Behavioural Brain Research 412 (2021) 113410

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Behavioural Brain Research

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

Stress, memory, and implications for major depression

Geovan Menezes de Sousa Júnior a, b, Hector David Quinones Vargas a, b,
Flávio Freitas Barbosa c, d, Nicole Leite Galvão-Coelho a, b, e, *
a
Laboratory of Hormone Measures, Department of Physiology & Behavior, Federal University of Rio Grande do Norte, Natal, Brazil
b
Postgraduate Program of Psychobiology, Center for Biosciences, Federal University of Rio Grande do Norte, Natal, Brazil
c
Laboratory of Studies on Memory and Cognition, Department of Psychology, Federal University of Paraíba, João Pessoa, Brazil
d
Laboratory of Psychopharmacology, Federal University of Paraíba, João Pessoa, Brazil
e
National Science and Technology Institute for Translational Medicine, São Paulo, Brazil

A R T I C L E I N F O A B S T R A C T

Keywords: The stress response comprises a phylogenetically conserved set of cognitive, physiological, and behavioral re­
Memory systems sponses that evolved as a survival strategy. In this context, the memory of stressful events would be adaptive as it
Stress could avoid re-exposure to an adverse event, otherwise the event would be facilitated in positively stressful or
Depression
non-distressful conditions. However, the interaction between stress and memory comprises complex responses,
Cortisol
Catecholamines
some of them which are not yet completely understood, and which depend on several factors such as the memory
system that is recruited, the nature and duration of the stressful event, as well as the timing in which this
interaction takes place. In this narrative review, we briefly discuss the mechanisms of the stress response, the
main memory systems, and its neural correlates. Then, we show how stress, through the action of its biochemical
mediators, influences memory systems and mnemonic processes. Finally, we make use of major depressive
disorder to explore the possible implications of non-adaptive interactions between stress and memory to psy­
chiatric disorders, as well as possible roles for memory studies in the field of psychiatry.

1. Introduction memory formation, storage, and retrieval in several different ways,

Both stress and memory are markedly present both in our phyloge­
netic history, as well as in our daily lives, guiding behavioral responses
and aiding survival. These are complex physiological processes that
depend on context, prior experiences, and the interaction between these.
The stress response is mainly guided by the sympathoadrenalmedullary
system and the hypothalamic-pituitary-adrenal axis, along with the
contribution of immune and metabolic systems. It promotes a physio­
logical, behavioral, and cognitive response which is highly adaptive [1].
The stress response influences the recruitment of memory systems,
depending on the duration and timing of stress, for instance, but also on
the operational phase of memory [2]. Nevertheless, a long-lasting stress
response can be harmful and may be involved in the development of
psychopathological conditions that have an impact on memory pro­
cesses, such as major depression [3]. Memory disruptions, primarily in
autobiographical and working memory, are a symptom of major
depression commonly used for diagnosis that may remain as a residual
symptom after remission [4,5]. In this narrative review, we aim to
outline the physiological basis of both the stress and memory systems,
and to overview the main findings regarding their adaptive and

Abbreviations: ACTH, adrenocorticotropic hormone; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BDNF, brain-derived neurotrophic
factor; BLA, basolateral amygdala; CA1,2,3, cornus amonis 1,2,3; CREB, cyclic AMP response element binding; CRH, corticotropin releasing hormone; DA, dopamine;
DG, dentate gyrus; dlCPF, dorsolateral prefrontal cortex; DNA, deoxyribonucleic acid; EC, entorhinal cortex; FKBP5, FK506 binding protein 51; GABA, γ-amino­
butyric acid; GC, glucocorticoid; GR, glucocorticoid receptor; GRE, glucocorticoid response element; HPA, hypothalamus-pituitary-adrenal axis; ilCPF, infralimbic
prefrontal cortex; LC, locus coeruleus; LTM, long-term memory; LTP, long-term potentiation; MR, mineralocorticoid receptor; NA, noradrenaline; NMDAR, N-methyl-
D-aspartate receptor; NTS, nucleus of the solitary tract; p75NTR, pan-neurotrophin receptor 75; PFC, prefrontal cortex; POMC, proopiomelanocortin; PVN, para­
ventricular nucleus of hypothalamus; sANS, sympathetic division of the autonomic nervous system; STM, short-term memory; TrkB, tropomyosin receptor kinase B;
TRD, treatment-resistant depression; vmCPF, ventromedial prefrontal cortex; VTA, ventral tegmental area; WM, working memory.
* Corresponding author at: Universidade Federal do Rio Grande do Norte, Departamento de Fisiologia & Comportamento, Caixa Postal, 1511, 59078-970, Natal,
RN, Brazil.
E-mail address: nicole.galvao@ufrn.br (N.L. Galvão-Coelho).

