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Amygdala Circuit Substrates for Stress Adaptation and Adversity

Open AccessPublished:January 07, 2021DOI:https://doi.org/10.1016/j.biopsych.2020.12.026

      Abstract

      Brain systems that promote maintenance of homeostasis in the face of stress have significant adaptive value. A growing body of work across species demonstrates a critical role for the amygdala in promoting homeostasis by regulating physiological and behavioral responses to stress. This review focuses on an emerging body of evidence that has begun to delineate the contribution of specific long-range amygdala circuits in mediating the effects of stress. After summarizing the major anatomical features of the amygdala and its connectivity to other limbic structures, we discuss recent findings from rodents showing how stress causes structural and functional remodeling of amygdala neuronal outputs to defined cortical and subcortical target regions. We also consider some of the environmental and genetic factors that have been found to moderate how the amygdala responds to stress and relate the emerging preclinical literature to the current understanding of the pathophysiology and treatment of stress-related neuropsychiatric disorders. Future effort to translate these findings to clinics may help to develop valuable tools for prevention, diagnosis, and treatment of these diseases.

      Keywords

      Coping with environmental stress is key to the adaptive success of many species, including our own (
      • McEwen B.S.
      Physiology and neurobiology of stress and adaptation: Central role of the brain.
      ,
      • Schneiderman N.
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      ). An ever-growing body of preclinical and clinical research shows that the amygdala, a region located deep inside the temporal lobe, is one of the critical mediators of response to stress and a primary target of stress’s effects on the brain (
      • McEwen B.S.
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      Stress effects on neuronal structure: Hippocampus, amygdala, and prefrontal cortex.
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      • Chattarji S.
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      Neighborhood matters: Divergent patterns of stress-induced plasticity across the brain.
      ). In recent years, with the aid of state-of-the-art technologies such as optogenetics, virally assisted tracing, and in vivo neuronal imaging, there has been a renewed focus on dissecting the inputs and outputs of amygdala subnuclei and disentangling the circuit mechanisms through which the amygdala exerts its effects on stress-relevant functions and behaviors, particularly fear and anxiety (
      • Chattarji S.
      • Tomar A.
      • Suvrathan A.
      • Ghosh S.
      • Rahman M.M.
      Neighborhood matters: Divergent patterns of stress-induced plasticity across the brain.
      ,
      • Janak P.H.
      • Tye K.M.
      From circuits to behaviour in the amygdala.
      ,
      • Herry C.
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      Encoding of fear learning and memory in distributed neuronal circuits.
      ,
      • Duvarci S.
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      Amygdala microcircuits controlling learned fear.
      ,
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      ). The goal of this review is to consider emerging insights into long-range amygdala circuits that mediate response to stressors, with a particular emphasis on regulation of the hypothalamic-pituitary-adrenal (HPA) axis and stress-induced changes in anxiety.
      We begin by briefly outlining the anatomical features of the amygdala and the local and long-range connections of neurons located in the major amygdala subnuclei: the basolateral amygdala (BLA), central amygdala (CeA), and medial amygdala (MeA). We then discuss findings from rodent studies that support a role for these projections in modulating behavioral and neuroendocrine responses to stress, with particular emphasis being placed on discussing how stress produces structural and functional remodeling of the amygdala’s afferent and efferent connections to produce behavioral abnormalities, such as heightened anxiety-related behavior. Some key environmental and genetic factors that affect the amygdala’s response to stress are also noted. Finally, we relate the emerging preclinical literature to current understanding of the pathophysiology and treatment of stress-related neuropsychiatric disorders.

      A Brief Overview of Amygdala Anatomy

      The amygdala is an almond-shaped structure that can be subdivided into 13 or more subnuclei (
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      The amygdaloid complex: Anatomy and physiology.
      ,
      • McDonald A.J.
      Is there an amygdala and how far does it extend? An anatomical perspective.
      ). Of these, the BLA, CeA, and MeA are the most heavily studied. The BLA comprises the lateral and basal amygdala, while the CeA is divisible into medial, central, and lateral subdivisions (
      • Sah P.
      • Faber E.S.
      • Lopez De Armentia M.
      • Power J.
      The amygdaloid complex: Anatomy and physiology.
      ,
      • Gilpin N.W.
      • Herman M.A.
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      The central amygdala as an integrative hub for anxiety and alcohol use disorders.
      ). Because of differing developmental origins, certain amygdala nuclei exhibit a distinct neuronal composition (
      • Sah P.
      • Faber E.S.
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      • Power J.
      The amygdaloid complex: Anatomy and physiology.
      ,
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      What is the amygdala?.
      ). The BLA has a more cortical-like profile, primarily containing excitatory neurons, whereas the CeA and MeA have a striatal-like composition of largely inhibitory neurons (
      • Sah P.
      • Faber E.S.
      • Lopez De Armentia M.
      • Power J.
      The amygdaloid complex: Anatomy and physiology.
      ,
      • McDonald A.J.
      Is there an amygdala and how far does it extend? An anatomical perspective.
      ,
      • McDonald A.J.
      Cytoarchitecture of the central amygdaloid nucleus of the rat.
      ). Another discrete set of inhibitory nuclei, known as intercalated cell clusters, is located at the intersection of the BLA and CeA (
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      • Obata K.
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      A specialized subclass of interneurons mediates dopaminergic facilitation of amygdala function.
      ).
      Anatomically, the BLA is well positioned to integrate information from diverse sources (Figure 1). The lateral amygdala receives multimodal sensory information from the thalamus, associative cortex, and brainstem (
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      The lateral amygdaloid nucleus: Sensory interface of the amygdala in fear conditioning.
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      • Tully K.
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      Norepinephrine enables the induction of associative long-term potentiation at thalamo-amygdala synapses.
      ,
      • McDonald A.J.
      Cortical pathways to the mammalian amygdala.
