,
whereas loss of pleasure, interest and energy may be due to
dopaminergic and noradrenergic deficits [7]. Cholinergic dysfunc-
tions may account for the development of cognitive symptoms
associated with depression, especially when the disease is long-
lasting and treatment resistant. Moreover, changes in hippocampal
neurogenesis may be in part mediated by the cholinergic system
and may also relate to the cognitive disturbances diagnosed in
depression.
Here, we review the literature regarding involvement of the
cholinergic system in the pathophysiology of depressive disorder.
First, the history of the cholinergic hypothesis of depression is
summarized. Then, the contribution of cholinergic changes to the
development of mood and cognitive impairments associated with
depression is discussed. In view of this, we outline a potential link
between the cholinergic system, hippocampal neurogenesis and
cognitive dysfunction in depression. In addition to the hippocampal
changes mediated by cholinergic transmission, we briefly discuss
the alterations in other brain areas, implicated in depression and
innervated by cholinergic neurons, i.e. the prefrontal cortex, amyg-
dala, and the suprachiasmatic nucleus (SCN). On a final note, we
emphasize that depression-associated symptoms depend on com-
plex changes in a variety of neurobiological systems and multiple
brain areas. Thus, future research would benefit from an integrated
view on depression, attempting to unravel these multi-factorial
interactions in search of novel therapeutic targets.
2. The cholinergic hypothesis of depression
Implication of the cholinergic system in the etiology of major
depression, although not as widely accepted as the monoamine
575
hypothesis, was postulated several decades ago. It was suggested
that central cholinergic activation caused depressant inhibitory
effects, while anticholinergic drugs or adrenergic stimulation
induced behavioral activation and arousal [8–10]. Based on these
observations, Janowsky et al. postulated the cholinergic–adrenergic
imbalance hypothesis of depression and mania [11]. Central cholin-
ergic factors were suggested to play a role in the etiology of
affective disorders, and depression was proposed to be a dis-
ease of cholinergic dominance. This hypothesis originated from
reports showing that cholinesterase inhibitors induced depressive
symptoms, presumably through increased central acetylcholine
levels. The first study of this kind involved administration of
the irreversible cholinesterase inhibitor diisopropylfluorophos-
phonate (DFP), which was found to induce depression-like
symptoms in normal subjects and decrease mania-like symp-
toms in manic patients [12]. This was supported by the case
reports of individuals poisoned with cholinesterase inhibitor insec-
ticides, who developed depression symptoms and peripheral
parasympathetic toxicity [13]. Another irreversible cholinesterase
inhibitor, EA-1701, was also noted to cause depressed mood
and lethargy in healthy volunteers [14]. Later, the reversible
inhibitor of cholinesterase, physostigmine, was shown to induce
depressive symptoms and exacerbate mood disorders [15–17].
Choline treatment was also associated with depressive symp-
toms, but only sporadically [18]. Additional evidence for a
cholinergic mechanism in depression came from the obser-
vation that the monoamine depletor reserpine, a drug which
induced mood depressing effects, had central cholinomimetic
properties [11,19]. Cholinergic hypersensitivity was thus consid-
ered essential in depression with evidence of anticholinesterases
and cholinomimetics producing acute syndromes characterized
by dysphoria, psychomotor retardation and energy loss [20].
Despite their seemingly acute depressiogenic and antimanic prop-
erties, however, it is unclear whether these were illustrative
of specific depression symptomology or a non-specific response
of behavioral inhibition, secondary to cholinergic manipulation
[21]. Nevertheless, given these clinical observations, anticholin-
ergic drugs have been investigated as potential treatments for
depression, but studies have not reported consistent antidepres-
sant effects [22–24]. In fact, the agonists of cholinergic nicotinic
receptors have been associated with antidepressant properties,
arguing against the cholinergic dominance hypothesis of depres-
sion [25,26].