https://doi.org/10.1016/j.bbr.2021.113410
Received 12 October 2020; Received in revised form 4 June 2021; Accepted 6 June 2021
Available online 9 June 2021
0166-4328/© 2021 Elsevier B.V. All rights reserved.
G.M. Sousa Júnior et al.
disrupted interactions, considering the type and phase of memory, and
the duration of stress (acute or chronic). We also use major depressive
disorder to illustrate some of these maladaptive interactions.
2. Stress response
When faced with a challenge or situation that disrupts homeostasis
and/or threatens survival – that is, a stressor – a set of physiological,
behavioral and cognitive changes are triggered, in order to prepare the
individual for an adequate performance regarding the resolution of the
stressor and subsequently, reestablish homeostatic patterns [6,7]. The
rapid response to stress, named by Hans Selye as the alarm phase, in­
cludes the mobilization and targeting of energetic compounds to brain
and skeletal muscles, which is essential to promote, respectively,
cognitive and physical readiness to the individual [6]. This is possible
thanks to the sympathetic division of the autonomic nervous system
(ANS), which increases cardiorespiratory function and inhibits insulin
secretion, as well as trigger the release of catecholamines (adrenaline
and noradrenaline) by the adrenal glands, to promote a diffuse systemic
physiological response [7]. In addition, catecholamines modulate the
immune system, stimulating the innate immune system’s readiness [8].
At the central level, cognitive arousal is mainly mediated by the
noradrenergic activity of the brainstem nuclei locus coeruleus (LC) and
nucleus of the solitary tract (NTS). These nuclei stimulate the release of
corticotropin-releasing hormone (CRH) by the parvocellular cells of the
paraventricular nucleus of the hypothalamus (PVN) into the hypophy­
seal portal system. The CRH reaches the anterior pituitary and induces
the release of adrenocorticotropic hormone (ACTH). ACTH is synthe­
sized from pro-opiomelanocortin peptide (POMC) and secreted by cor­
ticotropic cells in the systemic circulation, where it reaches the adrenal
glands and stimulates the synthesis and release of glucocorticoids (GC)
[9].
The main active glucocorticoid found in humans is cortisol, a
cholesterol-derived steroid hormone which rises in plasma approxi­
mately 15 min after a stressful event, initiating the second phase of the
stress response - the resistance phase [6,10]. In the context stress
response, this neuroendocrine loop, the hypothalamus-pituitary-adrenal
axis (HPA), is responsible for the maintenance of the physiological
changes primarily activated by the ANS and modulates other body sys­
tems, including the adaptive immune system and the inhibition of the
reproductive system [7,11,12]. Cortisol also crosses the blood-brain
barrier and acts on brain areas related to emotions and cognition,
such as the amygdala, the hippocampus, and the prefrontal cortex [13].
The HPA axis is the main endocrine response to stress, since it sustains it
for an indefinite period, as long as the stressor is maintained [7,10].
Cortisol acts by binding to two receptors: type I or MR (mineralo­
corticoid receptor) has a high affinity for cortisol and is mainly
responsible for the circadian functions of GCs, and type II or GR
(glucocorticoid receptor) has less affinity and mediates the effects and
termination of the stress response [14,15]. Classically, these receptors
have been known to have an intracellular distribution and stimulate
genomic responses, although nowadays the existence of G
protein-coupled versions of these receptors on the cell membrane is also
known, mediating rapid non-genomic and indirect genomic responses
[16–18]. The membrane-bound receptors show low affinity for cortisol
and participate in the stress response [19].
The canonical (intracellular) glucocorticoid receptors are transcrip­
tion factors that, in the absence of a ligand, have their nuclear locali­
zation sequence blocked by chaperone proteins [20]. The binding of the
GC to the receptor induces the dissociation of the chaperones, so that the
GC-receptor complex can be translocated to the nucleus, where it is able
to directly interact with DNA, – in regions responsive to glucocorticoids
(GRE, glucocorticoid response element) [21] – or indirectly, through
protein-protein interactions (tethering), for instance, with transcription
factors (see [22] for an in-depth discussion). Among the genes regulated
by GC in the brain, some are related to plasticity and synaptic
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Behavioural Brain Research 412 (2021) 113410
strengthening [17,23] and the synthesis of neurotransmitters [17,24,25]
in key areas for memory and other executive functions.
It is expected that the activation of the ANS and HPA axis promotes
an adaptive response that leads to the resolution of the stressor agent
while still in the resistance phase. Thus, the shutdown of the stress
response begins, by a cortisol-induced negative feedback on the HPA
axis, specifically in the hypothalamus and anterior pituitary. Typically,
this negative feedback occurs through a slow genomic mechanism
(delayed response). The intracellular hormone-receptor complex is
translocated from the cytoplasm to the nucleus, where it may, for
instance, decrease the transcription of crh and pomc genes, and increases
the transcription of the fkbp5 gene. Fkbp5 regulates the transcription of
the FKBP5 protein (or FK506 binding protein 51), a class of chaperone
that prevents the binding of GC to their receptors and, consequently, the
triggering of their response, comprising an ultrashort negative feedback
loop on the HPA axis [26].
Recently, a fast negative feedback, mediated by retrograde signaling
of endocannabinoids has been elucidated [27,28]. In the PVN, binding
of the GC to the membrane GR receptor induces the synthesis of endo­
cannabinoids, which diffuse through the postsynaptic neuron membrane
and act in inhibitory receptors at the presynaptic terminal to reduce CRH
secretion, for instance [27]. In addition to the delayed and fast negative
feedback, the HPA axis is also modulated at the PVN level by cortico­
limbic and brainstem areas, through transsynaptic neural pathways. The
PVN is inhibited by the ventral hippocampus [29,30] and the prelimbic
(dorsomedial region) prefrontal cortex [31,32], while it is stimulated by
the amygdala [33], infralimbic (ventromedial region) prefrontal cortex
(as it projects to sites of excitatory inputs to PVN [32,34]) and LC [35].
