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Neurobiological links between stress and anxiety


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Stress and anxiety have intertwined behavioral and neural underpinnings. These commonalities are critical for understanding each state, as well as their mutual interactions. Grasping the mechanisms underlying this bidirectional relationship will have major clinical implications for managing a wide range of psychopathologies. After briefly defining key concepts for the study of stress and anxiety in pre-clinical models, we present circuit, as well as cellular and molecular mechanisms involved in either or both stress and anxiety. First, we review studies on divergent circuits of the basolateral amygdala (BLA) underlying emotional valence processing and anxiety-like behaviors, and how norepinephrine inputs from the locus coeruleus (LC) to the BLA are responsible for acute-stress induced anxiety. We then describe recent studies revealing a new role for mitochondrial function within the nucleus accumbens (NAc), defining individual trait anxiety in rodents, and participating in the link between stress and anxiety. Next, we report findings on the impact of anxiety on reward encoding through alteration of circuit dynamic synchronicity. Finally, we present work unravelling a new role for hypothalamic corticotropin-releasing hormone (CRH) neurons in controlling anxiety-like and stress-induce behaviors. Altogether, the research reviewed here reveals circuits sharing subcortical nodes and underlying the processing of both stress and anxiety. Understanding the neural overlap between these two psychobiological states, might provide alternative strategies to manage disorders such as post-traumatic stress disorder (PTSD).
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Neurobiology of Stress
journal homepage:
Neurobiological links between stress and anxiety
Nuria Daviu
, Michael R. Bruchas
, Bita Moghaddam
, Carmen Sandi
, Anna Beyeler
Hotchkiss Brain Institute. Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N
4N1, Canada
Department of Anesthesiology and Pain Medicine. Center for Neurobiology of Addiction, Pain, and Emotion. University of Washington. 1959 NE Pacic Street, J-wing
Health Sciences. Seattle, WA 98195, USA
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, 97239, USA
Laboratory of Behavioral Genetics, Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Station 19, CH, 1015, Lausanne, Switzerland
Neurocentre Magendie, INSERM 1215, Université de Bordeaux, 146 Rue Léo Saignat, 33000 Bordeaux, France
Neural circuits
Corticotrophin releasing hormone
Emotional valence
Stress and anxiety have intertwined behavioral and neural underpinnings. These commonalities are critical for
understanding each state, as well as their mutual interactions. Grasping the mechanisms underlying this bi-
directional relationship will have major clinical implications for managing a wide range of psychopathologies.
After brieydening key concepts for the study of stress and anxiety in pre-clinical models, we present circuit, as
well as cellular and molecular mechanisms involved in either or both stress and anxiety. First, we review studies
on divergent circuits of the basolateral amygdala (BLA) underlying emotional valence processing and anxiety-
like behaviors, and how norepinephrine inputs from the locus coeruleus (LC) to the BLA are responsible for
acute-stress induced anxiety. We then describe recent studies revealing a new role for mitochondrial function
within the nucleus accumbens (NAc), dening individual trait anxiety in rodents, and participating in the link
between stress and anxiety. Next, we report ndings on the impact of anxiety on reward encoding through
alteration of circuit dynamic synchronicity. Finally, we present work unravelling a new role for hypothalamic
corticotropin-releasing hormone (CRH) neurons in controlling anxiety-like and stress-induce behaviors.
Altogether, the research reviewed here reveals circuits sharing subcortical nodes and underlying the processing
of both stress and anxiety. Understanding the neural overlap between these two psychobiological states, might
provide alternative strategies to manage disorders such as post-traumatic stress disorder (PTSD).
1. Introduction
Although the relationship between psychological stress and anxiety
seems intuitive, the biological nuances that distinguish the two states
are extremely complex. Indeed, after decades of research in psychology,
ethology and neurophysiology, overlapping neural substrates of these
two psychobiological states have been identied. However, the
boundaries between stress and anxiety remain an open discussion.
A stress response, created by a real or perceived threat (stressor),
can be dened as an emergency state of an organism in response to a
challenge to its homeostasis (Chrousos, 2009;Selye, 1936). During this
emergency state, the organism initiates an integrated reaction including
physiological and behavioral responses. Internal threats, or so-called
systemic stressors, include physical changes in the body, such as hy-
poglycemia or hypovolemia (decreased blood volume), happening, for
example, after a severe car accident. On the other hand, perceived
threats, or so-called psychological stressors, include situations that can
potentially lead to a danger and induce a homeostatic challenge, in-
troducing the critical factor of anticipation (de Kloet et al., 2005;
Koolhaas, 2011). The concept of anticipation in the stress response is
critical in understanding the relationship between stress and anxiety. In
that regard, stress as a physiological reaction to a stimulus is accom-
panied by a concomitant emotional response. That emotional response
is determined in part by the perception of the threat imminence
(Anderson and Adolphs, 2014;Davis et al., 2010). According to the
denition of The Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition (DSM-5) (American Psychiatric Association, 2013)Fear is
the emotional response to a real or perceived imminent threat, whereas
anxiety is the anticipation of a future threat. Thus, the emotional state
that our body experiences diers between fear when we encounter an
aggressive dog, and anxiety when we know we will visit a friend which
has an aggressive dog.
Received 5 April 2019; Received in revised form 18 June 2019; Accepted 2 August 2019
Corresponding author.
E-mail addresses: (N. Daviu), (M.R. Bruchas), (B. Moghaddam), (C. Sandi), (A. Beyeler).
Neurobiology of Stress 11 (2019) 100191
Available online 13 August 2019
2352-2895/ © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license
Anxiety is dened as a temporally diused emotional state caused
by a potentially harmful situation, with the probability or occurrence of
harm being low or uncertain (Goes et al., 2018;Spielberger et al., 1983;
Takagi et al., 2018). Historically, psychologists and psychiatrists have
dierentiated state and trait anxiety (Belzung and Griebel, 2001;Goes
et al., 2018;Spielberger et al., 1983;Takagi et al., 2018). The diverging
element of these two types of anxiety is their duration: state anxiety is
an acute response to a potential threat, while trait anxiety is chronic, as
it is expressed constantly during the life of the individual, and is
therefore considered as a trait of an individual's personality (Endler and
Kocovski, 2001;Spielberger et al., 1983). State anxiety can be dened
as hypervigilance in anticipation of a threat that can be triggered by
acute stress, and has the primary function of avoiding dangerous si-
tuations and also to facilitate memory consolidation (Roozendaal et al.,
2008). On the other hand, trait anxiety is a predisposition of an in-
dividual to express constant anxiety, and increases the probability of
state anxiety in potentially dangerous situations (Endler and Kocovski,
2001;Spielberger et al., 1983). State and trait anxiety are not mutually
exclusive, and state anxiety triggered by an event can be superimposed
on trait anxiety. Importantly, both state and trait anxiety responses
represent an evolutionary advantage to anticipate and avoid danger
(Goes et al., 2018;Spielberger et al., 1983;Takagi et al., 2018).
Therefore, anxiety per se is not a pathological state, as it can prevent
exposure to dangerous situations. However, when anxiety is sustained
and/or elicited by non-threating stimuli, it becomes maladaptive
(Belzung and Griebel, 2001;Sylvers et al., 2011). While state and trait
anxiety are essential psychological metrics to evaluate normal and pa-
thological levels of anxiety, these metrics do not consider the neural
substrate of anxiety, which partly explains the lack of new and eective
therapies for anxiety disorders.
