Open access peer-reviewed chapter

The Key Role of the Amygdala in Stress

Written By

Diego Andolina and Antonella Borreca

Submitted: October 11th, 2016 Reviewed: February 10th, 2017 Published: July 5th, 2017

DOI: 10.5772/67826

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Abstract

Several data highlighted that stress exposure is strongly associated with several psychiatric disorders. The amygdala, an area of the brain that contributes to emotional processing, has a pivotal role in psychiatric disorders and it has been demonstrated to be highly responsive to stressful events. Here we will review evidences indicating how the amygdala changes its functionality following exposure to stress and how this contributes to the onset of anxiety disorders.

Keywords

  • amygdala
  • stress
  • anxiety disorders

1. Introduction

The brain is a very complex organ and it establishes through complicated processes, which experiences are stressful, therefore determining behavioral and physiological responses.

Several clinical and preclinical data highlighted how acute or prolonged stress exposure may cause changes in brain that contribute to the onset of some psychiatric disorders.

The first effect of the stress response is the immediate activation of the hypothalamic-pituitary-adrenal (HPA) axis with release of specific hormones.

Specifically, HPA axis activation causes the secretion of neuropeptides, which are quickly released in the brain regulating the activity of some structures, and, among these, the amygdala plays a leading role in mediating the stress response.

The amygdala, an area of the brain that contributes to emotional processing, was seen to be very susceptible to stressful events, modifying its functionality and morphology. These modifications play an important role in stress-induced psychopathologies including anxiety, depression, and addiction. These alterations involve genetic, epigenetic and molecular mechanisms as well as dendritic and synaptic reorganization processes.

Stress exposure increases the release of amygdala neurotransmitters including glutamate, GABA, noradrenaline, and serotonin. This immediately activates a signal transduction pathway with a downstream molecular cascade involved in the strengthening of postsynaptic neurons resulting in the instant regulation of specific genes engaged in neuroplasticity processes.

Furthermore, epigenetic mechanisms, including noncoding RNA, have been proposed to be involved in the rapid, long-term dynamic gene expression regulation during stress response.

For instance, many microRNAs (miRs), small RNA molecules that regulate gene expression at posttranscriptional level, modulate the synaptic plasticity and neurotransmission processes and for this reason they are considered important for the neuronal response to external stimuli. Recent studies show that the stress is able to alter the expression of some miRs in amygdala pointing to a role of these small molecules in regulating the stress response and some stress-related behaviors.

Although synaptic plasticity occurs within the amygdala, this structure obviously regulates stress response by interacting with other brain structures. The amygdala is specifically connected to a number of downstream and upstream regions that play a key role in emotional and stress-related behavior. Several data have highlighted the neurocircuits associated with stress response resulting in connections between different brain areas such as amygdala, prefrontal cortex.

In this chapter, we will review clinical and preclinical evidences indicating how this structure modifies its “shape” and functionality following exposure to stress and how this contributes to the onset/expression of anxiety disorders. In particular, we will focus on literature regarding stress-induced changes in neuroplasticity in terms of dendritic remodeling of neurons, as well as the molecular and epigenetic mechanisms involved. Moreover, we will discuss briefly how the amygdala, through connections with the prefrontal cortex, modulates stress response and stress-induced anxiety behavior.

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2. Stress-induced changes in neurotransmission in the amygdala: evidence from microdialysis studies

Neurotransmission is the process by which the neurotransmitters are released by a neuron (the presynaptic neuron) and bind to and activate the receptors of another neuron (the postsynaptic neuron). Thus, neurotransmission is essential for communication between neurons, regulating behavior, emotional functioning, and cognition.

The in vivo microdialysis technique allows one to measure neurotransmitters in neuronal extracellular fluid in discrete regions of the brain in humans and laboratory animals [13]. The marked stress-responsiveness of several neurotransmitters in the amygdala has been demonstrated using this approach, including glutamate (GLU), γ-aminobutyric acid (GABA), noradrenaline (NE), and serotonin (5-HT).

In the following section, we review microdialysis studies on the stress-induced release of neurotransmitters in the amygdala in animals and their putative function in mediating the stress response.

2.1. Noradrenaline

A variety of stressful events, including physical and psychological stimuli, increase noradrenaline (NE) release markedly in several regions of the brain, such as the amygdala. The ascending noradrenergic neurotransmitter system is activated by stress [4, 5] and provides dense innervation to the extended amygdala [6]. Microdialysis studies have shown that stress exposure enhances the release of NE in the basolateral amygdala (BLA), medial amygdala (MeA), and central amygdala (CeA) [715], thus that NE transmission is linked to the onset of negative emotions, such as anxiety and fear, in individuals who are exposed to stress [7, 1619]. Consistently, benzodiazepine has been reported to attenuate this increase [7, 20, 21].