Neuroimaging studies have reported an increased concentration
of the acetylcholine precursor, choline, in the brains of patients
suffering from mood disorders and its reversal after recovery
from depression [27,28]. However, post-mortem brain analysis
yielded no consistent results on the involvement of acetylcholine
receptors in depression. Although a higher number of muscarinic
acetylcholine receptor binding sites was reported in the frontal
cortex of suicide victims [29], subsequent studies did not repli-
cate this finding [30–32] or even opposed it [33]. Cholinergic
hypersensitivity was linked to a personality trait predisposing to
depression, such as stress sensitivity, rather than to depression
itself [34].
Importance of the cholinergic hypothesis of depression dimin-
ished over time, due to insufficient evidence linking it to the
etiology of major depression. Even in the 1980s when this hypoth-
esis was prominent, it was recognized that cholinergic pathology
is unlikely to explain all the nuances of depression [20]. Neverthe-
less, recognizing the role of the cholinergic system in depression
may shed light upon mechanisms involved in certain aspects of
this disease. Therefore, the following text of this review will focus
on cholinergic changes that may develop during the course of
depression, and may thus account for specific clinical symptoms
associated with this disorder.
576 G.. Dagytė et al. / Behavioural Brain Research 221 (2011) 574–582
3. Altered cholinergic function in depression: involvement
in cognitive rather than affective symptoms?
Low mood is the most prominent clinical symptom of major
depressive disorder. Also, depression is often accompanied by sig-
nificant impairments in neurocognitive functioning that may be
independent of mood [35–37]. Cognitive symptoms of depres-
sion, such as poor attention and concentration as well as
impaired memory and information processing, point to deficits
in cholinergic function. Acetylcholine is largely responsible for
regulating these cognitive processes [38]. Cholinergic projections
from the basal forebrain system modulate the function of numer-
ous brain areas implicated in depression, and the optimal range
of cholinergic tone is vital for optimal behavioral and brain
function [39]. It is thus feasible that an imbalance of multiple
neurobiological systems underlying depression results in cholin-
ergic dysfunction which, in turn, causes further disruption (see
Fig. 1).
Fig. 1. Depressive disorder is thought to arise from the complex interaction of
multiple genetic and environmental factors. These factors may also lead to higher
susceptibility to stress. Whereas the acute stress response is adaptive, prolonged
stress may predispose to depression. Both chronic stress and depression are asso-
ciated with cholinergic dysfunctions as well as with structural and functional
alterations in multiple brain areas. Changes in the hippocampus, PFC and amyg-
dala, observed in chronically stressed animals and/or depressed subjects, may party
arise from the cholinergic dysfunction. Altogether, these neurobiological alterations
account for development of the cognitive symptoms of depression, such as atten-
tion deficit, memory impairment and negativity bias. Thus, cholinergic dysfunction
may in part underlie depression-associated cognitive impairments, that in turn can
precipitate the course of this illness. On the other hand, cholinergic dysfunction
may also predispose to depression, via dysregulation of numerous neurobiologi-
cal systems and circuits involved in the pathophysiology of this complex disorder.
Dashed arrows represent predisposing factors to depression. Solid arrows indicate
the consequences that arise from pathological states of chronic stress and depres-
sion, causing further disruptions, that in turn may predispose and/or precipitate
depressive disorder. DG, dentate gyrus; PFC, prefrontal cortex.
3.1. Neuropharmacological evidence
Evidence regarding altered cholinergic function in depression
mainly comes from drug studies targeting nicotinic or muscarinic
cholinergic receptors. These two types of cholinergic receptors
are widely expressed in the brain and often co-expressed within
neurons [40,41]. Their action is suggested to contribute to both
mood and cognitive symptoms of depression, although the latter
seem to be more plausible given the functional role of acetyl-
choline in the brain’s cognitive processes. Nevertheless, nicotine
has been shown to alleviate symptoms of depression in non-
smoking depressed patients [42]. On the other hand, nicotine
withdrawal can exacerbate depressive symptoms [43]. Nicotine
dependence is strongly correlated to mood disorders, e.g. smoking
behavior relates to the genetic susceptibility to depression [44,45].