Over the past twenty years, human functional imaging has identi-
ed multiple brain areas including the hypothalamus, amygdala, pre-
frontal cortex and nuclei of the brainstem which are active during both
stress and anxiety responses in healthy individuals (Mobbs et al., 2007;
Takagi et al., 2018). Interestingly, a subset of brain regions including
the basolateral amygdala (BLA), medial prefrontal cortex (mPFC), locus
coeruleus (LC), as well as reward processing areas such as the nucleus
accumbens (NAc), appear to be aected in animal models of both stress
disorders and anxiety disorders (Calhoon and Tye, 2015;Etkin and
Wager, 2007;Sailer et al., 2008;Shin and Liberzon, 2010). The inter-
mingled neural circuits controlling both stress and anxiety suggests a
strong bidirectional relationship between stress experiences and anxiety
in both healthy and pathological conditions. Therefore, alterations of
the connectivity between the brain regions inuencing both stress and
anxiety behaviors might contribute to the etiology of psychopathologies
such as generalized anxiety disorder (GAD), social anxiety disorders or
post-traumatic stress disorder (PTSD).
Herein, we summarize the views of the panel on Stress, Anxiety and
Corticolimbic Pathways, presented at the 2018 Stress Neurobiology
meeting, held in Ban, Canada. This perspective reects the diverse and
shared structures involved in both stress and anxiety responses. We aim
to reveal common subcortical processes that could support the interplay
between stress and anxiety-related behaviors.
2. Coding of emotional valence in the basolateral amygdala (BLA)
The attribution of emotional valence to sensory information is a key
process that allows individuals to navigate the world, and has been
shown to be altered in both anxiety and stress disorders (Etkin and
Wager, 2007;Sailer et al., 2008). Valence is the subjective value as-
signed to sensory stimuli, which determines subsequent behavior. Po-
sitive valence leads to approach and consummatory behaviors while
negative valence leads to defensive and avoidance behaviors (Pignatelli
and Beyeler, 2019;Russell, 1980). Attentional bias for stimuli of ne-
gative valence have been extensively demonstrated in patients with
anxiety disorders (MacLeod et al., 2019). For example, anxiety
increases negative interpretations of ambiguous sentences (Richards
and French, 1992) and scenarios (Hirsch and Mathews, 1997) sug-
gesting an anxiety-induced valence bias. Recent publications showed
that high trait anxiety individuals exhibit a bias towards negative in-
terpretations of surprised faces (Park et al., 2016a). The existence of a
correlation between negative valence bias and the level of anxiety in
health and disease observed in human studies supports the hypothesis
that the circuits encoding emotional valence could be dysfunctional in
anxiety disorders (Etkin and Wager, 2007;Lammel et al., 2014;
Mervaala et al., 2000;Pignatelli and Beyeler, 2019). A key structure
encoding emotional valence and therefore guiding animal behavior is
the basolateral nucleus of the amygdala (BLA). This region receives
sensory inputs of multiple modalities, and projects to output structures
controlling behavioral responses (Janak and Tye, 2015;McDonald,
1998). This central connectivity has made the BLA a focus for identi-
fying the neural substrate of valence processing. Moreover, a vast body
of literature has shown that BLA integrity is critical for processing po-
sitive (Bucy and Klüver, 1955;Tye et al., 2008;Weiskrantz, 1956) and
negative valence (Bucy and Klüver, 1955;LeDoux et al., 1990;
McDonald, 1998;Tye et al., 2008;Weiskrantz, 1956).
Interestingly, studies have shown that when dened by their pro-
jection target, neurons of the BLA dierentially control and encode
emotional valence (Fig. 1A). A set of studies revealed that photo-
stimulation of BLA neurons synapsing in the medial core/shell section
of the NAc (BLA-NAc) support reward seeking (Namburi et al., 2015).
Meanwhile, BLA neurons projecting to the medial section of the central
amygdala (BLA-CeA) mediate place avoidance (Namburi et al., 2015).
Importantly, these two dierent BLA populations have divergent re-
sponses to valence predicting cues. Indeed, single-unit in vivo recordings
combined with optogenetic photoidentication indicated that a higher
proportion of BLA-NAc neurons were excited by a cue predicting a re-
ward, while BLA-CeA neurons showed a higher proportion of neurons
excited by a stimulus predicting an aversive outcome (Beyeler et al.,
Furthermore, the authors identied a synaptic mechanism for
learning of valence associations. Specically, synaptic inputs onto BLA-
NAc neurons and BLA-CeA neurons undergo opposing synaptic changes
following reward or fear conditioning (Fig. 1C, Namburi et al., 2015).
Notably, BLA neurons projecting to those distinct areas are inter-
mingled within the BLA, but are distributed following topographical
gradients (Fig. 1D, Beyeler et al., 2018), which are correlated with a
dorso-ventral bias of negative to positive valence coding (Beyeler et al.,
Another set of optogenetic experiments have shown that activation
of the BLA projection to the ventral hippocampus (vHPC) is sucient to
induce real time anxiogenic eects and conversely, inhibition of those
projections causes an anxiolytic eect (Fig. 1B, Felix-Ortiz et al., 2013).
Single-unit recordings combined with optogenetic photoidentication
have shown that BLA-vHPC neurons have no coding bias for learned
stimuli predicting outcomes of positive or negative valence compared to
the entire BLA (Beyeler et al., 2016). This observation supports the idea
that BLA-vHPC neurons may mediate anxiety-related behaviors which
can be dened as an innate state of negative valence, rather than
learned valence.
Altogether, the BLA is a single structure which includes neural po-
pulations that underlie processing of learned emotional valence (BLA-
NAc and BLA-CeA) and a population that generates innate emotional
states (BLA-vHPC). This nding suggests that BLA is a key structure to
study how emotional states such as anxiety interfere with emotional
valence processing.
3. Locus coeruleus noradrenergic (LC-NE) projections to BLA:
acute stress-induced anxiety
Stressful experiences engage multiple structures to generate a co-
ordinated physical and psychological response to a challenge. The locus
N. Daviu, et al. Neurobiology of Stress 11 (2019) 100191
coeruleus noradrenergic system (LC-NE) presents a brain-wide projec-
tion pattern (Schwarz et al., 2015) and is linked to both physical and
emotional responses to stress (Berridge and Waterhouse, 2003;
Valentino and Van Bockstaele, 2008), as well as aversive memory
consolidation (Roozendaal et al., 2008). Noradrenaline release during
an acute stress induces a state anxiety response that allow the organism
to maintain high attention, facilitate sensory processing and enhance
executive functions in order to increase memory consolidation during
stressful experiences (Berridge and Waterhouse, 2003;Sara and Bouret,
Electrophysiological and optogenetic studies indicate that LC-NE
neurons normally display three activation proles: low tonic (12 Hz),
high tonic (38 Hz) and phasic activity (Carter et al., 2010). Acute stress
causes a robust increase in tonic ring rate in LC-NE (Valentino and Van
Bockstaele, 2008) and this stress-induced tonic ring is associated with
an increase in anxiety-like behavior. The role of tonic activation of LC-
NE neurons is further supported by the observations that optogenetic
stimulation of NE cell bodies in the LC, in the absence of a stressor,
mimics LC-NE tonic activity as well as acute-stress induced anxiety
(McCall et al., 2015). Furthermore, they suggest that this increase of
activity in LC-NE neurons is caused by synaptic inputs into the LC
containing corticotropin releasing hormone (CRH
). Specically,
stimulation of CRH
CeA-LC terminals increases activity in LC and
drives anxiety-like behaviors through type 1 CRH receptor (CRH1R)
activation (McCall et al., 2015).
Acute stress also promotes anxiety and other stress related behaviors
through BLA adrenergic receptor activation (Chang and Grace, 2013).