      ). This information is sent on to the basal amygdala, where it converges with top-down inputs from the medial prefrontal cortex (mPFC), contextual information from the ventral hippocampus (vHPC), and neuromodulatory signals from regions such as the ventral tegmental area, dorsal raphe nucleus, locus coeruleus, and basal forebrain (
      • Sharp B.M.
      Basolateral amygdala and stress-induced hyperexcitability affect motivated behaviors and addiction.
      ,
      • Sengupta A.
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      A discrete dorsal raphe to basal amygdala 5-HT circuit calibrates aversive memory.
      ). The basal amygdala sends extensive efferent fibers back to the mPFC and vHPC, and the circuits formed among these reciprocally connected regions are essential for stress coping (
      • Liu W.Z.
      • Zhang W.H.
      • Zheng Z.H.
      • Zou J.X.
      • Liu X.X.
      • Huang S.H.
      • et al.
      Identification of a prefrontal cortex-to-amygdala pathway for chronic stress-induced anxiety.
      ). The MeA receives bundles of fibers from the accessory olfactory bulbs (
      • Keshavarzi S.
      • Sullivan R.K.
      • Ianno D.J.
      • Sah P.
      Functional properties and projections of neurons in the medial amygdala.
      ) and sends efferents to the basal forebrain, brainstem, and hypothalamus (
      • Lin Y.
      • Li X.
      • Lupi M.
      • Kinsey-Jones J.S.
      • Shao B.
      • Lightman S.L.
      • O’Byrne K.T.
      The role of the medial and central amygdala in stress-induced suppression of pulsatile LH secretion in female rats.
      ), both directly and indirectly via intermediate nuclei such as the bed nucleus of the stria terminalis (BNST), to regulate various defensive and reproductive behaviors (
      • Choi G.B.
      • Dong H.W.
      • Murphy A.J.
      • Valenzuela D.M.
      • Yancopoulos G.D.
      • Swanson L.W.
      • Anderson D.J.
      Lhx6 delineates a pathway mediating innate reproductive behaviors from the amygdala to the hypothalamus.
      ,
      • Miller S.M.
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      • Shen A.
      • Zweifel L.S.
      Divergent medial amygdala projections regulate approach-avoidance conflict behavior.
      ).
      Figure thumbnail gr1
      Figure 1Input and output connections of the major amygdala subnuclei. Some of the major known functions of amygdala outputs are also indicated. BA, basal amygdala; BF, basal forebrain; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; DRN, dorsal raphe nucleus; EC, entorhinal cortex; GABAergic, gamma-aminobutyric acidergic; LA, lateral amygdala; LC, locus coeruleus; MeA, medial amygdala; mPFC, medial prefrontal cortex; NAC, nucleus accumbens; NTS, nucleus of the solitary tract; PAG, periaqueductal gray; PBN, parabrachial nucleus; SNL, lateral substantia nigra; VTA, ventral tegmental area.
      The CeA (specifically the medial CeA) is traditionally considered as the amygdala’s main output station (Figure 1). In addition to receiving dense projection from the BLA (
      • Duvarci S.
      • Pare D.
      Amygdala microcircuits controlling learned fear.
      ), some of which is routed through the intercalated cell clusters (
      • Asede D.
      • Bosch D.
      • Lüthi A.
      • Ferraguti F.
      • Ehrlich I.
      Sensory inputs to intercalated cells provide fear-learning modulated inhibition to the basolateral amygdala.
      ), the CeA receives afferents from the insular cortex to regulate feeding, from the paraventricular nucleus of the thalamus to regulate fear memory expression, and from the vHPC to mediate contextual fear retrieval and fear renewal (
      • Gilpin N.W.
      • Herman M.A.
      • Roberto M.
      The central amygdala as an integrative hub for anxiety and alcohol use disorders.
      ,
      • Fadok J.P.
      • Markovic M.
      • Tovote P.
      • Lüthi A.
      New perspectives on central amygdala function.
      ). The CeA projects extensively to stress- and fear-mediating brainstem regions, including the nucleus tractus solitarius, ventral tegmental area, ventrolateral periaqueductal gray, hypothalamus, lateral substantia nigra, and basal forebrain (
      • Gilpin N.W.
      • Herman M.A.
      • Roberto M.
      The central amygdala as an integrative hub for anxiety and alcohol use disorders.
      ,
      • Fadok J.P.
      • Markovic M.
      • Tovote P.
      • Lüthi A.
      New perspectives on central amygdala function.
      ). The CeA also makes reciprocal connections with regions such as the locus coeruleus and BNST, which, as discussed below, are critically engaged in regulating the stress response. Although not a focus of this review [refer to several excellent reviews on the topic (
      • Lebow M.A.
      • Chen A.
      Overshadowed by the amygdala: The bed nucleus of the stria terminalis emerges as key to psychiatric disorders.
      ,
      • Miles O.W.
      • Maren S.
      Role of the bed nucleus of the stria terminalis in PTSD: Insights from preclinical models.
      )], it should be noted that the BNST (part of the extended amygdala) plays an increasingly appreciated role in stress responsivity through connections with both the CeA and MeA (
      • Nordman J.
      • Ma X.
      • Li Z.
      Traumatic stress induces prolonged aggression increase through synaptic potentiation in the medial amygdala circuits.
      ).
      A feature that has traditionally complicated delineation of the function of the BLA and CeA is that projection neurons (PNs) with preferential output targets outside of the amygdala are not precisely spatially organized, but intermingled within the nuclei in a salt and pepper–like pattern. Nonetheless, individual PNs appear to be quite faithful to specific projection targets, insofar as mPFC-projecting BLA PNs infrequently collateralize to the vHPC, while those projecting to the CeA are separable from nucleus accumbens (NAc) projectors (
      • Beyeler A.
      • Namburi P.
      • Glober G.F.
      • Simonnet C.
      • Calhoon G.G.
      • Conyers G.F.
      • et al.
      Divergent routing of positive and negative information from the amygdala during memory retrieval.
      ,
      • Zhang W.H.
      • Liu W.Z.
      • He Y.
      • You W.J.
      • Zhang J.Y.
      • Xu H.
      • et al.
      Chronic stress causes projection-specific adaptation of amygdala neurons via small-conductance calcium-activated potassium channel downregulation.
      ). PNs also differ in their genetic profile in a manner that reflects their anatomical position within the BLA; for instance, Rspo2 is preferentially expressed in PNs in the anterior BLA, while Ppp1r1b is preponderant in the posterior part (
      • Kim J.
      • Pignatelli M.
      • Xu S.
      • Itohara S.
      • Tonegawa S.
      Antagonistic negative and positive neurons of the basolateral amygdala.
      ).
      While there appears to be a good degree of cross-species homology in terms of the regions to which the amygdala projects, the extent of certain connections varies; for instance, the BLA projects more extensively to the cortex in primates than in rodents (
      • Chareyron L.J.
      • Banta Lavenex P.
      • Amaral D.G.
      • Lavenex P.
      Stereological analysis of the rat and monkey amygdala.
      ). There is also evidence that the amygdala displays sexually dimorphic features. For example, men generally exhibit greater amygdala volume than women, but this difference manifests during late puberty (
      • Goddings A.L.
      • Mills K.L.
      • Clasen L.S.
      • Giedd J.N.
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      The influence of puberty on subcortical brain development.
      ).