Interestingly, schizophrenic subjects, also known to have a very
high rate of smoking, may be using nicotine to self-medicate their
cognitive impairments associated with schizophrenia [46,47]. The
precise changes in cholinergic signaling through nicotinic recep-
tors in depression are not known. Furthermore, the literature
is confounded by studies reporting that both nicotine receptor
agonists and antagonists may display antidepressant properties
[23,25,26,48]. However, their effects on cognitive functions seem
to be diverse; whereas nicotinic agonists can improve attention,
learning and memory, nicotinic antagonists can impair these pro-
cesses [49–51]. Although both activation and desensitization of
nicotinic acetylcholine receptors have been suggested to contribute
to behaviors related to nicotine addiction and mood [170], their
distinct role in depression remains unclear.
Similarly, there is little research providing direct evidence for
a role of muscarinic receptors in the pathophysiology of major
depressive disorder. Yet, pharmacological studies continue to rec-
ognize a potential for reducing depression-associated symptoms
via modulation of the muscarinic system [52]. Cholinergic mus-
carinic agonists are shown to facilitate learning and memory,
whereas antagonists are associated with deficits in these pro-
cesses [51,53,54]. M1 metabotropic muscarinic receptors represent
a viable target for amelioration of affective disorder-associated
cognitive deficits, given their role in cognition [52]. M2 receptors
were suggested to be involved in major depressive disorder by
single-nucleotide polymorphism (SNP) association studies [55,56].
This notion was further supported by a recent post-mortem study,
reporting decreased binding of M2 and/or M4 muscarinic receptors
in the dorsolateral prefrontal cortex of depressed subjects [33].
Loss of cholinergic terminals results in memory deficits, con-
firming the above described neuropharmacological findings on
cholinergic transmission and cognition [53]. Given the highly inter-
active nature of central nicotinic and muscarinic systems and
their receptor co-localization, it is likely that depression-induced
changes in one subset of the cholinergic system modulate the
other one too [40,41,57]. At present it is difficult to attribute dis-
tinct involvement of these two cholinergic receptor systems in the
pathophysiology of depressive disorder, and the extent of this com-
plexity goes beyond the scope of this review. As such, we will
not elaborate upon specific effects achieved through the choliner-
gic receptor subtypes, but focus instead on the greater framework
of cholinergic changes associated with mood disorders and their
treatment.
It appears that some classical antidepressants also partially tar-
get cholinergic neurotransmission. The SSRI, citalopram, has been
shown to reverse memory impairment by enhancing acetylcholine
release in the hippocampus of laboratory animals [58]. It has also
been reported to improve psychotic symptoms and behavioral
disturbances in patients with dementia [59] and facilitate mem-
ory consolidation in healthy volunteers [60]. Citalopram may thus
possibly improve memory impairment in depressed patients by
 G.. Dagytė et al. / Behavioural Brain Research 221 (2011) 574–582
enhancing acetylcholine release [58]. The mood stabilizer, lithium,
has also been shown to upregulate hippocampal cholinergic mus-
carinic receptors [61], further emphasizing a role for the cholinergic
system in the pathology of depression.
3.2. Cholinergic changes in depression and stress: contribution to
cognitive dysfunction
Altered acetylcholine release in depression has been hypoth-
esized but not clearly proven. Changes in central acetylcholine
turnover have been reported in response to prolonged stress, a
major predisposing risk factor for developing depression [62,63].