Even though the anatomical projections from LC and the role of NE in
stress and anxiety have been studied extensively, the mechanism by
which LC-NE inuences BLA function to promote negative emotional
states has only recently been unravelled. McCall and collaborators
(2017) demonstrated that optogenetic activation of LC-NE bers in the
BLA in acute brain slices causes norepinephrine release into the BLA. In
vivo photostimulation of these terminals modulates BLA activity, and
LC-BLA stimulation is sucient to cause conditioned place aversion as
well as anxiety-like behaviors. These stimulation-induced behavioral
changes require β-adrenergic receptor activity in the BLA, providing in
vivo evidence that endogenous NE release from LC terminals alters BLA
function and, as a consequence, modies behavior. Additional support
for β-adrenergic signaling promoting anxiety-like behaviors is provided
in Siuda et al. (2015), whereby selective optical activation of β-adre-
nergic signaling in CaMKII(+) neurons of the BLA produces robust
anxiety-like phenotypes.
LC-NE neurons preferentially target neurons in the BLA that project
Fig. 1. Valence coding in the basolateral amygdala (BLA) projector populations. A. Projector valence coding (adapted from Beyeler et al. 2016). a. Schematic of
Pavlovian conditioning paradigm. Head-xed mice were trained to discriminate between one cue paired with sucrose (CSS) and a dierent cue paired with quinine
(CS-Q). b. Peri-stimulus time histogram (PSTH) of the ring rates of representative units excited (top) or inhibited (bottom) during a CS-S presentation followed by a
sucrose delivery. c. Fraction of BLA neurons excited or inhibited by CS-S, CS-Q or both. d. PSTH of action potentials of a BLA single-unit photoidentied as a BLA-NAc
projector. e. Within-cell dierence of response to CS-S and CS-Q depending on the neurons projection targets. f. Percentage of positive and negative valence units in
the BLA. B. Behavioral impact of optogenetic activation of dierent BLA pathways (BLA-NAc and BLA-CeA projectors and BLA-vHPC terminals). C. Synaptic plasticity
mechanism observed in BLA-NAc and BLA-CeA projection neurons after learning of valence associations. D. Topographic maps of three projectors populations in the
BLA. CS: conditioned stimuli, S: sucorse, Q: quinine, NAc: nucleus accumbens, CeA: central amygdala, vHPC: ventral hippocampus.
N. Daviu, et al. Neurobiology of Stress 11 (2019) 100191
to the ventral hippocampus (BLA-vHPC) and CeA (BLA-CeA), both
downstream structures involved in negative valence and anxiety-re-
lated behaviors (Beyeler et al., 2018;Felix-Ortiz et al., 2013;Namburi
et al., 2015). This suggests that LC-NE projections to BLA increase an-
xiety-like behaviors following stress exposure, through projections to
downstream structures such as CeA or vHPC (Fig. 2A). This recent work
reveals that part of the circuit underlying acute-stress, induces state
3.1. A new mitochondrial function linking stress and emotional traits
Even in our modern society, the necessity of positioning ourselves in
a social group through social competition has an enormous impact on
our daily lives. In spite of the importance that social competition has in
organizing and structuring our society, the psychological characteristics
that aect social competitiveness of an individual have been largely
overlooked. Several brain regions such as the amygdala and the NAc
have been implicated in social status and competition in both humans
(Zink et al., 2008), and rodents (Goette et al., 2015). Recent studies
have specically revealed the critical role of the NAc in social compe-
tition and the establishment of social status (Hollis et al., 2015;Larrieu
et al., 2017;Van der Kooij et al., 2018). During social competition, D1-
containing medium spiny neurons (MSNs) in the NAc are activated and
show a positive correlation with the level of oensive behavior ob-
served in a social hierarchy test. In addition, when the NAc, but not the
BLA, is inactivated with a GABA
receptor agonist during a social
competition test, rats showed reduced social dominance (Hollis et al.,
The NAc is involved in motivation and has been implicated in the
regulation of anxiety and depressive-like symptoms (Lüthi and Lüscher,
2014). The neural mechanism through which anxiety might aect so-
cial hierarchy has been poorly investigated. In humans, high-anxiety
individuals tend to display subordinate roles and to be less competitive
in social environments (Gilbert et al., 2009). Likewise, high-anxiety rats
show less social dominance after a social competition for a territory
(Hollis et al., 2015). These results are consistent with data obtained in
humans where high anxiety traits predispose subjects for social sub-
mission (Goette et al., 2015). These behavioral results, together with
the new data revealing a unique role of the NAc in the establishment of
social hierarchy open a new path to investigating how NAc function can
bridge anxiety and social competition. In search of potential mechan-
isms within the NAc, which could dierentiate low and high anxiety
rats, Hollis et al. (2015) showed that high anxiety rats had lower mi-
tochondrial activity in NAc, compared to low anxiety rats. Specically,
with similar mitochondrial numbers and density, highly anxious rats
have lower levels of respiratory complexes I and II of the electron
transport chain, resulting in a reduced mitochondrial function (Fig. 2B).
Furthermore, social status also predicts behavioral stress susceptibility
and metabolic prole in the NAc after chronic social defeat (Larrieu
et al., 2017). These studies establish a key role of mitochondrial func-
tion in individual dierences that impact social dominance in a non-
pathological condition. Altogether, the newly discovered role of mi-
tochondrial energy metabolism in the NAc in anxiety-induced social
decits opens a new path for therapeutic treatment that targets cell
In regards to the relationship between stress and anxiety, social
competition itself induces an endocrine stress response (Turan et al.,
2015). In humans, stress exposure dierentially aects low and high
anxiety subjects in a competitive task. Under stressful conditions, low-
anxiety individuals become overcondent, while high-anxiety in-
dividuals show less social condence (Goette et al., 2015). Moreover,
several studies have reported increased risk of adult psychopathologies
after early life adversity (Haller et al., 2014;Maccari et al., 2014). In
preclinical models, early life stress paradigms have been proposed as a
tool to program or bias anxiety traits and, as a consequence, have ne-
gative impact in social competence (Tzanoulinou and Sandi, 2017).
Indeed, peri-pubertal stress leads to enhanced anxiety (Cordero et al.,
2016) and changes in social behavior in adulthood (Haller et al., 2014).
Interestingly, play-ghting is a peri-pubertal social behavior which has
been linked to aggression in adulthood. Specically, peri-puberal stress
increases play-ghting and increases the chances to display abnormal
aggressive behaviors later in adulthood (Papilloud et al., 2018). Im-
portantly, this study also revealed a role of mitochondrial energy bal-
ance in regulating stress-induced behaviors, by showing that enhanced
play-ghting behaviors following peri-pubertal stress was accompanied
by enhanced mitochondrial function in the amygdala.
4. Encoding reward-directed behavior under anxiety
In humans, patients suering from anxiety disorders have impaired
decision making and behavioral exibility (Park and Moghaddam,
2017a). For example, high levels of anxiety are accompanied by
Fig. 2. Circuit and molecular mechanisms of stress and anxiety. A. LC-NE
projections to BLA increases anxiety-like behaviors acting on β-adrenergic re-
ceptors (βARs) and through projections to downstream structures such as the
CeA. B. NAc mitochondrial function and anxiety, and its inuence on social
dominance. C. Circuit synchronicity between the PFC and VTA under dierent
punishment probabilities. LC: locus coeruleus, BLA: basolateral amygdala, CeA:
central amygdala, NAc: nucleus accumbens, PFC: prefrontal cortex, VTA: ven-
tral tegmental area, NE: norepinephrine; ATP: adenosine triphosphate CRH:
corticotropin-releasing hormone TH: tyrosine hydroxylase DBH: dopamine
beta-hydroxylase Gal: galanin.