      Contributions of Amygdala Subnuclei to Stress Mediation

      Many organisms have evolved dedicated systems for maintaining bodily homeostasis in the face of stress. Accumulating evidence has highlighted a critical role for the amygdala in regulating physiological and behavioral responses to stress that serve to promote such homeostasis (
      • Janak P.H.
      • Tye K.M.
      From circuits to behaviour in the amygdala.
      ,
      • Krabbe S.
      • Gründemann J.
      • Lüthi A.
      Amygdala inhibitory circuits regulate associative fear conditioning.
      ,
      • Mozhui K.
      • Karlsson R.M.
      • Kash T.L.
      • Ihne J.
      • Norcross M.
      • Patel S.
      • et al.
      Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability.
      ,
      • Masneuf S.
      • Lowery-Gionta E.
      • Colacicco G.
      • Pleil K.E.
      • Li C.
      • Crowley N.
      • et al.
      Glutamatergic mechanisms associated with stress-induced amygdala excitability and anxiety-related behavior.
      ,
      • Yang R.J.
      • Mozhui K.
      • Karlsson R.M.
      • Cameron H.A.
      • Williams R.W.
      • Holmes A.
      Variation in mouse basolateral amygdala volume is associated with differences in stress reactivity and fear learning.
      ). However, numerous findings indicate distinct contributions of specific amygdala subnuclei to these processes. While the BLA and MeA are preferentially activated by psychogenic (e.g., restraint) stressors (
      • Dayas C.V.
      • Buller K.M.
      • Crane J.W.
      • Xu Y.
      • Day T.A.
      Stressor categorization: Acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups.
      ,
      • Figueiredo H.F.
      • Bodie B.L.
      • Tauchi M.
      • Dolgas C.M.
      • Herman J.P.
      Stress integration after acute and chronic predator stress: Differential activation of central stress circuitry and sensitization of the hypothalamo-pituitary-adrenocortical axis.
      ), the CeA appears to be more readily responsive to systemic stressors (
      • Thrivikraman K.V.
      • Su Y.
      • Plotsky P.M.
      Patterns of Fos-immunoreactivity in the CNS induced by repeated hemorrhage in conscious rats: Correlations with pituitary-adrenal axis activity.
      ,
      • Prewitt C.M.
      • Herman J.P.
      Hypothalamo-pituitary-adrenocortical regulation following lesions of the central nucleus of the amygdala.
      ). For example, BLA lesioning was found to occlude habituation of HPA axis activity following restraint stress (
      • Bhatnagar S.
      • Vining C.
      • Denski K.
      Regulation of chronic stress-induced changes in hypothalamic-pituitary-adrenal activity by the basolateral amygdala.
      ), whereas CeA damage largely prevented hypothalamic corticotropin-releasing factor (CRF) release and adrenocorticotropic hormone secretion following systemic interleukin 1β injection (
      • Xu Y.
      • Day T.A.
      • Buller K.M.
      The central amygdala modulates hypothalamic-pituitary-adrenal axis responses to systemic interleukin-1beta administration.
      ) or herpes simplex virus-1 infection (
      • Weidenfeld J.
      • Itzik A.
      • Goshen I.
      • Yirmiya R.
      • Ben-Hur T.
      Role of the central amygdala in modulating the pituitary-adrenocortical and clinical responses in experimental herpes simplex virus-1 encephalitis.
      ).
      Not all findings are consistent with this dichotomy, however. Systemic stressors such as peripheral inflammation have been shown to increase BLA neuronal firing and glutamatergic transmission (
      • Munshi S.
      • Rosenkranz J.A.
      Effects of peripheral immune challenge on in vivo firing of basolateral amygdala neurons in adult male rats.
      ,
      • Zheng Z.H.
      • Tu J.L.
      • Li X.H.
      • Hua Q.
      • Liu W.Z.
      • Liu Y.
      • et al.
      Neuroinflammation induces anxiety- and depressive-like behavior by modulating neuronal plasticity in the basolateral amygdala.
      ), while restraint stress has been found to affect CeA activity through altering GABAergic (gamma-aminobutyric acidergic) transmission (
      • Ciccocioppo R.
      • de Guglielmo G.
      • Hansson A.C.
      • Ubaldi M.
      • Kallupi M.
      • Cruz M.T.
      • et al.
      Restraint stress alters nociceptin/orphanin FQ and CRF systems in the rat central amygdala: Significance for anxiety-like behaviors.
      ). In addition, the CeA regulates immune adaptations to stress via neuroendocrinal mediators (
      • Meerveld B.G.
      • Johnson A.C.
      Mechanisms of stress-induced visceral pain.
      ,
      • Varodayan F.P.
      • Khom S.
      • Patel R.R.
      • Steinman M.Q.
      • Hedges D.M.
      • Oleata C.S.
      • et al.
      Role of TLR4 in the modulation of central amygdala GABA transmission by CRF following restraint stress.
      ). A recent study identified a neural circuit in mice that links CRF-expressing neurons in the CeA and paraventricular nucleus of the hypothalamus (PVN) to the spleen (
      • Zhang X.
      • Lei B.
      • Yuan Y.
      • Zhang L.
      • Hu L.
      • Jin S.
      • et al.
      Brain control of humoral immune responses amenable to behavioural modulation.
      ). Pharmacogenetic activation of this pathway increased the abundance of antibody-producing plasma cells, whereas pharmacogenetic inhibition reduced plasma cell formation after immunization (
      • Zhang X.
      • Lei B.
      • Yuan Y.
      • Zhang L.
      • Hu L.
      • Jin S.
      • et al.
      Brain control of humoral immune responses amenable to behavioural modulation.
      ). These findings suggest that the CeA is part of a brain-spleen circuit exerting rapid control of stress-induced immune responses.
      Despite exerting a strong regulatory influence over the HPA axis, the major amygdala subnuclei have quite limited direct projections to the PVN and peri-PVN regions (
      • Prewitt C.M.
      • Herman J.P.
      Anatomical interactions between the central amygdaloid nucleus and the hypothalamic paraventricular nucleus of the rat: A dual tract-tracing analysis.
      ,
      • Ulrich-Lai Y.M.
      • Herman J.P.
      Neural regulation of endocrine and autonomic stress responses.
      ). The BLA could route its influence on the PVN through various intermediate relays, including the BNST and nucleus tractus solitarius (
      • Dong H.W.
      • Petrovich G.D.
      • Swanson L.W.
      Topography of projections from amygdala to bed nuclei of the stria terminalis.
      ,
      • Herman J.P.
      • Figueiredo H.
      • Mueller N.K.
      • Ulrich-Lai Y.
      • Ostrander M.M.
      • Choi D.C.
      • Cullinan W.E.
      Central mechanisms of stress integration: Hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness.
      ) (Figure 2) or through modulating BNST-projecting PFC neurons that are linked to stress responsivity and coping (
      • Johnson S.B.
      • Emmons E.B.
      • Lingg R.T.
      • Anderson R.M.
      • Romig-Martin S.A.
      • LaLumiere R.T.
      • et al.
      Prefrontal-bed nucleus circuit modulation of a passive coping response set.
      ,
      • Radley J.J.
      • Johnson S.B.
      Anteroventral bed nuclei of the stria terminalis neurocircuitry: Towards an integration of HPA axis modulation with coping behaviors - Curt Richter Award Paper 2017.
      ). The BNST is also a plausible intermediary connecting the CeA and MeA with the PVN (
      • Gungor N.Z.
      • Paré D.
      Functional heterogeneity in the bed nucleus of the stria terminalis.
      ); for example, inhibitory projections from the CeA and MeA onto inhibitory BNST-PVN neurons could represent a disinhibitory circuit mediating CeA-driven PVN responses to stress.
      Figure thumbnail gr2
      Figure 2Circuit basis for amygdala regulation of the HPA axis activity. Amygdala subnuclei, including the BLA, CeA, and MeA, modulate the HPA axis activity primarily through some intermediate nuclei, including the BNST, NTS, DMH, and mPOA, which send efferent fibers to the PVN. ac, anterior commissure; ACTH, adrenocorticotropic hormone; alBNST, anterolateral BNST; avBNST, anteroventral BNST; BLA, basolateral amygdala; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; CRF, corticotropin-releasing factor; dBNST, dorsal BNST; dmDMH, dorsomedial DMH; DMH, dorsomedial hypothalamus; GABAergic, gamma-aminobutyric acidergic; HPA, hypothalamic-pituitary-adrenal; LA, lateral amygdala; MeA, medial amygdala; mPOA, medial preoptic area; NTS, nucleus of the solitary tract; pBNST, posterior BNST; PVN, paraventricular nucleus of the hypothalamus; vlDMH, ventrolateral DMH.