Whereas an acute stress response is adaptive, chronic stress, espe-
cially when it is unpredictable and uncontrollable, may increase
brain vulnerability to neuropathology [64–66]. Stress is known
to alter the functioning of the cholinergic system [67,68]. The
stress response induces acetylcholine release in the forebrain and
activates the septohippocampal pathway [62]. This mediates phys-
iological and emotional responses, in part through acetylcholine
action on the HPA-axis [69]. While acute stressors increase acetyl-
choline release in the hippocampus [70,71], the effects of chronic
stress are less clear [67,72], but may involve a gradual decline of
cholinergic function. Chronic stress has been reported to decrease
acetylcholinesterase (AChE) activity in the hippocampus of labora-
tory animals [73,74]. Subsequently, such decrease in AChE activity
was associated with learning and memory deficits after expo-
sure to chronic stress [67]. Cholinergic dysfunctions have also
been reported in rats subjected to chronic unpredictable stress
or corticosterone treatment, where a decrease in AChE-stained
neurons in the medial septum was observed [75,76]. Such stress-
induced malfunctioning of the cholinergic system may in turn
impair learning and memory processes [67,68]. Preclinical studies
using in vivo microdialysis techniques have shown that increased
and decreased acetylcholine levels correlate with increased and
decreased memory performance, respectively [77,78]. In line with
this, pharmacological augmentation of septohippocampal cholin-
ergic activity enhances learning and memory performance in
cognitively impaired animals [39].
There is a wealth of evidence indicating that stress, especially
when severe and prolonged, can precipitate affective disorders
and impair learning and memory [79,80]. Chronic stress in labo-
ratory animals has been associated with deficits in several learning
and memory tasks, e.g. radial arm maze and Y-maze [67,81,82].
The hippocampal formation, governing these learning paradigms
and densely innervated by cholinergic neurons [83,84], is highly
impacted by stress. Exposure to chronic stress or glucocorticoids
has been demonstrated to affect the hippocampal neurons, caus-
ing a dendritic atrophy of CA3 pyramidal neurons, alteration in the
density of dendritic spines and excrescences, and neuronal cell loss
[85,86]. Among the multiple neurochemical changes that occur in
response to stress, excessive glutamatergic neurotransmission is
thought to play a major role in stress-induced hippocampal neu-
rotoxicity. Several studies have reported that exposure to stress
increased the release of glutamate in the hippocampus and other
brain regions, such as the prefrontal cortex and the basal ganglia
[87–89]. As such, excessive glutamate release is also implicated in
neurodegeneration [90]. As the glutamatergic and cholinergic sys-
tems act in concert, changes in the former may synergically affect
the latter, causing perturbations in learning, memory and other
cognitive processes [91].
3.3. Relationship between the cholinergic system and
hippocampal neurogenesis: implication in depression
Several lines of evidence support the enhanced neurodegen-
eration and decreased neurogenesis hypothesis of depression [4].
577
Structural brain changes have been reported in depressed patients,
involving volumetric changes in hippocampus, amygdala, pre-
frontal cortex, anterior cingulate cortex and basal ganglia [92,93].
Moreover, post-mortem studies have revealed neuronal and glial
cell modifications in the hippocampus in major depression [94].
The hippocampus serves as an integrator of input from various
brain regions related to mood, learning and memory. Structural
and functional changes in this vital brain area may thus contribute
to impairments associated with depression.
The hippocampus receives abundant cholinergic innervation
from the diagonal band and septum [83,95–97]. The decreased
cholinergic input may account for diminished hippocampal func-
tioning and increase its vulnerability to stress [98]. Lesion of
cholinergic neurons projecting to the hippocampus is known to
suppress adult neurogenesis [99,100] and concurrently impair
spatial memory in rats [101]. Acetylcholine thus appears cru-
cial for regulating hippocampal neurogenesis ([171], this issue).
Transgenic mice expressing an inactive form of AChE, and hence
expected to have elevated acetylcholine levels, show increased cell
proliferation in the dentate gyrus [102]. Likewise, pharmacological
inhibition of AChE also enhances hippocampal neurogenesis
[101,103]. The AChE inhibitor, donepezil, widely used to enhance
cognitive function in Alzheimer’s disease, has even been shown to
reverse chronic stress-induced decrease in survival of the newly
born hippocampal neurons [104].