N. Daviu, et al. Neurobiology of Stress 11 (2019) 100191
diculty of shifting between strategies in the presence of changes in
task demand, and/or are easily distracted by irrelevant stimuli (Eysenck
et al., 2007). That inability to change strategies during a task can have
detrimental consequences in a person, by aecting personal life and
professional performance. The prefrontal cortex (PFC) is a pivotal
structure in organizing behavior in a context dependent-manner
(Bechara et al., 2000;Miller and Cohen, 2001). Thus, during stress, the
PFC controls high order adaptive responses such as choosing optimal
behavioral output with an online evaluation of the situation
(Moghaddam, 2016).
In rodents, anxiety levels are also related to decreased cognitive
exibility (Park and Moghaddam, 2017a). Recent studies have revealed
the functional consequence of anxiety upon PFC activity, by identifying
that a negative emotional state elicits sustained reduction of sponta-
neous ring rate in the dorso-medial PFC (dmPFC) and orbitofrontal
cortex (OFC, Park et al., 2016b). This hypofrontality, and specically
the reduced activity in the dmPFC, is linked to decreased behavioral
exibility in the set-shifting task (Park et al., 2016b). In this task the
subjects learn an instrumental behavioral response based on two dif-
ferent rules that sit on two dierent dimensions (for example: shape and
color). The ability to switch between rules to maximize the prot
(number of rewards) is PFC-dependent. The ventral tegmental area
(VTA) is also a critical component of reward-guided behavior, and to-
gether with the PFC, has been proposed as a circuit underlying deci-
sions during reward-seeking under punishment. VTA neurons are a key
component of the reward circuit (Morales and Margolis, 2017;Wood
et al., 2017) and their projections to the mPFC are involved in reg-
ulating mood and emotional states (Lammel et al., 2014).
Park and Moghaddam designed and developed a task to study the
dynamics of reward-based behavior while risking potential punishment
(Park and Moghaddam, 2017b). The task was designed to link instru-
mental action to reward, but at the same time, the same action will be
followed by a punishment with varying probabilities. This task aims to
recreate an environment where uncertainty of a negative outcome in-
duces anxiety. The probability of getting punished aects behavioral
performance by increasing the variability of the time to react, sug-
gesting a transitory anxiety state caused by the possibility of being
punished. Single-unit recordings from both dopaminergic (DA) VTA
neurons, and mPFC neurons, during this task revealed that their ring
rate around the motor response (time surrounding the action execution)
is correlated with the punishment risk, suggesting both neural popu-
lations encode the risk probability. Even though both VTA-DA and non-
DA neurons, as well as mPFC neurons, showed punishment risk en-
coding responses, VTA-DA neurons showed a higher temporal resolu-
tion around the action time than mPFC neurons, which showed a more
diuse response around the action window. Interestingly, the single-
unit recordings did not correlate with the behavioral changes during
the task, and a more detailed analysis revealed that the variability in
the reaction time was related to a circuit dynamic. The correlation of
the ring of VTA and mPFC neurons with the reaction time was evident
only in the riskiest part of the session, when the probability to be
punished was higher.
At the network level, the synchronicity of the theta oscillations is
important to coordinate groups of neurons to complete a behavioral
response (Akam and Kullman, 2010;Buschman et al., 2012). Interest-
ingly, during non-punished trials, the oscillations that emerged in the
VTA and mPFC are in the theta range (around 8 Hz, Park and
Moghaddam, 2017b). Moreover, increased probability of punishment
decreases the oscillations in both areas and weakens synchrony within
and between both structures.
These studies revealed that synchrony between the VTA and PFC
decreases with punishment probability, suggesting that VTA-PFC net-
work encodes punishment risk (Fig. 2C). Under normal conditions, VTA
drives oscillation synchronicity between both regions exerting a
bottom-up control of the network. When there is risk of punishment,
this bottom-up network control is diminished. Transient anxiety may,
therefore, aect behavior in a reward-based task by disrupting the VTA-
PFC functional circuit.
5. Role of hypothalamic corticotropin (PVN-CRH) neurons in
stress-related behaviors
Although the relationship between stress and anxiety is bidirec-
tional, the inuence of stress as a risk factor for anxiety disorders has
been extensively studied (Armario et al., 2008;Tye and Deisseroth,
2012). Mapping of neural circuits involved in stress-induced anxiety
have mostly revolved around structures of the amygdala and extended
amygdala (Davis et al., 2010;Gross and Canteras, 2012). Surprisingly,
relatively less attention has been directed towards the paraventricular
nucleus of the hypothalamus (PVN), which is a crucial component of
the visceral stress response. The PVN receives and integrates informa-
tion about the stressor and controls the endocrine, behavioral and au-
tonomic response to stress (Denver, 2009;Herman et al., 2003;Ulrich-
Lai and Herman, 2009). Specically, parvocellular neurosecretory cells
release corticotropin-releasing hormone (CRH) into the anterior pitui-
tary that stimulates the synthesis and release in the blood stream of
adrenocorticotropic hormone (ACTH). Once ACTH reaches the adrenal
glands it stimulates the release of glucocorticoid (Denver, 2009;
Herman et al., 2003;Ulrich-Lai and Herman, 2009). In the past ve
years, the classical view of PVN-CRH neurons has been challenged by
demonstrations that these neurons also control multiple and complex
behaviors that are linked to stress (De Marco et al., 2016;Füzesi et al.,
2016;Sterley et al., 2018;Zhang et al., 2017). These observations open
an exciting line of research to investigate how this specic set of neu-
rons can drive stress-induced behavioral alterations.
The standard methods to study anxiety in rodents have relied on
established laboratory tests such as the elevated plus maze. However,
over the last decade, an increasing number of studies have focused on
developing new tools of behavioral analysis that are less invasive, re-
quire less subjective interpretations, and harken back to original etho-
logical approaches (Lezak et al., 2017). One of these approaches relies
on monitoring freely-behaving mice in their home-cage environment
without any intervention (Fig. 3A). Multiple behaviors such as
grooming, freezing, rearing or surveying can be detected. Importantly,
these behaviors show a specic but exible temporal distribution. Using
this approach, it was shown that a single stressful experience results in
the emergence of an organized and structured behavioral pattern where
self-directed behaviors such as grooming become predominant, taking
over exploratory behaviors such as locomotion or rearing (Fig. 3B,
Füzesi et al., 2016). The role of brainstem in generating stress-induced
behavioral responses such as freezing (Deng et al., 2016;Silva and
McNaughton, 2019), grooming (Kalueet al., 2016), defensive beha-
viors or even anxiety-like behavior (McCall et al., 2015), has been ex-
tensively studied over the years (Myers et al., 2017). A recent study
from Füzesi et al. (2016) proposes the contribution of a dierent
structure, by revealing a new role for PVN-CRH neurons in coordinating
the spontaneous behavioral patterns that emerge after acute stress.
Specically, optogenetic silencing of PVN-CRH activity during the post-
stress period reduces grooming in a safe environment. On the contrary,
activating PVN-CRH neurons modies the intensity, but not necessarily
the temporal sequence of context appropriate behaviors (Fig. 3C). The
behavioral prole that arises after an acute stress experience is context
dependent and related to PVN-CRH neuron activity.
Further work on PVN-CRH has revealed that these cells are neces-
sary and sucient for stress-induced social investigation that is re-
quired for the transmission of stress from one individual to another
(Sterley et al., 2018). This social transmission of stress results in
changes in synaptic function and metaplasticity in the recipient mice,
which mirror the synaptic changes observed in stressed mice. This study
positions PVN-CRH neurons as a critical node for alarm signal proces-
sing and oers a potential explanation for how individuals who have
not had a rst-hand traumatic experience can develop symptomology
N. Daviu, et al. Neurobiology of Stress 11 (2019) 100191
consistent with post-traumatic stress disorders (Haugen et al., 2012;
Sial et al., 2016).