      Projection-Specific Amygdala Circuits in Stress Mediation

      The amygdala and other major components of the limbic system, particularly the PFC and hippocampus, have well-established roles in the regulation of stress (
      • Ulrich-Lai Y.M.
      • Herman J.P.
      Neural regulation of endocrine and autonomic stress responses.
      ,
      • Herman J.P.
      • McKlveen J.M.
      • Ghosal S.
      • Kopp B.
      • Wulsin A.
      • Makinson R.
      • et al.
      Regulation of the hypothalamic-pituitary-adrenocortical stress response.
      ,
      • Calhoon G.G.
      • Tye K.M.
      Resolving the neural circuits of anxiety.
      ,
      • Maren S.
      • Holmes A.
      Stress and fear extinction.
      ). However, how interconnections between these regions serve to support this function is only beginning to be understood.
      The amygdala has extensive and reciprocal connections with the hippocampus (
      • Pikkarainen M.
      • Rönkkö S.
      • Savander V.
      • Insausti R.
      • Pitkänen A.
      Projections from the lateral, basal, and accessory basal nuclei of the amygdala to the hippocampal formation in rat.
      ). Projections from the vHPC to the BLA and CeA have defined contributions to the mediation of contextual fear retrieval and renewal (
      • Jimenez J.C.
      • Su K.
      • Goldberg A.R.
      • Luna V.M.
      • Biane J.S.
      • Ordek G.
      • et al.
      Anxiety cells in a hippocampal-hypothalamic circuit.
      ,
      • Kim W.B.
      • Cho J.H.
      Encoding of contextual fear memory in hippocampal-amygdala circuit.
      ,
      • Xu C.
      • Krabbe S.
      • Gründemann J.
      • Botta P.
      • Fadok J.P.
      • Osakada F.
      • et al.
      Distinct hippocampal pathways mediate dissociable roles of context in memory retrieval.
      ). To date, only limited investigations avail on the role of BLA-to-vHPC projections in stress-related behaviors and HPA axis activity. We have recently shown that chronic restraint stress (CRS) increases anxiety-like behavior that, as we discuss further below, is associated with various functional and structural abnormalities in vHPC-projecting BLA neurons (
      • Zhang J.Y.
      • Liu T.H.
      • He Y.
      • Pan H.Q.
      • Zhang W.H.
      • Yin X.P.
      • et al.
      Chronic stress remodels synapses in an amygdala circuit-specific manner.
      ). These observations suggest that the BLA-vHPC pathway may play a prominent role in linking stress with behavioral sequelae, notably increased anxiety-like behavior.
      BLA neurons targeting the vHPC are located at both its anterior (aBLA) and posterior (pBLA) portions (
      • Pikkarainen M.
      • Rönkkö S.
      • Savander V.
      • Insausti R.
      • Pitkänen A.
      Projections from the lateral, basal, and accessory basal nuclei of the amygdala to the hippocampal formation in rat.
      ,
      • Felix-Ortiz A.C.
      • Beyeler A.
      • Seo C.
      • Leppla C.A.
      • Wildes C.P.
      • Tye K.M.
      BLA to vHPC inputs modulate anxiety-related behaviors.
      ,
      • Yang Y.
      • Wang Z.H.
      • Jin S.
      • Gao D.
      • Liu N.
      • Chen S.P.
      • et al.
      Opposite monosynaptic scaling of BLP-vCA1 inputs governs hopefulness- and helplessness-modulated spatial learning and memory.
      ). Some evidence emerges that aBLA and pBLA projections to the vHPC exhibit functional differences. Hence, optogenetic stimulation or inhibition of the aBLA→vHPC pathway, respectively, enhances and suppresses anxiety-like behavior in the elevated plus maze (
      • Felix-Ortiz A.C.
      • Beyeler A.
      • Seo C.
      • Leppla C.A.
      • Wildes C.P.
      • Tye K.M.
      BLA to vHPC inputs modulate anxiety-related behaviors.
      ). Conversely, optogenetic stimulation of vHPC-projecting pBLA neurons reduces elevated plus maze anxiety-like behavior (
      • Pi G.
      • Gao D.
      • Wu D.
      • Wang Y.
      • Lei H.
      • Zeng W.
      • et al.
      Posterior basolateral amygdala to ventral hippocampal CA1 drives approach behaviour to exert an anxiolytic effect.
      ). One possible explanation for these differences is that the aBLA primarily targets calbindin1-negative neurons in the deeper layer of the ventral CA1, whereas the pBLA innervates calbindin1-positive neurons in the superficial layer of the ventral CA1 (
      • Pi G.
      • Gao D.
      • Wu D.
      • Wang Y.
      • Lei H.
      • Zeng W.
      • et al.
      Posterior basolateral amygdala to ventral hippocampal CA1 drives approach behaviour to exert an anxiolytic effect.
      ). At a more general conceptual level, these findings suggest that BLA outputs to the vHPC pathway may represent a stress-mediating pathway that complements or even bypasses the canonical BLA→CeA circuit to regulate extra-amygdala regions. It is clear that irrespective of the source of input drive, the CeA is well placed to generate aversive and anxiety-like behaviors, for example, through a recently described population of CRF-expressing CeA neurons projecting to the locus coeruleus (
      • McCall J.G.
      • Al-Hasani R.
      • Siuda E.R.
      • Hong D.Y.
      • Norris A.J.
      • Ford C.P.
      • Bruchas M.R.
      CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety.
      ).
      The mPFC is traditionally thought to exert top-down control of the amygdala and, thus, fear and anxiety (
      • Quirk G.J.
      • Beer J.S.
      Prefrontal involvement in the regulation of emotion: Convergence of rat and human studies.
      ,
      • Adhikari A.
      • Lerner T.N.
      • Finkelstein J.
      • Pak S.
      • Jennings J.H.
      • Davidson T.J.
      • et al.
      Basomedial amygdala mediates top-down control of anxiety and fear.
      ,
      • Bukalo O.
      • Pinard C.R.
      • Silverstein S.
      • Brehm C.
      • Hartley N.D.
      • Whittle N.
      • et al.
      Prefrontal inputs to the amygdala instruct fear extinction memory formation.
      ). Interactions between these regions are central to modulating the effects of stress on higher-order behaviors (
      • Liu W.Z.
      • Zhang W.H.
      • Zheng Z.H.
      • Zou J.X.
      • Liu X.X.
      • Huang S.H.
      • et al.
      Identification of a prefrontal cortex-to-amygdala pathway for chronic stress-induced anxiety.
      ,
      • Lowery-Gionta E.G.
      • Crowley N.A.
      • Bukalo O.
      • Silverstein S.
      • Holmes A.
      • Kash T.L.
      Chronic stress dysregulates amygdalar output to the prefrontal cortex.
      ). Supporting this view, functional magnetic resonance imaging (fMRI) in humans has linked functional connections between the amygdala and mPFC to the emotional and cognitive aspects of stressful experience (
      • Jung W.H.
      • Lee S.
      • Lerman C.
      • Kable J.W.
      Amygdala functional and structural connectivity predicts individual risk tolerance.
      ,
      • Robinson O.J.
      • Vytal K.
      • Cornwell B.R.
      • Grillon C.
      The impact of anxiety upon cognition: Perspectives from human threat of shock studies.
      ). For example, the threat of an electric shock in healthy volunteers increases coupling between the dorsomedial PFC (dmPFC) and amygdala, and this correlates with shock-related anxiety (
      • Robinson O.J.
      • Charney D.R.
      • Overstreet C.
      • Vytal K.
      • Grillon C.
      The adaptive threat bias in anxiety: Amygdala-dorsomedial prefrontal cortex coupling and aversive amplification.
      ,
      • Robinson O.J.
      • Krimsky M.
      • Lieberman L.
      • Allen P.
      • Vytal K.
      • Grillon C.
      The dorsal medial prefrontal (anterior cingulate) cortex-amygdala aversive amplification circuit in unmedicated generalised and social anxiety disorders: An observational study.
      ).
      Further refining this view, studies in rodents have shown that manipulation of mPFC inputs to the BLA and BLA reciprocal connections to the mPFC affect anxiety-like behaviors in a manner that depends on the specific subregion of the mPFC. For example, while optogenetic activation of ventromedial PFC (vmPFC) projections to the amygdala pathway decreased anxiety-like behavior, activation of the amygdala-projecting dmPFC neurons was without effect (
      • Adhikari A.
      • Lerner T.N.
      • Finkelstein J.
      • Pak S.
      • Jennings J.H.
      • Davidson T.J.
      • et al.
      Basomedial amygdala mediates top-down control of anxiety and fear.
      ). There is also evidence that optogenetic manipulations of BLA inputs to the vmPFC and dmPFC produce differing alterations in anxiety-related and fear behaviors in the face of extinction and uncertainty (
      • Lowery-Gionta E.G.
      • Crowley N.A.
      • Bukalo O.
      • Silverstein S.
      • Holmes A.
      • Kash T.L.
      Chronic stress dysregulates amygdalar output to the prefrontal cortex.
      ,
      • Burgos-Robles A.
      • Kimchi E.Y.
      • Izadmehr E.M.
      • Porzenheim M.J.
      • Ramos-Guasp W.A.
      • Nieh E.H.
      • et al.
      Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment.
      ,
      • Felix-Ortiz A.C.
      • Burgos-Robles A.
      • Bhagat N.D.
      • Leppla C.A.
      • Tye K.M.
      Bidirectional modulation of anxiety-related and social behaviors by amygdala projections to the medial prefrontal cortex.
      ,
      • Senn V.
      • Wolff S.B.
      • Herry C.
      • Grenier F.
      • Ehrlich I.
      • Gründemann J.
      • et al.
      Long-range connectivity defines behavioral specificity of amygdala neurons.
      ,
      • Klavir O.
      • Prigge M.
      • Sarel A.
      • Paz R.
      • Yizhar O.
      Manipulating fear associations via optogenetic modulation of amygdala inputs to prefrontal cortex.
      ). Notably, the response of the amygdala-PFC circuit to stress also displays between-sex differences. For example, females show stronger amygdala and PFC activation than males in the face of affect-laden, mostly negative, cues (
      • Helpman L.
      • Zhu X.
      • Suarez-Jimenez B.
      • Lazarov A.
      • Monk C.
      • Neria Y.
      Sex differences in trauma-related psychopathology: A critical review of neuroimaging literature (2014-2017).
      ). They also exhibit stronger negative amygdala-PFC connectivity and positive amygdala-insula connectivity in the process of emotional regulation (
      • Wu Y.
      • Li H.
      • Zhou Y.
      • Yu J.
      • Zhang Y.
      • Song M.
      • et al.
      Sex-specific neural circuits of emotion regulation in the centromedial amygdala.
      ).