The MeA is innervated by noradrenergic neurons that arise primarily from the locus coeruleus [10, 22, 23]. An in vivo microdialysis study demonstrated that immobilization stress elevated NE levels in the MeA over threefold versus baseline [10].

Moreover, the administration of α1- or β-adrenergic receptor antagonists directly into the MeA mitigates the adrenocorticotropic hormone (ACTH) response to immobilization stress [10]. These data support the hypothesis that greater release of NE in the MeA, acting primarily through ACTH receptors, facilitates activation of the HPA axis in response to acute stress [10].

Stress-induced noradrenergic activity in the MeA, through projections to the bed nucleus of the stria terminalis (BNST) and preoptic area, is one possible mechanism by which the MeA modulates the stress-induced activation of the HPA axis.

The effects of stimulation of the MeA on increases in plasma corticosterone levels are partially blocked by lesioning the preoptic area or BNST alone but inhibited to a greater extent following the development of lesions in both structures and are blocked completely by bilateral lesions to the stria terminalis [24].

Immobilization stress also enhances NE release in the BLA [1315, 21, 25]. Notably, in rats, long-term administration of citalopram, an antidepressant that belongs to the class of selective serotonin reuptake inhibitors (SSRIs), decreases the extracellular levels of NE in the BLA, suggesting that the therapeutic effect of citalopram is attributed to the loss of the NEergic stress response in the BLA that is caused by supersensitivity of α2-adrenoceptors in this region [13].

Immobilization stress affects a robust increase in NE release in the CeA [5, 26]. This release appears to be involved in stress-induced gastric ulcer formation [27, 28]. The expression of aggression during stress exposure attenuates stress-induced elevations in NE release in the CeA and the development of gastric ulcer [27], whereas another study has indicated that ß-adrenoreceptor-mediated NEergic mechanisms in the CeA are important for the maintenance of gastric mucosal integrity during immobilization stress [28].

2.2. Serotonin

Several serotonin (5-HT) receptor subtypes are expressed in the amygdala, particularly in the basolateral regions [2932]. The amygdala receives dense projections from the dorsal raphe nucleus (DRN) [33], and psychological stress activates ascending serotonergic neurons from the DRN to the BLA [34]. Injection of 5-HT into the amygdala evokes anxiogenic effects in various test situations [3537]. However, the stress effects depend on features of the stressors and the genetic makeup of individuals. Regarding the former, for example, controllable stressors tend to have a less measurable impact than those that are uncontrollable, and the lack of behavioral control over stress might be critical to the development of mood disorders [3840].

Exposure to uncontrollable stressors often increases anxiety behavior in humans and rodents, whereas controllable stress drastically reduces these effects [38]. An in vivo microdialysis study found that 5-HT neurotransmission in the amygdala—specifically in the BLA—is sensitive to the controllability of stress. In rats, inescapable stress (IS) activates DRN 5-HT neurons to a greater extent than escapable stress (ES), increasing 5-HT release in the BLA [35].

Moreover, serotonergic neurotransmission in the amygdala undergoes sensitization (a process in which there is progressive amplification of a response due to repeated administration of a stimulus) in response to stressful stimuli following IS. For instance, Amat and colleagues reported that two footshocks were sufficient to increase 5-HT efflux in the BLA in subjects who had experienced IS 24 h earlier but not in rats that had been subjected to ES [35]; a separate study found that 5-HT2C receptor in the BLA has significant function during this process in rats [41].

5-HT transmission in the BLA is also influenced by sex differences in the stress response. In rats, restraint stress significantly elevates extracellular 5-HT levels in the BLA in both genders, but females develop a greater response [42]. The authors suggest that this difference is related to sex-specific emotional responses to stress [42]. As proposed by Mitsushima and colleagues, the mechanism that underlies sex differences in the 5-HT response to restraint stress in the BLA is attributed to disparities in gonadal steroid hormone receptor expression on DRN 5-HT neurons, the major site from which 5-HT axons extend to the BLA in rats [42].

Consistent with these findings, androgen receptors abound in the DRN in male rats, whereas little or none is expressed in female rats [43]. Because several steroid hormones are released in the brain during stress exposure [for review, see 44], it is possible that sex-related differences in steroid hormone receptors govern 5-HT neurons in the DRN gender-specifically, differentially regulating extracellular 5-HT levels and the 5-HT response to stress in the BLA [42].

The DRN also provides 5-HT innervation to the CeA [45], and preclinical studies have shown that the upregulation of 5-HT in the CeA is related to the expression of stress-induced anxiety and depression [46].