Recent studies have shown that PVN-CRH neurons are able to re-
spond dierentially to stimuli with positive or negative valence (Kim
et al., 2019;Yuan et al., 2019). Using in vivo ber photometry to
monitor population calcium dynamics, Kim et al. (2019) have shown
that the activity of PVN-CRH neurons rapidly increases in response to
stimuli with negative valence, and decreases when an appetitive sti-
mulus such as food or social interaction is presented. Moreover, a re-
ward presentation during stress can buer PVN-CRH activation, and, as
a consequence, modify stress-related behaviors, such as grooming,
correlate with the activity of those neurons (Yuan et al., 2019). The
bidirectional response of PVN-CRH neurons based on stimulus valence
opens a new perspective to study stress coping and relieve.
Beyond CRH neurons, a distinct neuronal population in the PVN
containing CRH1R has been recently described. This population is 90%
GABAergic and has direct synaptic contact with PVN-CRH neurons, and
CRH, released from PVN-CRH neurons, modulates signaling between
both populations (Jiang et al., 2018;Ramot et al., 2017). This intra-
PVN network of CRH1R+ and CRF + neurons has been associated with
anxiety-like behavior, as knocking out CRH1R from PVN neurons has
anxiolytic eects (Ramot et al., 2017;Zhang et al., 2017).
All these new data are contributing to update the role of
hypothalamic neural populations in stress-related behaviors.
Specically, growing evidence implicates PVN-CRH neurons in mod-
ulating specic behaviors in a stress-related context. From controlling
how an individual responds to stress exposure (Füzesi et al., 2016;Kim
et al., 2019;Yuan et al., 2019) to regulating anxiety-like behaviors
(Ramot et al., 2017;Zhang et al., 2017), or driving social transmission
of stress (Sterley et al., 2018), the PVN-CRH neuron population appears
to be a central player linking stress and anxiety.
6. From research to clinics: new categorization of post-traumatic
stress disorder (PTSD)
The idea that stress and anxiety have segregated neurobiological
substrates despite their reciprocal inuence has now moved beyond the
research eld to reach the clinical practice, resulting in changes in di-
agnostic tools. Specically, according to the DSM-5 (American
Psychiatric Association, 2013) PTSD is not classied as an anxiety
disorder anymore, and the new manual categorizes it among the trauma
or stressor-related disorders. This new category requires explicitly an
exposure to a traumatic or stressful event as a diagnostic criterion, and
in particular, the PTSD requires a life threatening experience. Re-
classifying PTSD from anxiety disorders to this newly created trauma or
stressor-related disorders category has helped to move the focus away
Fig. 3. PVN-CRH neurons coordinate beha-
vioral patterns after stress (adapted from
Füzesi et al., 2016).A. Behavioral quantication
of mice in their home-cage, before (naïve) and
immediately after a footshock (stress). Eight
distinct behaviors are prominent. Each row re-
presents one mouse. B. Histogram of grooming
behavior at each time-point for naïve and stress
mice. C. Schematic of in vivo photostimulation of
PVN-CRH to LH projections (20 Hz, 5 min) in-
creases grooming time and stimulated CORT
release. PVN: paraventricular nucleus of the
hypothalamus CRH: corticotropin-releasing
hormone LH: lateral hypothalamus ME: median
eminence CORT: corticosterone.
N. Daviu, et al. Neurobiology of Stress 11 (2019) 100191
from anxiety, which is now rather considered as a comorbid pathology.
The new classication in DSM-5 also emphasizes the abnormal re-
activity to a stimulus. Interestingly, an altered ightresponse has
been observed in patients with PTSD (Park et al., 2017) and, in the last
ve years, the interest in how microcircuits controlling threat proces-
sing are altered in PTSD has grown considerably. This emergent lit-
erature supports the idea that aberrant subconscious threat-related
processes are underlying part of the PTSD symptomatology (Lanius
et al., 2017). Current data indicates an increased connectivity between
areas involved in the innate alarm system, such as the LC, amygdala,
hypothalamus, and PFC in PTSD patients (Rabellino et al., 2016). In
humans, when a challenge is not life-threating, the subjects choose the
most suitable cost-eective strategy to overcome that situation by en-
gaging the vmPFC, medial orbitofrontal cortex (mOFC) and other non-
cortical structures including the BLA which is causally involved in va-
lence processing. However, when the level of danger is life threatening
and the organism must prepare for a defensive response, subcortical
structures, such as the periaqueductal gray area (PAG) and CeA over-
rule the cognitive control, and guide the behavioral response (Mobbs
et al., 2007). The balance between cortical and subcortical systems
could also cast out key points to understand some anxiety disorders.
Negative emotional states such as anxiety may lead a person to over-
estimate the possibility of danger, leading to a shift in the balance of
these two systems. The dynamics between the cognitive and innate
circuitry in response to a challenge may reveal a path to a better
comprehension of how stressful experiences inuence our emotional
state, and in turn, shape our future behaviors.
7. Perspective
Although the dissection of multiple brain circuits controlling an-
xiety- and stress-related behaviors has made substantial advances, our
understanding of the neural substrates underlying the interplay be-
tween these two psychophysiological responses remains fragmented.
Here, we described specic roles of neural populations in the amygdala,
nucleus accumbens, prefrontal cortex, hypothalamus and locus coer-
uleus in emotional valence, stress and anxiety. The work described here
is providing foundational knowledge, however future investigation is
necessary to unravel the contribution of specic circuits to stress and/or
anxiety. Specically, future work should use activity dependent map-
ping and recordings of genetically or anatomically dened neural po-
pulations during stress exposure and at dierent levels of anxiety within
the same animal. Beyond the technical advances catalyzing our un-
derstanding of the neural circuits underpinning stress and anxiety,
disentangling them will require the development of new behavioral
paradigms in pre-clinical models in order to nely capture the changes
of neural coding in these two conditions.
Conicts of interest
The authors have no conict of interest to declare.
We thank Matt Hill and Jaideep Bains for organizing the 2018 Stress
Neurobiology Workshop, and for their invitation to write this review to
summarize the major ndings presented during the sessions including
the authors of this review. ND is supported by Fellowships from Alberta
Innovates-Health Solutions. We acknowledge the support of the Région
Nouvelle-Aquitaine and the INSERM-Avenir program of the French NIH
to the Beyeler Lab and of the Brain and Behavior Research Foundation
NARSAD young investigator grant to AB.
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... The basolateral amygdala (BLA) is a primary site that orchestrates reward-related and emotional processes. Thus, BLA dysfunction is thought to be directly involved in anxietylike responses and addictive behaviors (Sharp, 2017;Daviu et al., 2019). The BLA is necessary to promote responses to natural rewards, respond to second-order drug-conditioned cues, express stress-enhanced reacquisition of drug intake, and reinstate cue-dependent drug seeking (Sharp, 2017). ...
... Previous studies suggested that BLA excitability was positively associated with increased anxiety-like responses and addiction (Sharp, 2017;Daviu et al., 2019). One distal BLA projection target implicated in anxiety-related behaviors was the vHip. ...