The termination of the HPA axis after the stressful event is as
adaptive as its activation. The acute stress response (alarm and resis­
tance phases) is essential for survival [6]. However, the inability to
finish the stressor may lead to the third phase of the stress response: the
exhaustion phase [6]. In this phase there is a dysregulation of the ac­
tivity or reactivity of the HPA axis, which may be associated with
pathological conditions such as cardiovascular, autoimmune diseases,
type II diabetes mellitus, as well as some psychiatric disorders, such as
unipolar and bipolar depression, post-traumatic stress disorder and
anxiety disorders [1,36].
3. Memory systems and stress
The knowledge obtained from the study of amnesic patients as a
result of injuries in regions of the medial temporal lobe contributed to
the elucidation that memory is not unitary. Also, the use of animal
models for the study of memory and the search for the engram (i.e., the
physical trace of memory in the brain) allowed the identification of
multiple memory systems and key structures regulating such systems
[37,38]. However, memory should not be thought of as the confined
activity of a brain region, but as neural circuits distributed across the
brain, that allow different memory systems to coordinate the several
behavioral responses essential for daily life [39,40].
In this way, memory has been classified, in terms of its nature, into
two types: The first is explicit memory, the memory of facts and events,
which can be expressed by language and is a conscious process in
humans. In contrast, the second type, implicit memory, includes a set of
other types of memory in which consciousness is not needed for their
expression, such as emotional memory, priming, conditioning, habits,
motor skills, habituation and sensitization [37,41].
Another categorization of memory is made regarding its duration.
Short-term memory (STM) is responsible for storing information for
seconds to hours, allowing the efficient execution of activities or goals; it
is conscious, limited and very vulnerable to interference [42]. In the
field of cognitive neuroscience, this terminology has been overwritten
by the working memory model [43,44], which is the reason why we will
address it in this review. Such a model is ahead of the passive storage of
information in the short-term, as according to the concept of STM, to be
G.M. Sousa Júnior et al.
also able to actively manipulate and update such information [45].
Long-term memories (LTM), on the other hand, are those from which we
can recall, consciously or not, the information retained for more than six
hours [46,47].
In an attempt to provide an alternative to conscious/non-conscious
retrieval-based classification, some other models have been proposed,
although an in-depth discussion on this topic is outside the scope of this
review, we suggest ref [48] for a full review. Since the model that dis­
tinguishes between explicit and implicit memory is well-established, and
studies of the influence of stress on mnemonic processes usually use
terminologies from this model, we make use of this traditional model,
addressing different topics such as working memory (as a synonym for
short-term memory) and long-term memories, as constituted by explicit
and implicit memories.
3.1. Working memory
The term working memory (WM) is used to designate the conscious
maintenance and manipulation of relevant transient information during
the performance of a task that requires the use of complex executive
functions [43]. WM has a limited capacity for manipulating information
and can work independently of long-term memories (LTM), however,
once its capacity is exceeded, the LTM contribute to the action that was
being performed by WM [49]. Animals whose prefrontal cortex (PFC)
has been injured or surgically cooled present losses in the performance
of delayed response tasks, placing the PFC as a possible region of
working memory processing [50]. The prefrontal cortex is a phyloge­
netically recent area of the neocortex, located in the anterior portion of
the frontal lobe, and is related to executive functions, top-down control
(visceral and emotional regulation), preparation in response to envi­
ronmental conditions (preparatory set), and inhibitory control [51].
Working memory can be divided into four subsystems: visuospatial,
verbal, episodic buffer, and central executive control [43]. Visuospatial
WM comprises the components of spatial knowledge and object recog­
nition, which depend on the connections between the PFC and the pa­
rietal and temporal cortex, respectively [52]. The verbal subsystem, also
called phonological loop, maintains representations of spoken language;
although its underlying circuitry is not well understood, it is known that
it depends on the temporal and prefrontal cortices [53,54]. The episodic
buffer combines sensory modalities and allows interaction with
perception or long-term memory [43,55]. The subsystems are regulated
by an executive control center, also in the PFC, which allocates and
directs energy and attention to the subsystems [56].
PFC activity is mediated by glutamate and its receptors, mainly
NMDAR (N-methyl-D-aspartate receptor), and modulated by diffuse
projections, especially dopamine (DA) and noradrenaline (NA) [57,58].
The noradrenergic activity under the PFC occurs in an inverted U-shape
manner, mediated by the affinity to its receptors. At moderate levels, NA
binds to postsynaptic α2A receptors, preventing membrane hyperpo­
larization; therefore, it enhances the transmission of the nerve impulse.
However, in excess, NA binds to postsynaptic α1 receptors, inducing
hyperpolarization and weakening the synapse. The PFC hypofunction
that results due to this weakening of the synapse may impair working
memory [57,59].
The dopaminergic activity in the PFC is mediated mainly by the D1
receptors’ family (D1 and D5) and, just as NA, it has an inverted U-shape
response [60]. DA acts mainly by inhibiting neurons whose transmitted
information is irrelevant to the main mnemonic information that must
be maintained during the delay phase (when the mental representation
of a stimulus in its absence takes place) of a working memory task [60],
acting as an inhibitor of noise or distractors, helping to focus attention.
3.1.1. Stress and working memory
The evidence of the effects of acute stress on WM are mixed, with
studies pointing out either impairment [61,62] or increase in working
memory performance [25,63]. Possible determinants of such contrasting