In rats, stressful stimuli enhance the release of 5-HT in the CeA [47], and serotoninergic receptor stimulation in the CeA is sufficient and necessary for stress-induced activation of the HPA axis [48, 49]. Agonist-induced stimulation of 5-HT1A receptors (8-OH-DPAT) in the CeA stimulates the HPA axis [49], whereas depletion of 5-HT in CeA or infusion of 5-HT2 receptor antagonists in the CeA blocks its excitatory effects on the HPA axis [48]. Electrical stimulation of the CeA raises plasmatic ACTH and corticosterone levels [5053]. 5-HT in the CeA has been suggested to have an important function in the stimulatory effects on the HPA axis through 5-HT in the paraventricular nucleus of the hypothalamus (PVN) [49].

Feldman and colleagues showed that hypothalamic lesions that were induced by 5,7-DHT, a neurotoxin that is used to decrease the concentrations of serotonin in the brain, prevented the stimulatory effects of a 5-HT1A agonist (8-OH-DPAT) that was injected into the CeA on plasmatic ACTH levels [49].

In conclusion, 5-HT release and activity in the CeA appear to be important for behavioral and endocrine responses that are related to stress exposure.

2.3. GABA

γ-Aminobutyric acid (GABA) is the chief inhibitory neurotransmitter in the mammalian brain and has significant function in reducing neuronal excitability in the nervous system. GABAergic transmission in the amygdala is an important pathway by which the flow of information, activity, and function can be controlled [5456], and considerable evidence has shown that this neurotransmitter in the amygdala is critical in mediating several aspects of the stress response. Studies in rats have demonstrated that acute restraint stress increases GABA efflux in the BLA [5760]. Conversely, GABAergic transmission in the BLA declines the following exposure to chronic or repeated stress [57]. It has been demonstrated that, by in vivo microdialysis, acute restraint stress enhanced GABA outflow in the BLA, whereas efflux in the CeA was unaffected [57]. Animals that were subjected to repeated stress (10 days of restraint) showed no acute stress-induced rise in GABA release in the BLA and did not experience any effects on GABA outflow in the CeA [57].

This evidence suggests that reduced GABAergic activity underlies the relationship between exposure to repeated stress and excessive fear responses to certain stimuli, characteristic of several anxiety disorders, such as posttraumatic stress disorder (PTSD). Manzanares and colleagues reported that previous restraint stress increases the fear response in a contextual fear paradigm in rats [61]. They also showed that infusion of midazolam, an agonist of GABAA receptors, into the BLA or systemic pretreatment with it prevents facilitation of the fear response that results from previous stress exposure [61]. Also, repeated stimulation of corticotropin-releasing factor receptors in the BLA enhances anxiety-like behaviors, which are associated with decreased GABAergic inhibition [62].

The impact of stress is also determined by the ability of the organism to cope with its situation [63]. Several reports have highlighted the function of GABAergic transmission in the mouse amygdala, particularly the BLA, in shaping an individual’s coping style to stress [58, 59], which, with other factors, can in turn affect one’s predisposition to affective disorders, such as anxiety (for review, see [64]). Rats having more passive strategy of coping with an aversive event (i.e., a longer freezing response in the conditioned freezing test) are associated with upregulation of c-Fos (an index of neuronal activation) in the BLA and CeA, as a result of lower GABAergic activity in the amygdala [65]. With regard to individual coping styles to stress, GABArgic transmission in the BLA has been shown to function in the response of C57BL/6 and DBA/2 mice in the forced swimming test. C57BL/6 mice exhibit the highest levels of passive-coping behavior [58, 59, 6668]. We have found that C57BL/6 mice show greater immobility in the forced swimming test (an index of passive-coping behavior), likely due to greater GABA outflow in the BLA, compared with DBA/2 mice [59].

Thus, the evidence from the animal studies above implicate BLA GABAergic neurotransmission in individual differences in stress-coping behavior, helping us understand the neurobiological mechanisms that underlie the susceptibility to stress-induced psychopathologies.

2.4. Glutamate

The amygdala receives glutamatergic afferents from several areas of the brain, including cortical and thalamic regions [6971].

The function of glutamate (GLU) in acute rapid neurotransmission and processes that are related to long-term synaptic plasticity implicates extracellular GLU as a significant mediator of the effects of stress on amygdalar activity. Microdialysis studies have shown that acute restraint stress increases extracellular GLU levels in rat BLA and CeA complexes [7274], which in turn activates the HPA axis [75, 76].