Adult hippocampal neurogenesis is hypothesized to be rele-
vant in the pathophysiology and treatment of major depression
[105,106]. In animal models, rodents often display decreased
hippocampal neurogenesis [5,107,108]. Such reductions in the
generation of new neurons are reversible by antidepressants, com-
prising in part their mood-improving actions [109]. However,
artificially disrupted hippocampal neurogenesis in laboratory ani-
mals has not led to the depressive phenotype [110,111]. Also,
subsequent research has failed to uniformly confirm that the
mood-alleviating effects of antidepressants depend on hippocam-
pal neurogenesis [112]. Although disruption of the neurogenesis
process does not fully explain the etiology of depression, yet
it may account partly for the associated cognitive impairments
as altered cholinergic transmission can reduce neurogenesis and
subsequently induce learning and memory deficits. Changes in
hippocampal neurogenesis are thus thought to contribute to
the hippocampal aspects of major depression. The hippocam-
pus plays a major role in declarative (explicit) memory function
[113–115]. People who suffer from major depression exhibit
memory deficits that are characteristic of hippocampal damage
[116,117]. In a subset of depressed subjects, reduced hippocam-
pal volumes have also been related to functional consequences,
such as depression-specific neurocognitive deficits [116,118,119].
Reduced hippocampal neurogenesis has been suggested as a final
common pathway in many brain disorders associated with mood
[106] and cognitive dysfunction, such as geriatric depression and
the depression-mild cognitive impairment (MCI)–dementia com-
plex [4]. Since acetylcholine regulates neurogenesis, changes in
new neuron production may follow the more global changes in the
cholinergic system. Depression-associated cognitive and memory
deficits may thus represent potential clinical correlates of impaired
cholinergic transmission and altered hippocampal neurogenesis
[6,117].
A major predisposing factor to depression, chronic stress,
induces damage to hippocampal structure and function in animal
models [79,120,121]. Besides affecting the cholinergic system, it
decreases hippocampal neurogenesis, and impairs hippocampal-
dependent learning and memory [108,122,123]. Accumulating
evidence supports a relationship between hippocampal neuroge-
nesis and various types of learning and memory [124]. It remains
unknown, however, whether hippocampal neurogenesis is causally
578 G.. Dagytė et al. / Behavioural Brain Research 221 (2011) 574–582
implicated in memory function [122,125–128]. It seems unlikely
that changes in hippocampal neuron production would have an
immediate effect on processes underlying learning since the newly
born cells require time to differentiate into functional neurons
and become integrated into the pre-existing circuitry [124,129].
Therefore, although stress may diminish hippocampal cell pro-
liferation, it may not necessarily induce acute learning deficits
on hippocampus-dependent tasks [130]. It has been suggested
that hippocampal neurogenesis underlies remote, rather than
recent, memory formation, although contradicting evidence exists
[127,131]. Alternatively, adult dentate neurogenesis has been pro-
posed to play a role in periodic clearance of outdated hippocampal
memory traces [127,132]. This notion has been supported by
a recent study demonstrating that suppressed neurogenesis in
rodents is accompanied by a prolonged hippocampus-dependent
period of associative fear memory [131]. Reduced neurogenesis
might thus hinder erasure of the hippocampal memory trace and
its transfer to the neocortex. Such impaired clearance of old dis-
used memories from the hippocampus could in turn compromise
its learning capacity and affect the formation of long-term memory.
In view of the above, presumed chronic impairment of hippocam-
pal neurogenesis in depression may at least partly account for
development of hippocampal dysfunction leading to cognitive and
mnemonic deficits.
Taken together, alterations in the central cholinergic system
could affect adult neurogenesis and hippocampal function, giving
way to depression-associated memory deficits. However, besides
the explicit memory dysfunction, depressed patients often show
a more widespread impairment in cognitive function, deficits in
attention and working memory [35–37], suggesting that dysfunc-
tions are not focally localized to the hippocampus, but may be
present more globally.