      Stress-Induced Amygdala Remodeling and Functional Adaptation

      Structural Remodeling

      Amygdala neurons exhibit considerable structural remodeling in response to stress. However, these effects vary as a function of subnucleus and the stressor type and chronicity of stressor applied. While elevated platform exposure produces rapid increase in BLA PN spine density (
      • Maroun M.
      • Ioannides P.J.
      • Bergman K.L.
      • Kavushansky A.
      • Holmes A.
      • Wellman C.L.
      Fear extinction deficits following acute stress associate with increased spine density and dendritic retraction in basolateral amygdala neurons.
      ), acute restraint stress causes delayed spinogenesis in BLA PNs, appearing 10 days after the stress and accompanied by increases in anxiety-like behavior (
      • Mitra R.
      • Jadhav S.
      • McEwen B.S.
      • Vyas A.
      • Chattarji S.
      Stress duration modulates the spatiotemporal patterns of spine formation in the basolateral amygdala.
      ). In contrast, CRS causes seemingly irreversible dendritic hypertrophy and spine outgrowth in BLA PNs (
      • Vyas A.
      • Pillai A.G.
      • Chattarji S.
      Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior.
      ,
      • Vyas A.
      • Jadhav S.
      • Chattarji S.
      Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala.
      ) but dendritic hypotrophy in BLA and MeA, but not CeA, interneurons (
      • Gilabert-Juan J.
      • Castillo-Gomez E.
      • Pérez-Rando M.
      • Moltó M.D.
      • Nacher J.
      Chronic stress induces changes in the structure of interneurons and in the expression of molecules related to neuronal structural plasticity and inhibitory neurotransmission in the amygdala of adult mice.
      ,
      • Vyas A.
      • Bernal S.
      • Chattarji S.
      Effects of chronic stress on dendritic arborization in the central and extended amygdala.
      ,
      • Bennur S.
      • Shankaranarayana Rao B.S.
      • Pawlak R.
      • Strickland S.
      • McEwen B.S.
      • Chattarji S.
      Stress-induced spine loss in the medial amygdala is mediated by tissue-plasminogen activator.
      ). Differential neuronal remodeling by distinct stress paradigms extends to regions such as the hippocampus and mPFC (
      • Radley J.J.
      • Rocher A.B.
      • Rodriguez A.
      • Ehlenberger D.B.
      • Dammann M.
      • McEwen B.S.
      • et al.
      Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex.
      ,
      • Urban K.R.
      • Geng E.
      • Bhatnagar S.
      • Valentino R.J.
      Age- and sex-dependent impact of repeated social stress on morphology of rat prefrontal cortex pyramidal neurons.
      ,
      • Melo S.R.
      • Antoniazzi C.T.D.
      • Hossain S.
      • Kolb B.
      Short predictable stress promotes resistance to anxiety behavior and increases dendritic spines in prefrontal cortex and hippocampus.
      ,
      • Patel D.
      • Anilkumar S.
      • Chattarji S.
      • Buwalda B.
      Repeated social stress leads to contrasting patterns of structural plasticity in the amygdala and hippocampus.
      ). However, stress-induced dendritic hypertrophy in BLA PNs represents a striking contrast with dendritic retraction and spine loss evident in hippocampal and mPFC neurons (
      • McEwen B.S.
      Stress-induced remodeling of hippocampal CA3 pyramidal neurons.
      ,
      • Holmes A.
      • Wellman C.L.
      Stress-induced prefrontal reorganization and executive dysfunction in rodents.
      ). The reasons for these profound regional differences remain poorly understood, although some studies posit the importance of differences in BDNF (brain-derived neurotrophic factor) signaling (
      • Bennett M.R.
      • Lagopoulos J.
      Stress and trauma: BDNF control of dendritic-spine formation and regression.
      ).
      It is becoming increasingly clear that stress also differentially affects BLA PNs depending on their output targets. In this context, we recently found that CRS produced dendritic hypertrophy in mouse BLA PNs that generalized across major output pathways but increased spine density in BLA PNs targeting the vHPC (BLA→vHPC), while sparing BLA neurons projecting to the dmPFC (BLA→dmPFC) and NAc (BLA→NAc) (
      • Zhang J.Y.
      • Liu T.H.
      • He Y.
      • Pan H.Q.
      • Zhang W.H.
      • Yin X.P.
      • et al.
      Chronic stress remodels synapses in an amygdala circuit-specific manner.
      ) (Figure 3A, B). The same study found that CRS selectively enhanced excitatory transmission in BLA→vHPC PNs, demonstrating that this stressor produced both structural remodeling and synaptic function alterations in a circuit-specific manner.
      Figure thumbnail gr3
      Figure 3Chronic stress causes circuit-specific remodeling of BLA PNs to increase anxiety. (A) Summary diagram showing how chronic stress preferentially remodels vHPC-projecting BLA PNs (BLA→vHPC PNs) but not PNs projecting to the NAc (BLA→NAc PNs) or dmPFC (BLA→dmPFC PNs). This remodeling occurs at the levels of synaptic outgrowth, input integration, and neuronal activity. (B) Chronic stress causes spinogenesis in BLA→vHPC, but not BLA→NAc or BLA→dmPFC, PNs to elicit anxiety. (C) Chronic stress increases dmPFC transmission to BLA→vHPC but not BLA→dmPFC PNs as a consequence of enhanced presynaptic glutamate release, leading to increased anxiety. (D) Chronic stress downregulates the function of SK2 channel in and increases the activity of BLA→vHPC, but not BLA→NAc or BLA→dmPFC, PNs to increase anxiety. BLA, basolateral amygdala; dmPFC, dorsomedial prefrontal cortex; NAc, nucleus accumbens; PN, projection neuron; vHPC, ventral hippocampus.