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Anxiety is one of the most common comorbid conditions reported in people with opioid dependence. The basolateral amygdala (BLA) and ventral hippocampus (vHip) are critical brain regions for fear and anxiety. The kappa opioid receptor (KOR) is present in the mesolimbic regions involved in emotions and addiction. However, the precise circuits and molecular basis underlying anxiety associated with chronic opioid use are poorly understood. Using a mouse model, we demonstrated that anxiety-like behaviors appeared in the first 2 weeks after morphine withdrawal. Furthermore, the BLA and vHip were activated in mice experiencing anxiety after morphine withdrawal (Mor-A). KORs in the BLA to vHip projections were significantly increased in the Mor-A group. Optogenetic/chemogenetic inhibition of BLA inputs ameliorated anxiety-like behaviors and facilitated conditioned place preference (CPP) extinction in Mor-A mice. Knockdown of the BLA to vHip circuit KOR alleviated the anxiety-like behaviors but did not affect CPP extinction or reinstatement. Furthermore, combined treatment of inhibition of the BLA to vHip circuit and KOR antagonists mitigated anxiety-like behaviors and prevented stress-induced CPP reinstatement after morphine withdrawal. These results revealed a previously unknown circuit associated with the emotional component of opioid withdrawal and indicated that restoration of synaptic deficits with KOR antagonists might be effective in the treatment of anxiety associated with morphine withdrawal.
... Evidence suggests that individuals' help-seeking attitudes can be enhanced with better mental health literacy [3]. In addition, anxiety and depression in young adults are linked with higher stress levels and poorer psychological well-being [4]. ...
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Mental health literacy (MHL) promotes mental health among youths. We aimed to evaluate the effectiveness of the newly developed HOPE intervention in improving depression literacy, anxiety literacy, psychological well-being, and reducing personal stigma and stress levels amongst young adults at a university in Singapore. After two pilot studies, we conducted a randomised controlled trial (RCT) and recruited 174 participants aged 18–24 years old through social media platforms. The HOPE intervention group received four online sessions over two weeks and the control group received online inspirational quotes. Study outcomes were measured with self-reported questionnaires and they were assessed at baseline, post-intervention, and two-month follow-up ( NCT04266119). Compared with the control arm, the intervention group was associated with increased depression and anxiety literacy levels at post-intervention and two-month follow-up. In addition, personal stigma for depression was reduced at the post-intervention juncture. However, there were no statistically significant changes in the ratings of psychological well-being and stress levels between the two groups. Longitudinal studies with larger sample sizes are warranted to replicate and extend the extant findings.
... The neurobiology of anxiety is extensively described in the literature. The main structures implied in fear and anxiety are the mPFC, the amygdala, the locus coeruleus, the hippocampus and the periaqueductal gray (PAG) [80][81][82][83]. ACh plays an important role in anxiety. ...
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The cholinergic system is an important modulator of brain processes. It contributes to the regulation of several cognitive functions and emotional states, hence altering behaviors. Previous works showed that cholinergic (nicotinic) receptors of the prefrontal cortex are needed for adapted social behaviors. However, these data were obtained in mutant mice that also present alterations of several neurotransmitter systems, in addition to the choliner-gic system. ChAT-IRES-Cre mice, that express the Cre recombinase specifically in choliner-gic neurons, are useful tools to investigate the role of the cholinergic circuits in behavior. However, their own behavioral phenotype has not yet been fully characterized, in particular social behavior. In addition, the consequences of aging on the cholinergic system of ChAT-IRES-Cre mice has never been studied, despite the fact that aging is known to compromise the cholinergic system efficiency. The aim of the current study was thus to characterize the social phenotype of ChAT-IRES-Cre mice both at young (2-3 months) and middle (10-11 months) ages. Our results reveal an alteration of the cholinergic system, evidenced by a decrease of ChAT, CHT and VAChT gene expression in the striatum of the mice, that was accompanied by mild social disturbances and a tendency towards anxiety. Aging decreased social dominance, without being amplified by the cholinergic alterations. Altogether, this study shows that ChAT-IRES-Cre mice are useful models for studying the cholinergic sys-tem's role in social behavior using appropriate modulating technics (optogenetic or DREADD).
... The neural overlap between these two has been explained via intermingled emotion circuits. 10 Anxiety can often be brought upon by emotions related to the fear of the unknown. Amidst the COVID-19 pandemic, there are many unknowns, similar to previously studied infectious disease outbreaks. ...
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Background Early studies during the COVID-19 pandemic identify the dissonance between feeling anxious about contracting the illness and the innate desire to serve the sick, as a main stressor for students. Purpose The purpose of this study is to better understand psychological stress and self-reported wellness of Physician Assistant (PA), Physical Therapy (PT), dental, and medical students during the early portions of the COVID-19 pandemic. Methods We utilized the 10-item Perceived Stress Scale (PSS) together with additional questions to assess self-perceived stress, anxiety, and wellness of healthcare students. Discussion There were no significant differences in PSS between professions. As PSS increased (indicating more stress), the odds of answering “worse” versus “same” or “better” to descriptions of anxiety level increased (OR: 2.318). Conclusion Student survey respondents experienced similar levels of perceived stress throughout the COVID-19 pandemic. Institutions should consider students’ perceived levels of stress and the many aspects of student wellness that may have been affected by the COVID-19 pandemic.
... The locus coeruleus, containing neurons releasing noradrenalin, is sensitive to chronic stress (Lee and Han, 2019;Daviu et al., 2019). Its activity and number of neurons are reduced, resulting in decreased NA levels in the PFC and HPC. ...
Mood disorders, including major depressive disorder and bipolar disorders, are frequent and heterogeneous psychiatric diseases. In order to better understand their pathophysiology, a new research area based on dimensions has emerged. It consists of exploring domains derived from fundamental behavioral components to link them to neurobiological systems. Beyond mood, emotional biases differentiate mood states in patients. Mania episodes are associated with positive biases, i.e. emotional stimuli become more rewarding and less aversive, while the opposite characterizes depression. The objective of this thesis was to identify hedonic bias in mouse models of depression and mania, and to study the underlying neural mechanisms. Using the GBR 12909-induced mouse model of mania, we found apart from the classical mania-like phenotype characterized by hyperlocomotion, strong negative olfactory and gustatory hedonic biases, at the opposite of what we expected. On the contrary, we uncovered a negative olfactory hedonic bias in the corticosterone-induced mouse model of depression, as we predicted. This bias was accompanied by specific basolateral amygdala (BLA) circuits activity disturbances. Furthermore, manipulating some of these BLA circuits activity thanks to chemogenetics was sufficient to partially improve the negative olfactory hedonic bias induced by chronic corticosterone administration. Taken together, our results highlight the interest of olfactory hedonic evaluation in mouse models of depression and mania, and demonstrate the causal role of BLA circuits in hedonic biases associated with depressive-like states.
... Chronic stress is linked to disturbances of mitochondrial functions (van der Kooij, 2020) and mitochondria have been demonstrated to be altered in highly anxious rodents but also mitochondrial disease is associated with higher rates of anxiety, as recently reviewed (Filiou and Sandi, 2019). The impairment of mitochondria in chronic stress may therefore be a link to the development of anxiety (Daviu et al., 2019). With regard to anxiety, impaired mitochondrial respiration, dynamics and disposal of damaged mitochondria (mitophagy) have been reported in the ventral tegmental area (Gebara et al., 2020;Hollis et al., 2015) and in the amygdala (Duan et al., 2021) of rodents, both brain regions with major roles in anxiety disorders. ...