The release of GLU in the amygdala also increases with other types of stress and is modulated by fear responses. For instance, in rats, the expression of fear that is conditioned to a context that has been paired to shock induces a rapid increase in GLU in the BLA [77].

As for GABA, the effects of acute stress on GLU efflux differ fundamentally from those in individuals who have been subjected to repeated stress and challenged with acute stress. Whereas acute restraint stress elicits the quick and robust release of GLU in the BLA and CeA [7274], the glutamatergic response to an acute stress challenge is diminished in the BLA and CeA following exposure to repeated restraint stress in rats [78].

The changes in GLU release following the administration of certain classes of psychotropic drugs during a stressful experience are notable. For instance, agomelatine (an antidepressant that acts as a melatonergic receptor agonist and a 5HT2C antagonist) and tianeptine (a tricyclic antidepressant that functions through indirect alteration of glutamate receptor activity and release of BDNF) blunt the increase in GLU that is elicited by acute stress in the BLA and CeA and prevent the stress-induced decline in GLU efflux in the CeA in repeatedly restrained rats, thereby reestablishing the responsiveness of glutamatergic neurons [78, 79]. These data suggest that stress-induced alterations in amygdalar glutamatergic systems have clinical relevance as potential therapeutic targets in stress-related psychopathologies, including anxiety.

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3. The amygdala, stress, and dendritic alterations

The brain shows remarkable structural and functional plasticity in response to stressful experiences, including neuronal replacement, dendritic remodeling, and synapse turnover, and several studies have demonstrated that these events occur in the amygdala following stress exposure.

Neuroplasticity can be evaluated using various functional and morphological endpoints, ranging from molecular and cellular indices and changes in synaptic transmission to neurochemical alterations and changes in dendritic architecture and spine density.

The most significant evidence on stress-induced modifications in amygdalar neuronal plasticity refers to the morphological changes in dendrites. Currently, microscopy methods and associated algorithms permit one to perform a comprehensive dendritic neuronal morphological analysis, from 3D dendritic reconstruction to the estimation of spine numbers and density [for review, see 80].

In response to stress, dendritic branches extend or retract, on which dendritic spines emerge, disappear, or change in shape or size. Stress affects the morphology of neurons, primarily in the hippocampus, medial prefrontal cortex (mpFC), and amygdala. Furthermore, neurons in these regions are highly plastic and undergo dramatic transformations following traumatic experiences. In response to stressful conditions, amygdala neurons undergo differential changes compared with other structures that are implicated in the stress response. For instance, in the mpFC and hippocampus, stress triggers the dendritic atrophy and reduces spine numbers. Conversely, in the amygdala—in particular, the BLA—it increases dendritic length and spine density (for review, see [81, 82]).

Several studies have demonstrated that the effects of stress on amygdalar structural plasticity correlate with behavioral changes, such as the manifestation of anxious behavior [8387].

The BLA can undergo structural reorganization in response to several stressors, such as immobilization, maternal stress, and external application of the stress hormone corticosterone [83, 85, 88, 89]. In rats, chronic stress causes hypertrophy of pyramidal neurons in the BLA. Specifically, repeated restraint increases the total dendritic length, the number of branch points, and spine density in BLA pyramidal neurons—effects that are accompanied by greater anxiety-like behaviors [83, 90]. Notably, compared with mpFC and the hippocampus, the structural changes in the BLA after repeated stress persist, even after a stress-free recovery period of 3 weeks [84], suggesting the high sensitivity of amygdalar neurons to the long-term effects of stress.

The changes in BLA dendrites likely involve higher stress-induced corticosterone levels. Chronic exposure of rats to corticosterone increases the spine density in BLA pyramidal neurons and anxiety-like behavior [91]. Similarly, acute stress worsens anxiety and induces dendritic hypertrophy in the BLA. A single episode of immobilization stress in rats and mice raises the spine density in BLA neurons, which is accompanied by anxiety-like behavior [60, 90, 9295]. Pharmacological interventions for the treatment of mood disorders, including anxiety, reduce the stress-induced morphological changes in the rat amygdala. Specifically, the mood-stabilizer lithium prevents hypertrophy of BLA pyramidal neurons that is elicited by stress [96]. This evidence highlights how the amygdalar morphological alterations that are induced by stress underlie the pathophysiology of neuropsychiatric disorders, such as PTSD, major depressive disorder, and anxiety.