      Functional Adaptations

      Insofar as the mPFC exerts a top-down influence over the amygdala, this function is thought to be weakened by chronic stress, leading to aberrant amygdala activation and associated emotional disturbances (
      • Adhikari A.
      • Lerner T.N.
      • Finkelstein J.
      • Pak S.
      • Jennings J.H.
      • Davidson T.J.
      • et al.
      Basomedial amygdala mediates top-down control of anxiety and fear.
      ,
      • Piggott V.M.
      • Bosse K.E.
      • Lisieski M.J.
      • Strader J.A.
      • Stanley J.A.
      • Conti A.C.
      • et al.
      Single-prolonged stress impairs prefrontal cortex control of amygdala and striatum in rats.
      ). Circuit-level support for this view comes from data that mice exposed to chronic unpredictable stress exhibited attenuated glutamatergic signaling from the PFC to GABAergic neurons in the BLA (
      • Wei J.
      • Zhong P.
      • Qin L.
      • Tan T.
      • Yan Z.
      Chemicogenetic restoration of the prefrontal cortex to amygdala pathway ameliorates stress-induced deficits.
      ). These effects were found to be paralleled by a reduction in feed-forward inhibition onto BLA PNs and behavioral abnormalities, including increased aggression and impaired novel object recognition (
      • Wei J.
      • Zhong P.
      • Qin L.
      • Tan T.
      • Yan Z.
      Chemicogenetic restoration of the prefrontal cortex to amygdala pathway ameliorates stress-induced deficits.
      ). Similar effects have been reported after chronic cold stress (
      • Correll C.M.
      • Rosenkranz J.A.
      • Grace A.A.
      Chronic cold stress alters prefrontal cortical modulation of amygdala neuronal activity in rats.
      ).
      Extending these data, CRS was recently shown to cause a net disinhibition in the BLA owing to overexcitation of BLA PNs as a result of augmented presynaptic glutamate release from dmPFC synapses, without altering feed-forward inhibition and thereby yielding a shift in favor of excitation over inhibition (increased excitation/inhibition ratio) in the dmPFC→BLA pathway (
      • Liu W.Z.
      • Zhang W.H.
      • Zheng Z.H.
      • Zou J.X.
      • Liu X.X.
      • Huang S.H.
      • et al.
      Identification of a prefrontal cortex-to-amygdala pathway for chronic stress-induced anxiety.
      ) (Figure 3A, C). Such a shift is expected to increase reactivity of BLA PNs and thereby contributes to stress-induced anxiety. Notably, these changes appear to be specific to this afferent pathway, given that the same study found that CRS failed to produce similar changes in vmPFC or vHPC inputs to the BLA (
      • Liu W.Z.
      • Zhang W.H.
      • Zheng Z.H.
      • Zou J.X.
      • Liu X.X.
      • Huang S.H.
      • et al.
      Identification of a prefrontal cortex-to-amygdala pathway for chronic stress-induced anxiety.
      ).
      The excitation/inhibition imbalance in the dmPFC→BLA circuit and associated increases in anxiety-like behavior following CRS were shown to be reversible by low-frequency optogenetic stimulation of dmPFC→BLA neurons (
      • Liu W.Z.
      • Zhang W.H.
      • Zheng Z.H.
      • Zou J.X.
      • Liu X.X.
      • Huang S.H.
      • et al.
      Identification of a prefrontal cortex-to-amygdala pathway for chronic stress-induced anxiety.
      ). Moreover, the effect of CRS was not generalized across these BLA PNs but was absent in a subpopulation that projected back to the dmPFC. The latter finding is intriguing because, as already stated, CRS increases glutamatergic transmission and dendritic morphology in mPFC-projecting BLA neurons (
      • Zhang J.Y.
      • Liu T.H.
      • He Y.
      • Pan H.Q.
      • Zhang W.H.
      • Yin X.P.
      • et al.
      Chronic stress remodels synapses in an amygdala circuit-specific manner.
      ,
      • Lowery-Gionta E.G.
      • Crowley N.A.
      • Bukalo O.
      • Silverstein S.
      • Holmes A.
      • Kash T.L.
      Chronic stress dysregulates amygdalar output to the prefrontal cortex.
      ). Besides these, a recent study found that acute footshock stress elevates glutamatergic synaptic transmission (and decreases levels of the endocannabinoid 2-arachidonic acid glycerol) at BLA inputs to those dmPFC PNs that have reciprocal connections to the BLA (
      • Marcus D.J.
      • Bedse G.
      • Gaulden A.D.
      • Ryan J.D.
      • Kondev V.
      • Winters N.D.
      • et al.
      Endocannabinoid signaling collapse mediates stress-induced amygdalo-cortical strengthening.
      ). Taken together, this emerging literature suggests that different stressors may either weaken or strengthen reciprocal connections between the BLA and mPFC, with potentially important repercussions for the functions of these circuits.
      In a similar vein, different stressors also appear to produce varying alterations in BLA-hippocampus connectivity and behavior. On the one hand, mice exhibiting learned helplessness following footshock stress display weakening of synaptic connectivity between the (posterior) BLA and CA1 region of the vHPC and impaired spatial memory, effects that are rescued by optogenetic stimulation of the pathway and mimicked by optogenetic silencing (
      • Yang Y.
      • Wang Z.H.
      • Jin S.
      • Gao D.
      • Liu N.
      • Chen S.P.
      • et al.
      Opposite monosynaptic scaling of BLP-vCA1 inputs governs hopefulness- and helplessness-modulated spatial learning and memory.
      ). On the other hand, CRS-induced mouse anxiety-like behavior is associated with increased excitatory glutamate transmission in BLA→vHPC PNs and functional downregulation of the small conductance calcium-activated potassium channel in these neurons (
      • Zhang W.H.
      • Liu W.Z.
      • He Y.
      • You W.J.
      • Zhang J.Y.
      • Xu H.
      • et al.
      Chronic stress causes projection-specific adaptation of amygdala neurons via small-conductance calcium-activated potassium channel downregulation.
      ,
      • Zhang J.Y.
      • Liu T.H.
      • He Y.
      • Pan H.Q.
      • Zhang W.H.
      • Yin X.P.
      • et al.
      Chronic stress remodels synapses in an amygdala circuit-specific manner.
      ) (Figure 3A, D). A virally assisted strategy to overexpress the small conductance calcium-activated potassium channel specifically in BLA→vHPC PNs sufficed to prevent both the CRS-induced increases in anxiety and hyperexcitability of these neurons (
      • Zhang W.H.
      • Liu W.Z.
      • He Y.
      • You W.J.
      • Zhang J.Y.
      • Xu H.
      • et al.
      Chronic stress causes projection-specific adaptation of amygdala neurons via small-conductance calcium-activated potassium channel downregulation.
      ). Clearly, detailed studies are needed to parse the effects of stressors of differing type and chronicity on this and other amygdala output circuits.
      Another key avenue for future work is determining how stress produces changes in other amygdala circuits. Recent findings reveal that acute and chronic stress can impair synaptic plasticity in BLA projections to the NAc (
      • Segev A.
      • Rubin A.S.
      • Abush H.
      • Richter-Levin G.
      • Akirav I.
      Cannabinoid receptor activation prevents the effects of chronic mild stress on emotional learning and LTP in a rat model of depression.
      ,
      • Segev A.
      • Akirav I.
      Cannabinoids and glucocorticoids in the basolateral amygdala modulate hippocampal-accumbens plasticity after stress.
      ). One recent study found that sleep deprivation reduces glutamate release in aBLA projections to the ventrolateral portion of NAc but not pBLA projections to the medial NAc (
      • Wang Y.
      • Liu Z.
      • Cai L.
      • Guo R.
      • Dong Y.
      • Huang Y.H.
      A critical role of basolateral amygdala-to-nucleus accumbens projection in sleep regulation of reward seeking.
      ). Another showed that chronic social defeat stress selectively increases the excitatory output of cholecystokinin-expressing BLA neurons to dopamine D2-expressing medium spiny neurons in the NAc in stress-susceptible mice (
      • Shen C.J.
      • Zheng D.
      • Li K.X.
      • Yang J.M.
      • Pan H.Q.
      • Yu X.D.
      • et al.
      Cannabinoid CB1 receptors in the amygdalar cholecystokinin glutamatergic afferents to nucleus accumbens modulate depressive-like behavior.
      ). These synaptic and behavioral effects were related to the downregulation of the presynaptic cannabinoid CB1 receptor and could be mimicked by CB1 receptor knockdown in the cholecystokinin-expressing BLA neurons to dopamine D2-expressing medium spiny neurons in the NAc circuit (
      • Shen C.J.
      • Zheng D.
      • Li K.X.
      • Yang J.M.
      • Pan H.Q.
      • Yu X.D.
      • et al.
      Cannabinoid CB1 receptors in the amygdalar cholecystokinin glutamatergic afferents to nucleus accumbens modulate depressive-like behavior.
      ). Given the known role of NAc in reward, it will be interesting to explore how BLA→NAc PNs function under experimental conditions that generate a conflict between stress- and reward-related behaviors.
      The CeA has dense CRF-secreting neurons (
      • Partridge J.G.
      • Forcelli P.A.
      • Luo R.
      • Cashdan J.M.
      • Schulkin J.
      • Valentino R.J.
      • Vicini S.
      Stress increases GABAergic neurotransmission in CRF neurons of the central amygdala and bed nucleus stria terminalis.
      ). Chemogenetic activation of CRF projections from the CeA to the BNST increased the anxiety-like behavior of mice, a process depending on the activation of CRF1 receptors and CRF neurons within the BNST (
      • Pomrenze M.B.
      • Tovar-Diaz J.
      • Blasio A.
      • Maiya R.
      • Giovanetti S.M.
      • Lei K.
      • et al.
      A corticotropin releasing factor network in the extended amygdala for anxiety.
      ). In contrast, selective Crf gene knockdown in the CeA has been shown to reduce stress-induced anxiety-like behavior and prevent stress-induced alterations in CRF receptor expression in the BNST (
      • Ventura-Silva A.P.
      • Borges S.
      • Sousa N.
      • Rodrigues A.J.
      • Pêgo J.M.
      Amygdalar corticotropin-releasing factor mediates stress-induced anxiety.
      ). In turn, stress reduces GABAergic transmission from somatostatin-expressing neurons in the lateral CeA, leading to hyperactivity of somatostatin-expressing cells in the BNST and elevated anxiety-like behavior (
      • Ahrens S.
      • Wu M.V.
      • Furlan A.
      • Hwang G.R.
      • Paik R.
      • Li H.
      • et al.
      A central extended amygdala circuit that modulates anxiety.
      ). Finally, reduced dorsal raphe nucleus input to the CeA is associated with depressive-like behaviors produced by chronic pain, and these effects are reversible by chemogenetic or optogenetic dorsal raphe nucleus→CeA activation (
      • Zhou W.
      • Jin Y.
      • Meng Q.
      • Zhu X.
      • Bai T.
      • Tian Y.
      • et al.
      A neural circuit for comorbid depressive symptoms in chronic pain [published correction appears in Nat Neurosci 2019; 22:1945].
      ). These observations reveal how the CeA acts to be not a passive relay of amygdala output but a dynamic player in regulating the effects of stress.