Adequate oxygen supply is essential for the human brain to meet its high energy demands. Therefore, elaborate molecular and systemic mechanism are in place to enable adaptation to low oxygen availability. Anxiety and depressive disorders are characterized by alterations in brain oxygen metabolism and of its components, such as mitochondria or hypoxia inducible factor (HIF)-pathways. Conversely, sensitivity and tolerance to hypoxia may depend on parameters of mental stress and the severity of anxiety and depressive disorders. Here we discuss relevant mechanisms of adaptations to hypoxia, as well as their involvement in mental stress and the etiopathogenesis of anxiety and depressive disorders. We suggest that mechanisms of adaptations to hypoxia (including metabolic responses, inflammation, and the activation of chemosensitive brain regions) modulate and are modulated by stress-related pathways and associated psychiatric diseases. While severe chronic hypoxia or dysfunctional hypoxia adaptations can contribute to the pathogenesis of anxiety and depressive disorders, harnessing controlled responses to hypoxia to increase cellular and psychological resilience emerges as a novel treatment strategy for these diseases.
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The limbic system plays a pivotal role in stress-induced anxiety and intestinal disorders, but how the functional circuits between nuclei within the limbic system are engaged in the processing is still unclear. In our study, the results of fluorescence gold retrograde tracing and fluorescence immunohistochemistry showed that the melanin-concentrating hormone (MCH) neurons of the lateral hypothalamic area (LHA) projected to the basolateral amygdala (BLA). Both chemogenetic activation of MCH neurons and microinjection of MCH into the BLA induced anxiety disorder in mice, which were reversed by intra-BLA microinjection of MCH receptor 1 (MCHR1) blocker SNAP-94847. In the chronic acute combining stress (CACS) stimulated mice, SNAP94847 administrated in the BLA ameliorated anxiety-like behaviors and improved intestinal dysfunction via reducing intestinal permeability and inflammation. In conclusion, MCHergic circuit from the LHA to the BLA participates in the regulation of anxiety-like behavior in mice, and this neural pathway is related to the intestinal dysfunction in CACS mice by regulating intestinal permeability and inflammation.
Introduction: The COVID-19 pandemic disrupted the daily social lives of adolescents by severely limiting social interactions which likely heightened levels of loneliness and a variety of internalizing symptoms. However, little is known about how social distancing adherence and subsequent stress caused by the novel social regulations impact adolescents' feelings of loneliness, and later mental health difficulties, including anxiety and depression. Method: To close this gap, we examined the impact of social distancing regulations on adolescents' (N = 79; Mage = 16.16, SD = 1.15; 47 females; 23 males) depression and anxiety symptoms through loneliness by using data from a 5-week longitudinal study conducted on adolescents in the United States during the initial phases of COVID-19. Results and conclusions: Findings provided evidence that loneliness plays a unique mediating link between social distancing and symptoms of anxiety and depression. Overall, the present study highlights how social distancing during the COVID-19 pandemic has impacted adolescents' mental health during a developmental period that is considered a turning point for psychopathology.
Background Anxiety is a common comorbidity of cardiovascular diseases, which deteriorated cardiac function. Chaihujialonggumulitang (BFG) was reported to have antioxidant properties, alleviate myocardial ischemia injury and improve anxiety-like behavior. The Nuclear factor erythroid 2-related factor 2 (Nrf2) /heme oxygenase-1 (HO-1) pathway is the main mechanism to defend against oxidative stress, and improve cardiac function. This study was to investigate the possible mechanism of BFG in the treatment of psycho-cardiology. Methods AMI with comorbid anxiety rat model was established by ligation of the left anterior descending coronary artery combined with uncertain empty bottle stimulation, followed by the administration of BFG (1 mL/100 g/d by gavage) or Dimethyl fumarate (DMF, 10 mg/kg/d by intraperitoneal injection) for 6 days. Echocardiography, myocardial injury markers, H&E, and Masson staining were employed to evaluate cardiac function. Behavioral tests and hippocampus neurotransmitters were applied to record anxiety-like behavior. We employed immunohistochemistry, RT-PCR, western blotting, and biochemical analysis to detect the protein and gene expression of Nrf2/HO-1 pathway-related factors, and oxidative stress and apoptosis parameters. Results Rats in the AMI and complex groups showed cardiac function deterioration, as well as anxiety-like behavior. BFG improved echocardiography indicators, reduced myocardial injury markers, and attenuated myocardial pathological changes. BFG also ameliorated anxiety-like behaviors and elevated neurotransmitters levels. BFG promoted the activation of Nrf2/HO-1 pathway, increased antioxidant enzyme activities, reduced lipid peroxidation levels, and alleviated oxidative damage and apoptosis. DMF showed therapeutic effects and molecular mechanisms similar to BFG. Conclusion BFG may possess a psycho-cardiology therapeutic effect on AMI with comorbid anxiety by the activation of the Nrf2/HO-1 pathway and suppression of oxidative stress and apoptosis.
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The neurobiology and development of treatments for stress-related neuropsychiatric disorders rely heavily on animal models. However, the complexity of these disorders makes it difficult to model them entirely, so only specific features of human psychopathology are emulated and these models should be used with great caution. Importantly, the effects of stress depend on multiple factors, like duration, context of exposure, and individual variability. Here we present a review on pre-clinical studies of stress-related disorders, especially those developed to model posttraumatic stress disorder, major depression, and anxiety. Animal models provide relevant evidence of the underpinnings of these disorders, as long as face, construct, and predictive validities are fulfilled. The translational challenges faced by scholars include reductionism and anthropomorphic/anthropocentric interpretation of the results instead of a more naturalistic and evolutionary understanding of animal behavior that must be overcome to offer a meaningful model. Other limitations are low statistical power of analysis, poor evaluation of individual variability, sex differences, and possible conflicting effects of stressors depending on specific windows in the lifespan.
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Corticotropin-releasing factor (CRF) that is released from the paraventricular nucleus (PVN) of the hypothalamus is essential for mediating stress response by activating the hypothalamic–pituitary–adrenal axis. CRF-releasing PVN neurons receive inputs from multiple brain regions that convey stressful events, but their neuronal dynamics on the timescale of behavior remain unknown. Here, our recordings of PVN CRF neuronal activity in freely behaving mice revealed that CRF neurons are activated immediately by a range of aversive stimuli. By contrast, CRF neuronal activity starts to drop within a second of exposure to appetitive stimuli. Optogenetic activation or inhibition of PVN CRF neurons was sufficient to induce a conditioned place aversion or preference, respectively. Furthermore, conditioned place aversion or preference induced by natural stimuli was significantly decreased by manipulating PVN CRF neuronal activity. Together, these findings suggest that the rapid, biphasic responses of PVN CRF neurons encode the positive and negative valences of stimuli. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
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Play fighting is a highly rewarding behavior that helps individuals to develop social skills. Early-life stress has been shown to alter play fighting in rats and hamsters as well as to increase aggressive behaviors at adulthood. However, it is not known whether individual differences in stress-induced play fighting are related to differential developmental trajectories towards adult aggression. To address this question, we used a rat model of peripubertal stress (PPS)-induced psychopathology that involves increased aggression at adulthood. We report that, indeed, PPS leads to enhanced play fighting at adolescence. Using a stratification approach, we identify individuals with heightened levels of play fighting as the ones that show abnormal forms of aggression at adulthood. These animals showed as well a rapid habituation of their corticosterone responsiveness to repeated stressor exposure at peripuberty. They also showed a striking increase in mitochondrial function in the amygdala-but not nucleus accumbens-when tested ex vivo. Conversely, low, but not high players, displayed increased expression of the CB1 cannabinoid receptor in the nucleus accumbens shell. Our results highlight adolescence as a potential critical period in which aberrant play fighting is linked to the emergence of adult aggression. They also point at brain energy metabolism during adolescence as a possible target to prevent adult aggression.