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Behavioural Brain Research 412 (2021) 113410
results may be the time between the onset of stress and the assessment of
working memory (the longer the time, the greater the impairment), sex
(stronger impairment in men) and controllability over a stressor
(impairment when the stressor is uncontrollable) [59,64].
The phasic release of catecholamines during acute stress accentuates
glutamatergic neurotransmission in the PFC mediated by α2A adren­
ergic receptors, which reduce membrane hyperpolarization [59,65].
Then, the initial actions of glucocorticoids reinforce the release of PFC
glutamate, potentiating AMPA (α-amino-3-hydroxy-5-methyl-4-isoxaz
olepropionic acid receptor) and NMDA receptors ionic currents, as well
as inducing the expression of AMPA subunits and its traffic to the
postsynaptic membrane, via genomic and non-genomic mechanisms
[25,63,65]. Therefore, these initial actions induced by the stress
response would improve WM by enhancing PFC functioning.
However, it is important to highlight that, according to nonhuman
animal studies, even acute stress, if uncontrollable, may weaken PFC
synapses, causing impairments to working memory. In this context, the
release of catecholamines becomes tonic in the PFC. Thus, NA in excess
binds to low affinity receptors (α1), which weaken noradrenergic
neurotransmission due to the hyperpolarization of the postsynaptic
membrane [66]. The noise inhibition promoted by DA becomes unre­
stricted, leading to the weakening of glutamatergic synapses, also due to
hyperpolarization, which makes it difficult to propagate the post­
synaptic excitatory potential and therefore, impairs PFC-dependent ac­
tivities [59,67].
These contrasting effects of acute stress are also expressed at WM
subsystems levels, where reports show both loss of visual and verbal
working memory, mainly at high loads [61,68,69], but also improve­
ments [70].
Regarding the effects of chronic stress on WM, studies are clear in
pointing out the negative relationship between them, which is mediated
by high levels of cortisol [68,71,72]. The PFC is overly sensitive to
hypercortisolemia, with morphological changes such as the reduction of
dendrites and dendritic spines [73,74]. In this context, glutamatergic
transmission is buffered by an increase in GABAergic transmission in the
rodent prefrontal infralimbic cortex (ilPFC) [72,75,76]. During acute
stress, the interneurons that reduce the activity of ilPFC are inhibited via
the GR. In chronic stress such regulation is lost, due to high levels of
glucocorticoids that result in the downregulation of GR in parvalbumi­
nergic interneurons. In this sense, there is greater interneuron activity,
and consequently, inhibition of ilPFC pyramidal cells, which leads to
prefrontal hypofunction not only in this region, but also in pre-limbic,
lateral, and orbitofrontal regions [77–81]. Such changes are associated
with a loss in working memory and other executive functions dependent
on the PFC [75].
3.2. Long-term memory
Long-term memory is commonly divided into explicit and implicit
memories. Explicit memory allows the retrieval of facts and events that,
in humans, requires consciousness and can be expressed by language.
The memory of facts is also called semantic memory, as it consists of
knowledge about words and their meanings; while the event memory is
called episodic, as it represents personal experiences [44]. Implicit
long-term memory, on the other hand, is all non-explicit memory, which
can be expressed through behavior, and is difficult to verbalize, such as
emotional and motor memories. These can be either non-associative,
when learning results from a single stimulus (habituation and sensiti­
zation), or associative, when learning results from the association of two
stimuli (conditioning). Moreover, priming, which is the ability to un­
consciously access items to which the individual was previously
exposed, is also a form of implicit memory. An important feature of
implicit memories is their unconscious and automatic recall [44,82].
For LTM formation, three processes or operational phases are
required: acquisition, storage, and consolidation. Acquisition or
encoding consists of capturing, processing, and coding information into
G.M. Sousa Júnior et al.
neural signals. Memory storage happens through the association of new
information with already existing ones by means of cell assemblies in a
neural circuitry. The stored memory can then be consolidated (con­
nections are functionally and structurally strengthened) or forgotten
(connections are weakened or lost) [83].
For a memory to be consolidated, retention in the form of short-term
memory is not necessarily required, at least for some explicit memories,
as assessed by the inhibitory avoidance task [84]. Memory consolidation
is facilitated by repetition, by association with previously consolidated
information, or according to the emotional content associated with the
mnemonic information in question. Although both types of LTM, explicit
and implicit, are subject to forgetfulness, the latter is less flexible and,
therefore, less vulnerable to modifications and forgetfulness [85].
Finally, a fourth phase of LTM is retrieval, which consists of later
access to the previously consolidated memories. Retrieving a memory
makes it labile and susceptible to interference, requiring a new consol­
idation of reactivated memory to stabilize it, a process called reconso­
lidation [86,87].
3.2.1. Explicit and implicit memories
The neural substrate of semantic memory, a long-term explicit
memory, is distributed throughout the cortex, including the lateral and
ventral temporal cortex, the inferior parietal lobe, in addition to the
interactions of these areas with the prefrontal cortex [88]. The biological
substrate of episodic memory, in turn, depends on interactions between
the prefrontal cortex and the medial temporal lobe [89].
Much of the cellular and molecular mechanisms of explicit memory
are known thanks to the study of the hippocampus and anatomically
adjacent areas. The hippocampal formation is located inside the medial
temporal lobe, and is composed of the hippocampus (CA1, CA2, CA3),
dentate gyrus (DG), subicular complex and entorhinal cortex (EC) [89].
The hippocampal formation is peculiar since it has a unidirectional tri­
synaptic pathway: the EC projects to the DG (perforant pathway), which
in turn, projects to CA3 (mossy fibers) and from there to CA1 (Schaffer
collateral). CA1, in turn, projects to the EC and subiculum. In addition,