      Environmental and Genetic Influences on the Amygdala

      Environmental factors, particularly early-life adversity (ELA), ranging from poor parental care and childhood maltreatment to poverty and social isolation, negatively affect brain development and predispose individuals to neuropsychiatric disorders in adolescence and adulthood (
      • Juster R.P.
      • Bizik G.
      • Picard M.
      • Arsenault-Lapierre G.
      • Sindi S.
      • Trepanier L.
      • et al.
      A transdisciplinary perspective of chronic stress in relation to psychopathology throughout life span development.
      ,
      • McGowan P.O.
      Epigenomic mechanisms of early adversity and HPA dysfunction: Considerations for PTSD research.
      ,
      • Andersen S.L.
      Exposure to early adversity: Points of cross-species translation that can lead to improved understanding of depression.
      ,
      • Hanson J.L.
      • Nacewicz B.M.
      • Sutterer M.J.
      • Cayo A.A.
      • Schaefer S.M.
      • Rudolph K.D.
      • et al.
      Behavioral problems after early life stress: Contributions of the hippocampus and amygdala.
      ,
      • Caspi A.
      • Hariri A.R.
      • Holmes A.
      • Uher R.
      • Moffitt T.E.
      Genetic sensitivity to the environment: The case of the serotonin transporter gene and its implications for studying complex diseases and traits.
      ). What is becoming increasingly evident is that these variables also shape the amygdala in terms of its architecture, resting-state activity, and responsivity to external stimuli (
      • McEwen B.S.
      • Nasca C.
      • Gray J.D.
      Stress effects on neuronal structure: Hippocampus, amygdala, and prefrontal cortex.
      ,
      • Yang R.J.
      • Mozhui K.
      • Karlsson R.M.
      • Cameron H.A.
      • Williams R.W.
      • Holmes A.
      Variation in mouse basolateral amygdala volume is associated with differences in stress reactivity and fear learning.
      ,
      • Roozendaal B.
      • McEwen B.S.
      • Chattarji S.
      Stress, memory and the amygdala.
      ,
      • Qin X.
      • He Y.
      • Wang N.
      • Zou J.X.
      • Zhang Y.M.
      • Cao J.L.
      • et al.
      Moderate maternal separation mitigates the altered synaptic transmission and neuronal activation in amygdala by chronic stress in adult mice.
      ,
      • Swartz J.R.
      • Knodt A.R.
      • Radtke S.R.
      • Hariri A.R.
      A neural biomarker of psychological vulnerability to future life stress.
      ). In this section, we address this vast literature by highlighting just a few illustrative findings.
      Animal models have been used to explore the influence of ELA on amygdala circuits, showing that maternal separation in rats enhances both long-term potentiation and depression at amygdala synapses in the hippocampal dentate gyrus (
      • Blaise J.H.
      • Koranda J.L.
      • Chow U.
      • Haines K.E.
      • Dorward E.C.
      Neonatal isolation stress alters bidirectional long-term synaptic plasticity in amygdalo-hippocampal synapses in freely behaving adult rats.
      ). Furthermore, neuronal recordings in freely behaving rats have shown that maternal separation disrupts the coherence of spikes in the anterior cingulate cortex (ACC) of the mPFC to theta oscillations in the BLA and dysregulates BLA-ACC neuronal synchrony (
      • Cao B.
      • Wang J.
      • Zhang X.
      • Yang X.W.
      • Poon D.C.H.
      • Jelfs B.
      • et al.
      Impairment of decision making and disruption of synchrony between basolateral amygdala and anterior cingulate cortex in the maternally separated rat.
      ).
      However, rodent studies have reported rather inconsistent findings on the influence of ELA using resting-state fMRI amygdala activity. Limited bedding and nesting during early life reduced amygdala-mPFC connectivity in one study (
      • Guadagno A.
      • Kang M.S.
      • Devenyi G.A.
      • Mathieu A.P.
      • Rosa-Neto P.
      • Chakravarty M.
      • Walker C.D.
      Reduced resting-state functional connectivity of the basolateral amygdala to the medial prefrontal cortex in preweaning rats exposed to chronic early-life stress.
      ), whereas unpredictable postnatal stress increased connectivity between these regions (
      • Johnson F.K.
      • Delpech J.C.
      • Thompson G.J.
      • Wei L.
      • Hao J.
      • Herman P.
      • et al.
      Amygdala hyper-connectivity in a mouse model of unpredictable early life stress.
      ). It again seems likely that differences in the nature of the various stressors applied could account for these disparate effects. Timing may be another salient variable. In humans, ELA has been observed to reduce functional connectivity between the amygdala and subgenual ACC and precuneus in adults (
      • Herringa R.J.
      • Birn R.M.
      • Ruttle P.L.
      • Burghy C.A.
      • Stodola D.E.
      • Davidson R.J.
      • Essex M.J.
      Childhood maltreatment is associated with altered fear circuitry and increased internalizing symptoms by late adolescence.
      ) but to accelerate the development of functional PFC-amygdala coupling that typically occurs in puberty (
      • Gee D.G.
      • Gabard-Durnam L.J.
      • Flannery J.
      • Goff B.
      • Humphreys K.L.
      • Telzer E.H.
      • et al.
      Early developmental emergence of human amygdala-prefrontal connectivity after maternal deprivation.
      ), possibly to dampen excessive amygdala activity arising from ELA. Further research across species is warranted to dissect the dynamics of ELA effects on the amygdala across development and determine causal relationships between these effects and changes in behavior.
      The effects of environmental adversity interact with genetic variation and epigenetic factors to modify how amygdala circuits respond and adapt in the face of stress (
      • Schiele M.A.
      • Domschke K.
      Epigenetics at the crossroads between genes, environment and resilience in anxiety disorders.
      ,
      • Gunduz-Cinar O.
      • Brockway E.
      • Lederle L.
      • Wilcox T.
      • Halladay L.R.
      • Ding Y.
      • et al.
      Identification of a novel gene regulating amygdala-mediated fear extinction.
      ,
      • Dincheva I.
      • Drysdale A.T.
      • Hartley C.A.
      • Johnson D.C.
      • Jing D.
      • King E.C.
      • et al.
      FAAH genetic variation enhances fronto-amygdala function in mouse and human.
      ). Among the many genetic modifiers that have been implicated are genes encoding molecules in the CRF, glucocorticoid receptor, serotonin, BDNF, and endocannabinoid systems. Multiple genetic variants can also interact to affect risk. A well-known set of studies showed that (S) allele 5-HTT (serotonin transporter) carriers display lesser subgenual ACC-amygdala coupling during negative emotion processing (
      • Pezawas L.
      • Meyer-Lindenberg A.
      • Drabant E.M.
      • Verchinski B.A.
      • Munoz K.E.
      • Kolachana B.S.
      • et al.
      5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: A genetic susceptibility mechanism for depression.
      ) in a manner that was buffered by having a certain (Met) BDNF allele (
      • Pezawas L.
      • Meyer-Lindenberg A.
      • Goldman A.L.
      • Verchinski B.A.
      • Chen G.
      • Kolachana B.S.
      • et al.
      Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression.
      ).
      Adding to this complexity, epigenetic modifications, such as DNA methylation and microRNA, confer another level by which stress can alter amygdala circuit functions (
      • Gunduz-Cinar O.
      • Brockway E.
      • Lederle L.
      • Wilcox T.
      • Halladay L.R.
      • Ding Y.
      • et al.
      Identification of a novel gene regulating amygdala-mediated fear extinction.
      ). Heightened conditioned fear behavior in rodents subject to maternal separation has been associated with methylation of the promoter of neurotensin receptor 1 in the amygdala (
      • Toda H.
      • Boku S.
      • Nakagawa S.
      • Inoue T.
      • Kato A.
      • Takamura N.
      • et al.
      Maternal separation enhances conditioned fear and decreases the mRNA levels of the neurotensin receptor 1 gene with hypermethylation of this gene in the rat amygdala.
      ). Various microRNAs, such as miR-15a (
      • Volk N.
      • Pape J.C.
      • Engel M.
      • Zannas A.S.
      • Cattane N.
      • Cattaneo A.
      • et al.
      Amygdalar microRNA-15a is essential for coping with chronic stress.
      ) and miR-34 (
      • Andolina D.
      • Di Segni M.
      • Accoto A.
      • Lo Iacono L.
      • Borreca A.
      • Ielpo D.
      • et al.
      MicroRNA-34 contributes to the stress-related behavior and affects 5-HT prefrontal/GABA amygdalar system through regulation of corticotropin-releasing factor receptor 1 [published correction appears in Mol Neurobiol 2020; 57:586].
      ), have also been shown to modify stress-related gene expression changes to produce changes in a set of stress-responsive signaling pathways, including glucocorticoid receptor, CRF, and Wnt, with consequences for stress susceptibility (
      • Shen M.
      • Song Z.
      • Wang J.H.
      MicroRNA and mRNA profiles in the amygdala are associated with stress-induced depression and resilience in juvenile mice.
      ,
      • Sun J.
      • Lu Y.
      • Yang J.
      • Song Z.
      • Lu W.
      • Wang J.H.
      mRNA and microRNA profiles in the amygdala are relevant to susceptibility and resilience to psychological stress induced in mice.
      ,
      • Roy B.
      • Dunbar M.
      • Agrawal J.
      • Allen L.
      • Dwivedi Y.
      Amygdala-based altered miRNome and epigenetic contribution of miR-128-3p in conferring susceptibility to depression-like behavior via Wnt signaling.
      ,
      • Sun Y.
      • Lu W.
      • Du K.
      • Wang J.H.
      MicroRNA and mRNA profiles in the amygdala are relevant to fear memory induced by physical or psychological stress.
      ). However, these important insights provide only a start to understanding how epigenetic modifications influence how amygdala circuits are reshaped by stress.