Nevertheless, as discusses, individuals respond to stress and trauma differently. For example, traumatic experiences might lead to PTSD in certain individuals while others are less affected by the same incidents [9799], and it appears that dendritic amygdala neurons are sensitive to individual variations in stress coping and stress responsiveness. One study demonstrated that 2 weeks after stress exposure (predator exposure stress), maladapted rats (i.e., animals that showed high anxiety following the stress exposure) harbored longer dendrites and more highly branched dendrites with greater spine density in the BLA compared with well-adapted animals (those with low anxiety after stress exposure) [86]. These data suggest that disparate patterns of plasticity in BLA neurons in response to stress account for individual differences in coping responses to stress and trauma.

The findings in these preclinical studies are consistent with human neuroimaging evidence. Clinical studies have demonstrated enhanced responsiveness of the amygdala in patients with PTSD and other psychopathologies that are related to stress, including major depression. This is discussed below.

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4. The amygdala, stress, and epigenetic mechanisms: the function of miRs

Epigenetics is the study of heritable changes in gene expression (active versus inactive genes) that do not involve alterations to the underlying DNA sequence, which in turn affects how cells process the genes. Epigenetic mechanisms rely on specific gene sequences that normally lie in the 5′UTR or 3′UTR (regulatory sequences upstream and downstream of the coding sequence, respectively). These sequences regulate the expression of genes, based on the activities of various proteins (e.g., RNA-binding proteins) and short RNAs, which recognize, bind, and directly regulate the synthesis of specific genes. Such epigenetic modifications include histone modification, DNA methylation, and noncoding RNA mechanisms [100, 101].

Several studies have recently provided significant insight, suggesting that microRNAs (miRs)—small noncoding RNAs—are central in the epigenetic regulation of stress-induced psychopathologies, including anxiety disorders [102105]. miRs influence chromatin structure and protein binding to DNA and directly affect transcription and translation. Most frequently, mRNA stability is governed through the binding of miRs to the 3′UTR of target mRNAs, decreasing mRNA stability and mRNA cleavage and thus impeding protein assembly [106]. Most mammalian miRs are encoded by RNA polymerase II-transcribed genes, which can be tens of kilobases in length and are frequently spliced [107]. Approximately one-third of known miRs is embedded within introns of protein-coding genes and is cotranscribed with the host gene, allowing coordinate regulation of miR and protein expression.

In the brain, miRs are critical in modulating many neurobiological processes, including changes in neuronal morphology and neurotransmitter homeostasis.

The ability of miRs to selectively and reversibly silence mRNAs and their involvement in neuronal plasticity and neurotransmitter release render miRNAs well suited as fine-tuning regulators of the complex and extensive molecular network that drives stress responses [108]. Consistent with this model, miRs are altered by stress, glucocorticoids, and mood stabilizers, indicating that they are critical in the etiology of anxiety disorders (for review, see [103]).

In particular, recent studies have demonstrated a physiological function amygdalar miR-34 in regulating stress responses.

Haramati and colleagues reported that acute stress upregulates miR-34 in the CeA of mice and that virus-mediated overexpression of miR-34 in this area prevents stress-induced anxiety and blocks the response of CRFR1 to its ligand CRF, suggesting that miR-34 regulates the molecular machinery of the response to stress [93].

Moreover, a recent study from our group showed that the miR-34 expression in the BLA controls the stress response and stress-induced anxiety [60], in which acute restraint stress upregulated miR-34 in the BLA (approximately 3.5-fold higher than in unstressed mice) [60]. Notably, genetic deletion of miR-34 in mice rendered them resilient to stress-induced anxiety and facilitated fear extinction. Moreover, no increase in BLA GABA release or stress-induced amygdalar dendritic remodeling was evident in miR-34 KO mice, implicating miR-34 in the regulation of amygdalar functions during the stress response [60].

Other miRs, such as miR-135a and miR-124, are modulated in the amygdala in mouse by stress [109]. Also, studies in rats have demonstrated a putative function of miRs in the amygdala in modulating the stress response. In a rat model of learned helplessness, in which rats were subjected to 2 h of immobilization per day and tail shocks for 3 consecutive days, miRs in the amygdala were substantially altered, leading to a global increase in the expression of many miRs, including miR-142-5p, miR-19b, miR-1928, miR-223-3p, miR-322*, miR-324, miR-421-3p, miR-463*, and miR-674* [110].

Among these species, amygdalar miR-19b is modulated by chronic social defeat. Mice that have been subjected to an aggressive mouse experience a significant rise in miR-19b in the BLA and greater freezing in the cue fear conditioning test; further, in vitro studies have shown a direct effect of miR-19b on adrenergic receptor beta 1 (Adrb1) mRNA levels by luciferase assay [111]. Notably, mice that were injected with miR-19b into the BLA had lower freezing times compared with control mice, concomitant with downregulation of Adrb1. Thus, the authors suggested that miR-19b has significant function in modulating behavioral responses to chronic stress through the control of adrenergic receptor-1 mRNA [111]. A relationship between miRs, amygdalar function, and stress has been also proposed in human studies.