3.4. Involvement of the cholinergic system in depression: beyond
the hippocampus
Although major depressive disorder is associated with func-
tional impairment of multiple brain regions, the hippocampus has
been the preferred region of investigation. Such bias may have
occurred due to the discovery of hippocampal neurogenesis and
its linkage to depression, as well as due to the fact that hip-
pocampus is highly enriched with glucocorticoid receptors and is
severely affected by stress. Nevertheless, the structural and func-
tional changes associated with depression point to the involvement
of several other brain regions in addition [93]. Here, we limit our
discussion to a selected few. First, we will address the potential
role of the cholinergic system in depression-associated changes in
the prefrontal cortex and amygdala. Then, we will briefly discuss
the cholinergic input to the SCN, the regulator of circadian rhythms
shown to be often disturbed in depression.
Importantly, both the prefrontal cortex and amygdala receive
vast cholinergic input, suggesting a vital role for acetylcholine in the
modulation of their function [84,96,97]. Moreover, cognitive symp-
toms accompanying depression often reflect dysfunctions in these
limbic structures [37]. For instance, depressed individuals show
deficits in executive function, such as impaired performance in tests
of attention and working memory, which relate to structural abnor-
malities often observed in the prefrontal cortex during depression
[133]. Different subregions of the prefrontal cortex are suggested
to contribute to diverse symptoms of depression, and their role
has been previously reviewed [134]. Post-mortem analysis suggests
a causal role for altered muscarinic receptor expression, partic-
ularly in the dorsolateral prefrontal cortex of depressed subjects
[33]. Potential cholinergic involvement of the prefrontal cortex in
the cognitive dysfunctions of affective disorders is further substan-
tiated by a preclinical study reporting cognitive deficits in mice
lacking M2 muscarinic receptors [135].
Cognitive dysfunction in depression is also characterized by
a negativity bias—an enhanced responsiveness to, and memory
for, emotionally negative stimuli, attributed to the impaired func-
tioning of both the prefrontal cortex and the amygdala complex
[136]. Mental rumination is a frequent symptom of depression, and
may depend on hyperactivity of the amygdala leading to enhance-
ment of negative thoughts and memories. Increased activity of
the amygdala has been demonstrated in depressed patients, and
is thought to parallel the suppressed activity of the dorsolateral
prefrontal cortex and dampened hippocampal function [136–138].
Among the heterogeneous nuclei of amygdala, the basolateral
amygdala (BLA) is especially important since it serves as an inter-
face between the sensory and cognitive realms [139,140]. Notably,
the BLA is critically involved in the modulation of memory con-
solidation, which is achieved through influences from cholinergic,
noradrenergic and other brain systems [141]. The BLA is abun-
dantly innervated by cholinergic neurons, originating mainly from
the nucleus basalis of the forebrain [96,97,142–144]. In laboratory
animals, experimental suppression of this cholinergic transmis-
sion by lesion of the nucleus basalis or intra-amygdalar infusion
of muscarinic antagonists impairs memory for various learning
tasks. Conversely, intra-BLA infusion of muscarinic agonists or
AChE inhibitors enhances memory or attenuates its impairment
[145–147]. These findings suggest that cholinergic activity is essen-
tial for amygdalar modulation of memory consolidation [54,148].
Glucocorticoids also play a role in the consolidation of learning
experiences, and the BLA is critically involved in their memory-
modulating effects [149–151]. Glucocorticoids as well as stress
have been shown to change structure and function of the BLA,
resulting in hypertrophy and increased excitability [152,153]. Asso-
ciated impairments in working memory are attributed to the
interaction of the hyperactive BLA with the medial prefrontal cor-
tex [153,154]. The functional consequences of increased amygdala
influence on thoughts and emotions are however not possi-
ble to adequately assess in preclinical research models. Yet, the
stress and depression-associated prefrontal cortical and amyg-
dalar dysfunctions may be due, at least in part, to altered activity
of the cholinergic system, given its strong projections to these
areas.