      Amygdala Circuit Dysfunction in Stress-Related Disorders

      Human imaging studies implicate aberrant connectivity between the amygdala and its afferent/efferent regions in the etiology of a spectrum of stress-related neuropsychiatric diseases, including anxiety disorder (
      • Freitas-Ferrari M.C.
      • Hallak J.E.
      • Trzesniak C.
      • Filho A.S.
      • Machado-de-Sousa J.P.
      • Chagas M.H.
      • et al.
      Neuroimaging in social anxiety disorder: A systematic review of the literature.
      ), depression (
      • Veer I.M.
      • Beckmann C.F.
      • van Tol M.J.
      • Ferrarini L.
      • Milles J.
      • Veltman D.J.
      • et al.
      Whole brain resting-state analysis reveals decreased functional connectivity in major depression.
      ), posttraumatic stress disorder (
      • Nicholson A.A.
      • Densmore M.
      • Frewen P.A.
      • Théberge J.
      • Neufeld R.W.
      • McKinnon M.C.
      • Lanius R.A.
      The dissociative subtype of posttraumatic stress disorder: Unique resting-state functional connectivity of basolateral and centromedial amygdala complexes.
      ), and addiction (
      • Ma N.
      • Liu Y.
      • Li N.
      • Wang C.X.
      • Zhang H.
      • Jiang X.F.
      • et al.
      Addiction related alteration in resting-state brain connectivity.
      ). Patients with generalized anxiety disorder, social anxiety disorder, and panic disorder display amygdala hyperactivity in response to emotional stimuli and abnormal amygdala-ACC coupling (
      • Fonzo G.A.
      • Ramsawh H.J.
      • Flagan T.M.
      • Sullivan S.G.
      • Letamendi A.
      • Simmons A.N.
      • et al.
      Common and disorder-specific neural responses to emotional faces in generalised anxiety, social anxiety and panic disorders.
      ,
      • Etkin A.
      • Prater K.E.
      • Hoeft F.
      • Menon V.
      • Schatzberg A.F.
      Failure of anterior cingulate activation and connectivity with the amygdala during implicit regulation of emotional processing in generalized anxiety disorder.
      ). Indeed, the strength of connections between the dmPFC, insular cortex, and amygdala (
      • Williams L.M.
      Defining biotypes for depression and anxiety based on large-scale circuit dysfunction: A theoretical review of the evidence and future directions for clinical translation.
      ) positively correlates with state and trait anxiety levels in individuals with anxiety disorders (
      • Robinson O.J.
      • Krimsky M.
      • Lieberman L.
      • Allen P.
      • Vytal K.
      • Grillon C.
      The dorsal medial prefrontal (anterior cingulate) cortex-amygdala aversive amplification circuit in unmedicated generalised and social anxiety disorders: An observational study.
      ). In patients with major depressive disorder, resting-state fMRI has revealed decreased connectivity between the amygdala and left anterior insula (
      • Veer I.M.
      • Beckmann C.F.
      • van Tol M.J.
      • Ferrarini L.
      • Milles J.
      • Veltman D.J.
      • et al.
      Whole brain resting-state analysis reveals decreased functional connectivity in major depression.
      ) and impaired top-down connectivity from the dorsolateral PFC to the amygdala but increased bottom-up, amygdala-to-ACC connectivity during emotional processing (
      • Lu Q.
      • Li H.
      • Luo G.
      • Wang Y.
      • Tang H.
      • Han L.
      • Yao Z.
      Impaired prefrontal-amygdala effective connectivity is responsible for the dysfunction of emotion process in major depressive disorder: A dynamic causal modeling study on MEG.
      ). Connectivity between the amygdala and vmPFC in patients with posttraumatic stress disorder varies across studies and symptom clusters, with decreased connectivity related to impaired extinction and safety learning (
      • Quirk G.J.
      • Beer J.S.
      Prefrontal involvement in the regulation of emotion: Convergence of rat and human studies.
      ,
      • Morey R.A.
      • Dunsmoor J.E.
      • Haswell C.C.
      • Brown V.M.
      • Vora A.
      • Weiner J.
      • et al.
      Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder.
      ) and greater amygdala-prefrontal coupling associated with dissociative symptoms (
      • Nicholson A.A.
      • Densmore M.
      • Frewen P.A.
      • Théberge J.
      • Neufeld R.W.
      • McKinnon M.C.
      • Lanius R.A.
      The dissociative subtype of posttraumatic stress disorder: Unique resting-state functional connectivity of basolateral and centromedial amygdala complexes.
      ).
      The function of amygdala circuits is also associated with the efficacy of treatments for stress-related disorders. Selective serotonin reuptake inhibitors have been posited to ameliorate anxiety and depressive symptoms through modulating serotonin levels in amygdala-PFC circuits (
      • McCabe C.
      • Mishor Z.
      • Cowen P.J.
      • Harmer C.J.
      Diminished neural processing of aversive and rewarding stimuli during selective serotonin reuptake inhibitor treatment.
      ,
      • Phillips M.L.
      • Chase H.W.
      • Sheline Y.I.
      • Etkin A.
      • Almeida J.R.
      • Deckersbach T.
      • Trivedi M.H.
      Identifying predictors, moderators, and mediators of antidepressant response in major depressive disorder: Neuroimaging approaches.
      ). Cognitive behavioral therapy is also hypothesized to produce therapeutic benefit, in part through increasing PFC control over subcortical structures such as the amygdala, in patients with panic disorder, generalized anxiety disorder, and social anxiety disorder (
      • Peterson A.
      • Thome J.
      • Frewen P.
      • Lanius R.A.
      Resting-state neuroimaging studies: A new way of identifying differences and similarities among the anxiety disorders?.
      ). However, the extent to which these and other amygdala circuits underlie the effects of physiotherapeutic approaches, such as deep brain stimulation and repetitive transcranial magnetic stimulation, remains unclear.
      Nonetheless, there are novel treatment approaches designed to target amygdala circuits. For instance, a technique for real-time fMRI neurofeedback training of amygdala activity has been applied to patients with major depressive disorder and has shown preliminary promise for improved mood (
      • Young K.D.
      • Zotev V.
      • Phillips R.
      • Misaki M.
      • Yuan H.
      • Drevets W.C.
      • Bodurka J.
      Real-time FMRI neurofeedback training of amygdala activity in patients with major depressive disorder.
      ). With the increasing consensus on studying and treating neural circuit–defined biotypes in human psychiatry (
      • Williams L.M.
      Defining biotypes for depression and anxiety based on large-scale circuit dysfunction: A theoretical review of the evidence and future directions for clinical translation.
      ), there will be likely be a push for other amygdala circuit–based treatments to be developed in the coming years. In reality, however, we remain at the very early stages of translating an increasing understanding of the anatomy and cell-type specificity of amygdala circuits involved in stress to new diagnostic tools and therapeutic strategies that can be employed in the clinic. Yet, by the same token, these academic advances represent genuine opportunities in the coming years for revolutionizing how stress disorders are recognized and managed.

      Conclusions

      The effects of stressful experience are double edged. In some cases, prior stress can enhance resilience in dealing with future adversity, but when sufficiently intense and chronic, stress can lead to debilitating illnesses. Individuals vary greatly in how these effects play out. Acting as a central hub in the brain’s stress circuitry, the amygdala has a central role in conferring resilience and susceptibility to stress-related neuropsychiatric disorders (
      • McEwen B.S.
      Physiology and neurobiology of stress and adaptation: Central role of the brain.
      ,
      • Janak P.H.
      • Tye K.M.
      From circuits to behaviour in the amygdala.
      ) and represents a key target for alleviating the symptoms associated with these conditions. While our understanding of the precise mechanistic basis for the amygdala’s role in shaping response to stress remains preliminary, neuroscience studies in humans and rodents continue to provide important insights, particularly into the contribution of specific amygdala circuits. In the coming years, translating these findings to the clinic should provide new opportunities for developing valuable diagnostic tools and effective therapeutic interventions.

      Acknowledgments and Disclosures

      This work was supported by the National Natural Science Foundation of China (Grant Nos. 81930032 [to B-XP], 31970953 [to W-HZ], 81960257 [to J-YZ], and 81741759 [to B-XP]) and the Natural Science Foundation of Jiangxi Province (Grant Nos. 20192ACB20023 [to B-XP], 20192ACB21024 [to W-HZ], 20202ZDB01015 [to J-YZ], 20172BCB22005 [to B-XP], and 20181BAB204008 [to J-YZ]).
      The authors report no biomedical financial interests or potential conflicts of interest.

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