DICER1 is an enzyme that generates mature miRs through genomewide differential gene expression. A survey of patients with PTSD and comorbid depression [112] reported that blood DICER1 expression is significantly lower than in healthy subjects and that this effect is associated with increased amygdalar activation that is induced by fearful stimuli [112].

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5. Neuronal circuits in the stress response

The amygdala has emerged as a key region of the brain in the modulation of stress responses, thus having significant function in stress-induced psychopathologies, such as anxiety.

However, the amygdala orchestrates stress and anxiety responses, influencing many other brain areas by sending projections to such domains, as the pFC, that are involved in motor control and autonomic and neuroendocrine responses.

Many studies have implicated the prefrontal cortex-amygdala system in the stress response and stress-related disorders [113115]. The mpFC modulates neuroendocrine function during stress and regulates peripheral responses to stress, including heart rate, blood pressure, and cortisol responses [116, 117].

The mpFC and amygdala have reciprocal anatomical interconnections [118122], and the former appears to have regulatory function in amygdalar activation during the stress response.

Animal studies have demonstrated that activation of the mpFC increases the number of c-Fos-immunoreactive cells in intercalated amygdala neurons [123] and that electrical stimulation of the pFC inhibits central output neurons [124] and basolateral projection neurons [125] in the amygdala. Similarly, during stressful experiences, frontal cortical areas modulate emotional responsiveness through the inhibition of amygdalar function, and it has been hypothesized that stress-induced dysfunction of this mechanism underlies pathological emotional responses in patients with PTSD and, possibly, other anxiety disorders. Supporting this model, functional imaging studies in PTSD have reported amygdalar hyperactivation in response to threatening stimuli [126, 127] and decreased mPFC activation [128130] compared with healthy controls. Moreover, functional analyses have revealed less connectivity between the amygdala and mpFC in PTSD [130]. Copious evidence demonstrates that 5-HT neurotransmission in the mpFC constitutes a potential mechanism through which the mpFC regulates amygdala-mediated arousal in response to emotional stimuli, such as stressful events. In a human study, Fisher and colleagues observed that the prefrontal 5-HT2A receptor density is associated with lower threat-related right amygdalar reactivity [131]. Studies on serotonin transporters (5-HTT) have also proposed 5-HT to function in mediating mpFC-amygdala interplay. Wellman and colleagues showed that the loss of 5-HTT function in mice compromises their ability to cope with environmental stress and effects morphological abnormalities in the BLA and mpFC—changes that were related to amygdalar hyperactivity and hypofunction in the pFC [132]. Further, regarding the function of the prefrontal 5-HT system in modulating the amygdalar stress response, we have demonstrated that bilateral selective 5-HT depletion in the mpFC in mice decreases the BLA GABA release that is induced by restraint stress and passive coping in the forced swimming test, implicating 5-HT and GABA transmission-mediated pFC/amygdala connectivity as a critical neural mechanism of stress-induced behavior [58, 59].

Overall, connections between the mpFC and amygdala normally allow individuals to adjust their behavior in response to several stimuli, including stress. A loss in prefrontal control of the amygdala might underlie the inability to cope adequately with stressful situations, thus promoting the anxiety disorders that are related to stress exposure.

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6. The amygdala and stress: evidence from human studies

Individuals can be exposed to various stressful conditions, such as childhood violence, divorce, physiological disease, international terrorism, economic insecurity, and job stress, which can lead to various diseases, including anxiety disorders, depression, and schizophrenia.

In humans and animals, the amygdala is activated by stressful stimuli [133], and over the past decade, interest in the human amygdala in stress-related psychiatric disorders has grown considerably, due to the progress in animal studies and the development of functional imaging techniques.

In human imaging studies, altered amygdalar responsiveness to negative stimuli has been shown to be associated with psychopathologies that are induced by stress [134136].

Specifically, functional imaging studies have observed amygdalar hyperactivation [137142] in response to threatening stimuli in anxiety disorders [143]. Moreover, amygdala alterations occur in other psychopathologies that are related to stressful conditions, such as depression. For instance, fMRI studies have reported that depressed patients develop an abnormally exaggerated amygdala in response to negative stimuli [144] and that antidepressant treatment normalizes this activity [145].

In humans, the patent link between stress, the amygdala, and anxiety disorders is evident in PTSD patients.