The SCN, situated in the anterior hypothalamus, receives direct
cholinergic input from the nucleus basalis of the forebrain and
is responsible for controlling circadian rhythms [155–157]. Clini-
cal findings suggest that many diverse rhythms can be disrupted
in depression, including the 24-h profiles of various hormones,
neurotransmitters, body temperature as well as sleep architec-
ture and timing [158,159]. Given the cholinergic input to the SCN,
such depression-associated disturbances of internal rhythms and
sleep-wake cycle may at least partly arise from changes in the
cholinergic system. In fact, impaired cholinergic transmission has
recently been linked to disruptions in melatonin production, sleep-
wake cycle and other circadian rhythms in Alzheimer’s disease
[160]. Cholinergic regulation of the SCN has also been implicated
in cognitive processes [161]. As depression often accompanies
or even precedes the Alzheimer’s disease, similar changes may
underlie both pathologies [162]. Recognition that desynchroniza-
tion of circadian rhythms also plays an important role in depression
has led to the development of the first melatonergic antidepres-
sant, agomelatine [157,159,163]. Besides being a potent agonist
of the melatonergic (MT1 /MT2 ) receptors, agomelatine also acts
as an antagonist of the serotonergic (5-HT2C ) receptors [164,165].
This novel drug combines antidepressant efficacy with beneficial
effect on sleep quality, achieved via synergy between the mela-
tonergic and 5-HT2C receptors, highly expressed in the SCN and
limbic brain areas [163]. Preclinical studies have already demon-
 G.. Dagytė et al. / Behavioural Brain Research 221 (2011) 574–582
strated a variety of agomelatine-mediated changes on neural
plasticity [166–168], including its beneficial action in the stress-
compromised brain [169]. However, the effects of agomelatine on
the cholinergic transmission are not yet known and await future
investigation.
4. Conclusion and future directions
Dysfunctions in the cholinergic system alone do not fully explain
the etiopathophysiology of major depressive disorder, but they
represent likely contributors to its wide spectra of associated symp-
toms, particularly those involving cognition. Acetylcholine plays an
important role in regulation of hippocampal neurogenesis, believed
to be involved in the pathophysiology and treatment of depres-
sive disorder. Alterations in the central cholinergic system may
thus affect adult neurogenesis and hippocampal function, leading
in turn to the cognitive deficits observed in depression. Besides the
hippocampus, cholinergic neurons from the basal forebrain also
project to other brain structures implicated in depressive disorder.
Therefore, cholinergic changes may also account for depression-
associated circadian rhythm desynchronization as well as cognitive
symptoms related to the functions of such structures as the pre-
frontal cortex and amygdala. Future research is needed to elucidate
more precise cholinergic changes that underlie depression, but as
cholinergic drugs continue to modify cognitive deficits character-
istic of this disorder, application of these neuropharmacological
findings may provide a new therapeutic niche while yielding valu-
able insight into the pathophysiology of this complex illness.
In conclusion, the cholinergic system plays a considerable, albeit
poorly recognized, role in major depression-associated cognitive
dysfunctions (see Fig. 1). Yet, the cholinergic system represents
merely one of many players involved in this severe illness. The
complex interaction of multiple factors and neurobiological sys-
tems is thought to underlie the intricate changes associated with
depressive disorder, in a variety of brain areas. Future research
can thus greatly benefit from an integrated approach in attempts
to elucidate the interaction among diverse factors of depression,
rather than focusing on changes of one neurobiological system.
Such cohesive knowledge might not only shed light on the more
poorly understood aspects of this disorder but also pave the way to
development of novel multifaceted therapies against it.
Acknowledgment
We are grateful to Prof. Eddy Van der Zee for his helpful com-
ments.
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