CA3 has intrinsic connections and projects back to the DG. The EC
projects towards neocortical areas and the adjacent perirhinal and
parahippocampal (postrhinal in rodents) cortices [89]. Therefore, it is
possible to notice that the EC is both the main afferent and efferent
hippocampal pathway [90]. Not only the hippocampus itself but other
medial temporal lobe regions, such as perirhinal and parahippocampal
cortices, support different aspects of explicit memory [91]. However, we
will focus here on the proposed hippocampal cellular mechanisms sup­
porting explicit memory since it has a solid underlying literature.
Memory storage mediated by the hippocampus initially consists of
changes in the hippocampal circuit’s synaptic activities through long-
term potentiation (LTP). LTP is a special excitatory postsynaptic po­
tential resulting from a high frequency presynaptic stimulation associ­
ated with a long-lasting postsynaptic depolarization, which is translated
into neural plasticity with associative and long-lasting characteristics
[92]. LTP is well characterized in the hippocampal circuitry, where at
least two types of LTP are identified: one NMDAR-dependent (on
Schaffer collateral synapses), and another (on mossy fibers synapses)
that is independent of this receptor, mediated by voltage-dependent
Ca2+ channels and metabotropic glutamate receptors [93,94].
The concurrent activation of AMPAR and NMDAR leads to Ca2+
influx. The downstream effect of Ca2+ will activate several intracellular
signaling pathways, ultimately initiating the LTP’s protein synthesis
phase, responsible for the functional strengthening and, later, the
structural synaptic transmission. One of the key genes in this process is
bdnf, that encodes the brain-derived neurotrophic factor (BDNF), a
neurotrophin involved in several aspects of synaptic plasticity, that
range from the potentiation of function and the modulation of excitatory
neurotransmitters and receptors, to ultrastructural changes in the syn­
apse [95], making long-term changes on the synapse [96,97]. Therefore,
BDNF has a role on explicit memory consolidation, since blocking its
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Behavioural Brain Research 412 (2021) 113410
signaling impairs memory retention, as well as infusing it is able to
recover such impairments [46,98].
Currently, it is known that there are two biologically active isoforms
of BDNF: pro-BDNF (molecule with the pro domain still attached) and
mature BDNF (mBDNF, whose pro domain has been cleaved). Pro-BDNF
has higher affinity to the pan-neurotrophin receptor 75 (p75NTR), which
can lead to neuronal death, while mBDNF has higher affinity to the TrkB
receptor, that induces neuronal survival [95]. TrkB-mediated signaling
is required for LTP and hippocampal neurogenesis; consequently, it is
implicated in mnemonic processes [99–102]. Recently, it has been
shown that after cleavage of proBDNF, the pro domain (or pro-peptide)
has biological activity, activating p75NTR receptors [103,104].
Therefore, the repeated stimulation of a circuit by a given stimulus,
strengthens its functioning through LTP, and with the persistence of the
stimulus, induces structural changes in the synapses of this circuit; a
process that has been considered the cellular correlate of memory for­
mation [105].
Habits are a motor memory based on a trial-and-error behavioral
response, and, like other motor memories, it requires repetition for
learning [44]. Habits are valuable in the interaction between stress and
memory and here they will be approached as an example of long-term
implicit memory.
Initially, habits are susceptible to the value of the reward and the
effort-reinforcement, which is then developed when the balance is
positive. This type of motor memory, like the others, is rigid, automatic,
and repetitive [44,106]. Electrophysiological studies in animals show an
important and distinct participation of the striatum in the acquisition
and performance of habitual learning. Dopaminergic circuits between
the ventral striatum, the ventral tegmental area (VTA), and GABAergic
nigroventral-tegmental circuits, are related to the assessment of the
reward value of motivated (goal-directed) behaviors [106]. As the
behavior is repeated and the balance is positive, there is a transition in
the engagement of the ventral striatum to the dorsomedial striatum; at
the post-learning (i.e., when habitual memory is learned) there is the
participation of the dorsolateral striatum [106], which acts simulta­
neously with the infralimbic prefrontal cortex, necessary for both
forming and performing a habit in real time [44]. In humans, however,
the participation of striatum subregions is not well established [107,
108].
Moreover, the reciprocal communication between the cortex, basal
ganglia, and cerebellum contributes to the formation of motor memory,
recruiting different neural networks according to the stages of sequential
learning [92]: initially learning based on exploration or trial and error
(recruitment of vmPFC, ventral striatum and posterior cerebellum), then
recruiting the associative network (dlPFC, dorsomedial striatum and
lateral posterior cerebellum). Finally, after the establishment of the
habit or skill (formation of motor memory), the motor network (sup­
plementary motor area, putamen, and anterior cerebellum) is then
recruited [109,110].
Emotional memories are often studied in animals using a fear con­
ditioning paradigm, where an aversive stimulus (US, unconditioned
stimulus) is regularly paired with a neutral one (CS, conditioned stim­
ulus), generating a fear of the CS even in the absence of the US (CR,
conditioned response) [111], which may be expressed as the animal
freezing response. The amygdala nuclei are core to the processing, for­
mation, and expression of fear conditioning, as reviewed elsewhere
[111–114]. In humans, fear conditioning relies on similar brain regions
[115], but it is frequently assessed by the skin conductance response and
the startle reflex [116,117]. Central NA (via LC), and peripheral
adrenaline (via vagal-NTS signaling) [118], play a central role in
modulating fear conditioning, acting directly on the amygdala and on
brain areas related with amygdala regulation, such as PFC and hippo­
campus [119]. Amygdala-dependent memory is also an important
moderator for other memory systems, such as explicit memory. The
processing of contents’ valence and arousal are amygdala-dependent
and may change the direction of memory, mainly mediated by the
G.M. Sousa Júnior et al. Behavioural Brain Research 412 (2021) 113410