According to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders [146], anxiety and stress disorders are characterized by an excessive fear response or worry that interferes with normal functioning or causes significant distress. Fearful stimuli, such as fearful faces and fear-inducing images, have been found to activate the amygdala in several brain imaging studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) [147149]. PTSD appears to combine aspects of severe stress responsiveness and enhanced conditioned fear and the inability to extinguish or inhibit conditioned fear. Accordingly, in PTSD patients, amygdalar activity is enhanced in response to trauma reminders and general negative stimuli [150]. For instance, amygdalar hyperresponsivity in PTSD occurs during the presentation of personalized traumatic narratives [151, 152], combat sounds, [153, 154] combat photographs, [155, 156], and trauma-related words [157].

Childhood maltreatment also increases one’s susceptibility to PTSD and others anxiety disorders [158] and generally increases the sensitivity to stress in later life, of which amygdala hyperresponsiveness is an important aspect.

For instance, there is a strong association between childhood trauma questionnaire scores and amygdala responsiveness to sad—but not happy—facial expressions [159].

An fMRI study examined the emotional experiences and amygdalar responses of 50 healthy new recruits in the Israeli Defense Forces before they began their mandatory military service and after subsequent exposure to stressful events while deployed in combat units. Over time, some soldiers reported an increase in stress symptoms, an effect that correlated with greater amygdalar activation and hippocampal responsiveness to stress-related content [160]. Moreover, the authors noted that amygdalar reactivity before stress predicted the rise in stress symptoms [160].

The hypothesis that the amygdalar activity in response to negative stimuli predicts the individual vulnerability to stress is supported by several studies that have demonstrated that amygdalar responsiveness is strongly influenced by genotype. Genetic factors have been shown to govern amygdalar responsiveness to emotional stimuli and one of these is certainly represented by a polymorphism in serotonin transporter (5-HTT).

Studies reveal that polymorphisms in 5-HTT might be linked to the exaggerated responses of the amygdala on encountering environmental threats and to the risk for mood and anxiety disorders, especially in response to chronic or severe stress. Hariri and colleagues demonstrated that individuals with one or two copies of the short allele of the 5-HTT promoter polymorphism, which has been associated with reduced 5-HTT expression and function and increased fear and anxiety-related behaviors, exhibit greater amygdalar neuronal activity, as measured by BOLD functional magnetic resonance imaging, in response to fearful stimuli compared with long allele homozygotes [161]. Moreover, 5-HTT binding is suggested to correlate with threat-related amygdalar reactivity, up to 40% of the variability in threat-related amygdala reactivity predicted by 5-HTT binding levels [162]. Polymorphisms in genes that are linked to aminergic activity, such as catechol-O-methyltransferase (COMT), one of several enzymes that degraded catecholamines, might function in mediating the amygdalar activity in response to environmental threats.

In an fMRI study, healthy subjects who were genotyped for the COMT Val158Met polymorphism showed an increase predominantly in left-sided amygdalar activity in response to fearful and angry facial stimuli. This effect was observed online in the female subgroup, suggesting a gender-specific influence of COMT Val158Met on amygdalar activity in the processing of emotional stimuli [163].

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7. Conclusion

The expression of anxiety disorders, including generalized anxiety disorder, specific phobias, social anxiety disorder, separation anxiety disorder, agoraphobia, panic disorder, and PTSD, is commonly caused by stress. Yet, little is known about the specific etiological pathways that lead from a triggering stressor to the development of a specific pathological phenotype.

Overwhelming data report alterations in amygdalar functions in anxiety and stress disorders. Animal and clinical studies support the critical function of the amygdala in stress and anxiety, characterized by general amygdalar hyperactivity that is associated with the anxiety symptoms and the response to threatening or stressful stimuli. This hyperactivation has evidenced by, for example, dendritic hypertrophy and reductions in the inhibitory neurotransmitter GABA following stress exposure.

Despite the clear involvement of amygdalar circuits in anxiety disorders, it remains unknown how this structure contributes to the specificity of various pathological anxiety disorders. Moreover, studies on different anxiety disorders have reported similar alterations with regard to neurotransmitter activity, neuroplastic changes, and alterations in amygdalar function, suggesting that these properties are common in anxiety disorders and that the phenotypic specificity is rooted in upstream mechanisms.

In this context, epigenetic mechanisms might be good targets. In particular, in the past decade, growing evidence has shown that miRs regulate amygdalar functions during stress response and anxiety-like behaviors.

MiRs control the expression of specific genes that are involved in neurobiological processes, including dendritic morphological changes and neurotransmitter homeostasis, and their function in mediating stress responses has recently been described. A systematic study of the relationships between specific stress-related disorders and alterations in epigenetic mechanisms, such as miR expression in the amygdala, might be a good strategy to identify upstream mechanisms and, eventually, selective therapeutic interventions for various anxiety disorders, given that in clinical practice, the choice of the appropriate pharmacological strategy is driven by symptoms release and lacks of specificity, is characterized by low response rate and high recurrence.