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Anxiety is one of the most common mental states of humans. Although it drives us to avoid frightening situations and to achieve our goals, it may also impose significant suffering and burden if it becomes extreme. Because we experience anxiety in a variety of forms, previous studies investigated neural substrates of anxiety in a variety of ways. These studies revealed that individuals with high state, trait, or pathological anxiety showed altered neural substrates. However, no studies have directly investigated whether the different dimensions of anxiety share a common neural substrate, despite its theoretical and practical importance. Here, we investigated a brain network of anxiety shared by different dimensions of anxiety in a unified analytical framework using functional magnetic resonance imaging (fMRI). We analyzed different datasets in a single scale, which was defined by an anxiety-related brain network derived from whole brain. We first conducted the anxiety provocation task with healthy participants who tended to feel anxiety related to obsessive-compulsive disorder (OCD) in their daily life. We found a common state anxiety brain network across participants (1585 trials obtained from 10 participants). Then, using the resting-state fMRI in combination with the participants' behavioral trait anxiety scale scores (879 participants from the Human Connectome Project), we demonstrated that trait anxiety shared the same brain network as state anxiety. Furthermore, the brain network between common to state and trait anxiety could detect patients with OCD, which is characterized by pathological anxiety-driven behaviors (174 participants from multi-site datasets). Our findings provide direct evidence that different dimensions of anxiety have a substantial biological inter-relationship. Our results also provide a biologically defined dimension of anxiety, which may promote further investigation of various human characteristics, including psychiatric disorders, from the perspective of anxiety.
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The basolateral amygdala (BLA) mediates associative learning for both fear and reward. Accumulating evidence supports the notion that different BLA projections distinctly alter motivated behavior, including projections to the nucleus accumbens (NAc), medial aspect of the central amygdala (CeM), and ventral hippocampus (vHPC). Although there is consensus regarding the existence of distinct subsets of BLA neurons encoding positive or negative valence, controversy remains regarding the anatomical arrangement of these populations. First, we map the location of more than 1,000 neurons distributed across the BLA and recorded during a Pavlovian discrimination task. Next, we determine the location of projection-defined neurons labeled with retrograde tracers and use CLARITY to reveal the axonal path in 3-dimensional space. Finally, we examine the local influence of each projection-defined populations within the BLA. Understanding the functional and topographical organization of circuits underlying valence assignment could reveal fundamental principles about emotional processing.
Chronic, uncontrollable stress can lead to various pathologies [1-6]. Adaptive behaviors, such as reward consumption, control excessive stress responses and promote positive health outcomes [3, 7-10]. Corticotrophin-releasing hormone (CRH) neurons in paraventricular nucleus (PVN) represent a key neural population organizing endocrine, autonomic, and behavioral responses to stress by initiating hormonal cascades along the hypothalamic-pituitary-adrenal (HPA) axis and orchestrating stress-related behaviors through direct projections to limbic and autonomic brain centers [11-18]. Although stress and reward have been reported to induce changes of c-Fos and CRH expression in PVN CRH neurons [19-23], it has remained unclear how these neurons respond dynamically to rewarding stimuli to mediate the stress-buffering effects of reward. Using fiber photometry of Ca2+ signals within genetically identified PVN CRH neurons in freely behaving mice [24-26], we find that PVN CRH neurons are rapidly and strongly inhibited by reward consumption. Reward decreases anxiety-like behavior and stress-hormone surge induced by direct acute activation of PVN CRH neurons or repeated stress challenge. Repeated stress upregulates glutamatergic transmission and induces an N-methyl-D-aspartate receptor (NMDAR)-dependent burst-firing pattern in these neurons, whereas reward consumption rebalances the synaptic homeostasis and abolishes the burst firing. Anatomically, PVN CRH neurons integrate widespread information from both stress- and reward-related brain areas in the forebrain and midbrain, including multiple direct long-range GABAergic afferents. Together, these findings reveal a hypothalamic circuit that organizes adaptive stress response by complementarily integrating reward and stress signals and suggest that intervention in this circuit could provide novel methods to treat stress-related disorders.
Many see the periaqueductal gray (PAG) as a region responsible for the downstream control of defensive reactions. Here we provide a detailed review of anatomical and functional data on the different parts of the PAG together with the dorsal raphe, which completes the circle of periaqueductal nuclei. Based on anatomical features, we propose a new subdivision of the periaqueductal gray that accounts for the distinct characteristics of the area. We provide a comprehensive functional view of the periaqueductal gray, going beyond simple panic and escape to integrate data on fear, anxiety, and depression. Importantly, we conclude that this periaqueductal cluster of nuclei is broadly involved in motivated behavior controlling not only aversive but also appetitive behavior and with some involvement in more complex motivational processes such as approach-avoidance conflict resolution. In sum, these highly conserved nuclei surrounding the aqueduct appear to be the simplest, foundational, elements of integrated motivated goal-directed control of all types.
There is substantial evidence that heightened anxiety vulnerability is characterized by increased selective attention to threatening information. The reliability of this anxiety-linked attentional bias has become the focus of considerable recent interest. We distinguish between the potential inconsistency of anxiety-linked attentional bias and inconsistency potentially reflecting the psychometric properties of the assessment approaches used to measure it. Though groups with heightened anxiety vulnerability often exhibit, on average, elevated attention to threat, the evidence suggests that individuals are unlikely to each display a stable, invariant attentional bias to threat. Moreover, although existing assessment approaches can differentiate between groups, they do not exhibit the internal consistency or test-retest reliability necessary to classify individuals in terms of their characteristic pattern of attentional responding to threat. We discuss the appropriate uses of existing attentional bias assessment tasks and propose strategies for enhancing classification of individuals in terms of their tendency to display an attentional bias to threat. Expected final online publication date for the Annual Review of Clinical Psychology Volume 15 is May 7, 2019. Please see for revised estimates.
The neural substrate of anxiety response (state anxiety) to a threatening situation is well defined. However, a lot less is known about brain structures implicated in the individual's predisposition to anxiety (trait anxiety). Scientific evidences lead us to suppose that the medial prefrontal cortex (mPFC) is involved in both trait and state anxiety. Thus, the aim of this study was to investigate the involvement of mPFC in trait anxiety and to further evaluate its participation in state anxiety. Sixty six adult, Wistar, male rats were first tested in the free-exploratory paradigm (FEP) and were categorized according to their levels of trait anxiety (high, medium and low). Three to six days after this exposure, all animals were submitted to stereotaxic brain surgery. Half the animals from each anxiety category was allocated to the mPFC-lesioned group and the other half to the Sham-lesioned group. After seven to nine days, all animals were again tested in FEP. Eight to 10 days later, the animals were tested in the Hole Board test, a model of state anxiety. The mPFC lesion decreased levels of trait anxiety of highly anxious rats, whereas it reduced the state anxiety of all animals, regardless the level of trait anxiety. These data extend evidence of the participation of the mPFC in state anxiety and it demonstrate the involvement of this brain structure in trait anxiety, a personality trait supposed to be a predisposing factor for anxiety disorders.
Previous work has implicated projections from the acoustic thalamus to the amygdala in the classical conditioning of emotional responses to auditory stimuli. The purpose of the present studies was to determine whether the lateral amygdaloid nucleus (AL), which is a major subcortical target of projections from the acoustic thalamus, might be the sensory interface of the amygdala in emotional conditioning. Lesions were placed in AL of rats and the effects on emotional conditioning were examined. Lesions of AL, but not lesions of the striatum above or the cortex adjacent to the AL, interfered with emotional conditioning. Lesions that only partially destroyed AL or lesions placed too ventrally that completely missed AL had no effect. AL lesions did not affect the responses elicited following nonassociative (random) training. AL is thus an essential link in the circuitry through which auditory stimuli are endowed with affective properties and may function as the sensory interface of the amygdala during emotional learning.