noradrenergic activity [111].
3.2.2. Stress and the long-term memories
The influence of stress on LTM is dependent on several factors, such
as: the timing when the stressor event is experienced (that is, before,
during or after the task/learning), the emotional valence of the event
(neutral, positive, or negative), and the duration of the stressful event
(acute or chronic).
The acute stress can impair explicit LTM acquisition when the in­
terval between the stressor and the task is too long (that is, outside the
context of learning): the longer the interval, the greater the impairment,
as suggested by a meta-analysis of human studies [120] (Fig. 1).
Nevertheless, when acute stress is experienced in the context of learning,
that is, in the acquisition of information and prior to the consolidation of
memory, these memory operations are facilitated [120] (Fig. 1). How­
ever, we shall notice that this is true only when the items assessed by the
task show some relationship with the stressor event (i.e., they are
important for the response) [120].
Acute stress during acquisition or consolidation, free of the genomic
effects of GC, enhances memory consolidation through catecholamines
actions, with a substantial role for β receptor-mediated noradrenergic
activity in the BLA [121–124] (Fig. 1). Therefore, memories with
emotionally arousal content, positive or negative, are easily consoli­
dated, as compared to neutral ones, mediated by NA signaling
[125–127]. Furthermore, the GR-activated intracellular pathways in
acute stress recruit and increase BDNF signaling, that also has a role on
memory formation [98]. However, the relationship between GC and
BDNF is in an inverted U-shape [128,129], brain region-dependent: in
the PFC and in the hippocampus, chronic stress leads to a decrease in
BDNF [102,130], while in the amygdala, high levels of cortisol increase
BDNF expression, dendritic branching, and spinal growth [131–133]. It
is also suggested that BDNF-TrkB signaling is enhanced by an interaction
between GR and TrkB. When excessive, however, glucocorticoids bind to
the GR receptor, decreasing the GR-TrkB interaction and reducing the
downstream BDNF signaling [128,129].
When acute stress is experienced during retrieval, however, both
genomic and non-genomic effects of GC, via MR, inhibit the enhance­
ment of explicit LTM [134–139]. A proposed explanation points out that
the acquisition of stressor-related contents would suppress the retrieval
of previous content [140] (Fig. 1).
While the interaction between acute stress and explicit LTM depends
on the several factors considered above, chronic stress often tends to
impair explicit memory, whether it occurs before or after learning [102,
141] (Fig. 1). The harmful effects of chronic stress on explicit memory
are explained based on the glucocorticoid cascade hypothesis, in which
chronic exposure to GC would downregulate GR and BDNF in the hip­
pocampus, making it vulnerable and impairing the retrieval of explicit
memories [102,142]. Interestingly, inhibiting GC synthesis or endo­
cannabinoid metabolism prevents memory impairments [143,144].
Regarding implicit memory, acute stress may increase acquisition as
well as consolidation of fear conditioning both in humans [145] and
animals [146] (for review, see [147]), by stimulating the GC-NA inter­
action in the amygdala [148]. In fact, blocking BLA NA signaling with a
β receptor antagonist prevents this memory enhancement, but no loss or
enhancement effect is seen when GC is absent [149], suggesting only a
permissive effect of GC on the noradrenergic activity in the BLA. Con­
cerning memory retrieval, there are some reports of impairment induced
by acute stress on implicit memories both in rodents [150] and humans
[151]. Chronically stressed animals, in turn, seem to have an enhanced
fear memory [152–154], which may be due to the BDNF-induced tro­
phic effects of chronic stress on amygdala, alongside the weakening in
the PFC [148,153–155].
Besides the previously mentioned moderator factors of stress effects
on memory, the observed heterogeneity may also be due to methodo­
logical issues, such as the diversity of tasks and unclear stressor timing
definition. In this sense, this research field would benefit of having
guidelines to provide some standardization regarding the methods and
assessments.
3.2.3. Stress modulation between explicit and implicit memory systems
Several memory systems operate cooperatively or competitively to
guide the behavioral output responsible for our daily actions [156].
Stress is one of the factors that modulate the strategy used (i.e., the
recruited memory system) to perform a certain activity [157]. It is
possible to evaluate this modulation using tasks with a double possibility
of resolution - that is, through a cognitive or habit response -, for

Fig. 1. Stress influence on long-term memory operational phases is mainly dependent on stressor timing. When acute stress happens around learning (immediately
before acquisition or consolidation), noradrenergic (NA) and non-genomic glucocorticoids (GC) enhance explicit and implicit memory formation of the stressful
event, which is further maintained by genomic GC effects. The consolidation and retrieval of stress-unrelated items, however, is suppressed. Moreover, if the interval
of acute stress and learning is too long, the genomic GC effects impair the acquisition of the content. If the acute stress happens in the retrieval context, both NA/non-
genomic and genomic GC effects impair retrieval of explicit and implicit memory, since the brain is on the memory formation mode. Whatever happening before or
after learning, chronic stress often suppresses explicit memory while may enhance implicit memory.

5
G.M. Sousa Júnior et al. Behavioural Brain Research 412 (2021) 113410

instance, with the T-maze.
In this task, the rodent is placed in the center of a labyrinth with four
arms and must learn which arm the reward is on. During learning, a
cognitive strategy, mediated by explicit memory, can be recruited, in
which the individual uses distal spatial clues (allocentric strategy) to
solve the task (for example, memorizing the position of the arm con­
taining the reward in relation to the other or still being guided by clues,
such as objects positioned in the arms of the labyrinth) - or a habit
strategy - implicit memory in which the response is of the stimulus-
response type (for example, if whenever the animal turns right when
starting the task he gets the reward, the command “turn right” is then
associated with the reward; egocentric strategy). To assess which
memory system was recruited during learning, the rodent is placed in a
new point in the labyrinth: if the strategy of navigating through the
labyrinth is used, learning was cognitive (hippocampus-dependent); if
the “turn to the right” strategy was used, learning was habitual (striatal-
dependent) [157,158].
Exposure to either acute or chronic stress appears to modulate the
neural substrates of cognitive and habitual/emotional learning
distinctly. In humans, the weakening of the PFC and the hippocampus,
induced by chronic stress, also weakens the recruitment of cognitive and
instrumental learning to solve a task [159]. The effects of chronic stress
seem to be reflected at the cellular level, in terms of PFC atrophy and
dorsal striatum hypertrophy, as depicted in animal studies [160]. In
addition, weakening of the PFC leads to a loss of top-down regulation,
where the activity of the amygdala and the striatum overlaps the PFC,
inducing a rigid, quick, and instinctive behavioral response (lack of
behavioral flexibility), interfering with decision making [160,161]
(Fig. 2). The activity of the amygdala, mainly the BLA, is increased by
the permissive effect of GC on noradrenergic pathways; together, GC and
NA are essential to orient the action of the striatum [162,163]. When
administered with propranolol, a β receptor antagonist-adrenergic,
recruitment of the striatum is prevented even when there is an infu­
sion of GC [162].
Therefore, chronic stress favors a switch in the use of memory sys­
tems, from a more flexible cognitive memory (dependent on the hip­
pocampus and/or the prefrontal cortex), to a more rigid and instinctive
memory (dependent on the dorsal striatum) (Fig. 2). At first glance, an
inflexible, instinctive, and primitive behavioral response may seem
disadvantageous; however, such a strategy is less energetically expen­
sive than the cognitive one and becomes highly adaptive in contexts
where a rapid response is needed, such as in an ancestral environment,
where the circuits and behaviors underlying the stress response evolved
[38].
4. Stress, memory, and psychiatric implications: major
depressive disorder
Despite the fact that the Diagnostic and Statistical Manual of Mental
Disorders (DSM-5) [5] presents a chapter dedicated to stress-related
disorders, approaching, for instance, acute stress disorder and
post-traumatic stress disorder (PTSD), the relationship between stress
and mood disorders is well established [164–166]. Chronic stress is one
of the main etiologies of Major Depressive Disorder (MDD) [167], of
which impaired memory is part of its diagnosis [5]. Therefore, a better
understanding of memory impairments in MDD and how they are
associated with the chronic stress response can open the doors for its use
as a prognostic and diagnostic tool, as well as in prophylactic and
therapeutic approaches, and treatment follow-up investigations.
The changes in memory presented by depressive patients are mainly
related to long-term explicit memory (autobiographical and episodic
memories) and executive functions [168]. In depressed individuals,
mainly in the most severe cases, a hippocampal volumetric decrease and
suppression of adult hippocampal neurogenesis may occur [169,170].
Poor performance in tasks, such as the Autobiographical Memory Test
[171], and auditory and visual episodic memory tasks [172,173], is also
found and confirmed by meta-analytic results [174]. Moreover, episodic
memory impairments were shown to be correlated with smaller hippo­
campal volume [175]. These structural changes are also observed in
nonhuman animals submitted to chronic stress [176,177] and are
related to impairments on long-term memory [178].
The impairment of executive function, which includes poor perfor­
mance in working memory, attention, and recognition tasks [168,179],
suggests that working memory is impaired both in visuospatial [180,

Fig. 2. Stress duration differently influence the structure and function of key brain regions to processing of memory. Acute controllable stress may enhance synapses
within prefrontal cortex (PFC) as well as hippocampal (HIPP), therefore favoring working memory and long-term memory, respectively. In addition, the PFC top-
down control over the amygdala (AMY) suppresses instinctive and habitual responses mediated by amygdala and striatum (Str), favoring cognitive flexibility,
mediated by HIPP-PFC connection (upper left panel). When uncontrollable or intense, acute stress functionally impair PFC and hippocampal, as well as frontal-
hippocampal connectivity, weakening top-down control and enabling an amygdala-striatal-dependent instinctive response (upper right panel). The persistence of
chronic stress leads to different structural changes in these regions: atrophy in PFC and hippocampus, and hypertrophy in amygdala and striatum. In this context, the
top-down turns into an amygdala-striatal bottom-up control over frontal-hippocampal networks, shifting the memory system recruitment underlying learning to a
non-flexible, instinctive, and stimulus-response dependent habitual learning (lower left panel). Arrow’s thickness denotes connection strength.

6
G.M. Sousa Júnior et al.
181] and auditory [172,182] tasks. More importantly, executive effi­
ciency loss seems to be functionally associated with a decrease in PFC
activity [181,183,184].
In addition, in depressive patients, a stronger retrieval of negative
memories and attentional bias towards negative stimuli is found, while
the retrieval of positive memories is impoverished [168,178,185–187].
Evidence points to a greater activity of the amygdala in face of negative
emotional stimuli, and a blunted response to positive stimuli [151].
Therefore, changes in the processing of emotional memory by amygdala
dysfunction will mediate sensitization to negative stimuli, as well as the
larger retrieval of negative memories, which are both observed in
depression [188].
Changes in the HPA axis are a frequent finding in depressed in­
dividuals. Given the widespread location of the cortisol receptors in
important areas for memory, such as the PFC, hippocampus, and
amygdala, the HPA axis dysregulation may be one of the causes of
cognitive impairments in depressed individuals [166,189,190]. Both
cortisol levels and some genetic polymorphisms of their receptors are
predictors of cognitive performance in depressed patients [166]. Inter­
estingly, there seems to be a specificity between receptor variation and
the type of task, in which variations in GR are normally a predictor of
executive function tasks, while variations in MR generally predict
acquisition and retrieval of long-term memories [166].
Hypercortisolemia, the most frequent alteration of the HPA axis in
MDD, probably occurs due to a failure in the HPA axis feedback, trig­
gered by a loss of GR sensitivity, as suggested by studies with dexa­
methasone suppression tests [190,191]. However, a hypocortisolemic
profile has also been reported in depressive patients, particularly those
with severe depression, with comorbidities, or interned patients [192,
193]. Among the pathophysiological mechanisms proposed to explain
hypocortisolemia there is an uncompensated sensitivity in the feedback
of the HPA axis, and an insufficiency of the adrenal glands to synthesize
cortisol [192,193]. Both hypo- and hypercortisolemic profiles are shown
to impair memory. Hypocortisolemia was shown to be associated with
low performance in tasks such as auditory and visual memory as well as
executive function [194,195]. Similarly, individuals with in a hyper­
cortisolemic condition often show impaired performance in verbal and
visual memory tasks [196,197].
Although it does not occur consistently, changes in blood BDNF can
be reflected in the decrease in serum levels of depressed individuals
[198,199]. Interestingly, studies have been pointing out that the effect
of antidepressants seems to require an increase in BDNF synthesis and
hippocampal neurogenesis [200–202]. However, in a recent
meta-analysis, Semkovska and colleagues [4] found that even in­
dividuals who achieved remission after a depressive episode treated
with commercial antidepressants perform poorly on most cognitive
variables when compared to controls, with a high effect size for variables
related to long-term memory [4].
Therefore, having in mind the physiological relationship among
cortisol, memory, and mood [166], new treatments for MDD should not
only have the aim of decreasing depressed mood and anhedonia, but also
focus on memory improvement and cortisol balance, in order to have a
better treatment response and less recurrent episodes. Studies with ke­
tamine, a psychotropic with rapid antidepressant action recently
approved for clinical use for the treatment resistant depression (TRD),
have shown a quick ketamine-induced increase on BDNF release asso­
ciated with mood improvement, and decrease in negative mnemonic
associations [203]. Despite these reported benefits, impairment in
episodic memory associated with sub-anesthetic doses of ketamine in
animal models of depression has also been reported [204].
Another promising new treatment for TRD is ayahuasca. Ayahuasca
is an infusion of Amazonian plants, used in indigenous and non-
indigenous religious rituals, with psychedelic properties [205–207]. In
a study with hypocortisolemic patients with TRD, a single dose of
ayahuasca induced a rapid increase in serum BDNF levels (48 h after
drinking the brew), which were correlated with reductions in depressive
7
Behavioural Brain Research 412 (2021) 113410
symptoms [199]. In addition, after the treatment, salivary cortisol levels
were similar to those of healthy controls [192], as well as the reduced
levels of systemic inflammation that were found [208]. These im­
provements enhance homeostatic balance and favor cognitive processes.
Moreover, ayahuasca has a broad range of action in the brain, modu­
lating areas of the default mode network (implicated in ruminative
processes) [209], stimulating neurogenesis in vitro(through its active
compounds), preventing glutamate-induced excitotoxicity, and
improving spatial memory [210,211].
The use of memory as a tool for prevention, diagnosis and treatment
in psychiatry is an emerging field [212,213]. Some learning strategies in
a WM verbal task were used to differentiate psychotic from
non-psychotic depression helping to provide a more accurate diagnosis,
being a relatively passive strategy (serial clustering), the latter used by
volunteers with psychotic depression, and being the one that best
differentiated the groups [214]. In addition, memory reconsolidation
has been a target for modifying traumatic memories, proposing alter­
natives for both the prevention and treatment of psychopathologies
[215,216]. The retrieval of positive memories works as a resilience
factor in adolescents at risk of developing depression (who experienced
stressful events in the beginning of life) [217], supporting the role of
memory modulation as a prevention tool. In mice, behavioral and
stress-induced hippocampal neurogenesis impairments were reversed by
optogenetically activating an engram related to a previous positive
memory [218]. Therefore, plenty of approaches are currently being
developed to uncover the interplay between memory and various
research fields in psychiatry, which is placing memory as a promising
tool for Psychiatry.
5. Conclusions
There are several memory systems, classified generally based on
their content or duration, whose neurobiology is not yet fully elucidated.
Neuroendocrine mediators of the stress response are important modu­
lators of mnemonic processes, and their effects depend on certain
characteristics of the stressor, such as: the duration/intensity and
controllability, and the timing in which the stressful event is experi­
enced (before, during, or after the mnemonic context). In summary,
evidence is mixed for the effects of acute stress on working memory, and
points to contrasting effects on the acquisition, consolidation, and
retrieval of long-term memories, either explicit or implicit. Moreover, it
also influences the recruited memory system; the transition from
cognitive learning to habits. Chronic stress, on the other hand, impairs
both working memory and the operational phases of explicit long-term
memories. Therefore, impairments in memory are common in psychi­
atric disorders, such as major depressive disorder, which is accompanied
by extensive changes in episodic memory and executive functions. Such
impairments are usually due to biological changes underlying mne­
monic processes. In this context, the study of the neurobiology of
memory may contribute both to the validation of biomarkers, as well as
to point out therapeutic targets.
Source of funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
The authors report no declarations of interest.
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