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Acknowledgments

We are grateful to Professor Rossella Ventura for helpful suggestions. This research is supported by SIR, cod. “RBSI14G1HH”, Italian Ministry of Education, Universities and Research.

References

  1. 1. Darvesh AS, Carroll RT, Geldenhuys WJ, Gudelsky GA, Klein J, Meshul CK, Van der Schyf CJ. In vivo brain microdialysis: advances in neuropsychopharmacology and drug discovery. Expert Opin Drug Discov. 2011; 6(2):109-127. DOI: 10.1517/17460441.2011.547189
  2. 2. Persson L, Valtysson J, Enblad P, Warme PE, Cesarini K, Lewen A, Hillered L. Neurochemical monitoring using intracerebral microdialysis in patients with subarachnoid hemorrhage. J Neurosurg. 1996; 84(4): 606-16. DOI: NA
  3. 3. Ronne-Engström E, Hillered L, Flink R, Spännare B, Ungerstedt U, Carlson H. Intracerebral microdialysis of extracellular amino acids in the human epileptic focus. J Cereb Blood Flow Metab. 1992; 12(5):873-6. DOI: NA
  4. 4. Morilak DA, Fornal CA, Jacobs BL. Effects of physiological manipulations on locus coeruleus neuronal activity in freely moving cats. III. Glucoregulatory challenge. Brain Res. 1987; 422(1):32-39. DOI:10.1016/0006-8993(87)90537-3
  5. 5. Pacák K, Palkovits M, Kvetnanský R, Fukuhara K, Armando I, Kopin IJ, Goldstein DS. Effects of single or repeated immobilization on release of norepinephrine and its metabolites in the central nucleus of the amygdala in conscious rats. Neuroendocrinology. 1993; 57(4):626-633. DOI:10.1159/000126417
  6. 6. Moore RY, Bloom FE. Central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems. Annu Rev Neurosci. 1979; 2:113-168. DOI:10.1146/annurev.ne.02.030179.000553
  7. 7. Tanaka M, Yoshida M, Emoto H, Ishii H. Noradrenaline systems in the hypothalamus, amygdale and locus coeruleus are involved in the provocation of anxiety: basic studies. Eur J Pharmacol. 2000; 405(1-3):397-406. DOI: 10.1016/S0014-2999(00)00569-0
  8. 8. Cecchi M, Khoshbouei H, Morilak DA. Modulatory effects of norepinephrine, acting on alpha 1 receptors in the central nucleus of the amygdala, on behavioral and neuroendocrine responses to acute immobilization stress. Neuropharmacology. 2002; 43(7):1139-1147. DOI: 10.1016/S0028-3908(02)00292-7
  9. 9. Cecchi M, Khoshbouei H, Javors M, Morilak DA. Modulatory effects of norepinephrine in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress. Neuroscience. 2002; 112(1):13-21. DOI: 10.1016/S0028-3908(02)00292-7
  10. 10. Ma S, Morilak DA. Norepinephrine release in medial amygdala facilitates activation of the HPA axis in response to acute immobilisation stress. J Neuroendocrinol. 2005; 17(1):22-28. DOI: 10.1111/j.1365-2826.2005.01279.x
  11. 11. Pardon MC, Ma S, Morilak DA Chronic cold stress sensitizes brain noradrenergic reactivity and noradrenergic facilitation of the HPA stress response in Wistar Kyoto rats. Brain Res. 2003; 971(1):55-65. DOI: 10.1016/S0006-8993(03)02355-2
  12. 12. Morilak DA, Barrera G, Echevarria DJ, Garcia AS, Hernandez A, Ma S, Petre CO. Role of brain norepinephrine in the behavioral response to stress. Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29(8):1214-1224. DOI: 10.1016/j.pnpbp.2005.08.007
  13. 13. Kawahara Y, Kawahara H, Kaneko F, Tanaka M. Long-term administration of citalopram reduces basal and stress-induced extracellular noradrenaline levels in rat brain. Psychopharmacology. 2007; 194(1):73-81. DOI: 10.1007/s00213-007-0826-8
  14. 14. Galvez R, Mesches MH, McGaugh JL. Norepinephrine release in the amygdala in response to footshock stimulation. Neurobiol Learn Mem. 1996; 66(3):253-7. DOI: NA
  15. 15. Quirarte GL, Galvez R, Roozendaal B, McGaugh JL. Norepinephrine release in the amygdala in response to footshock and opioid peptidergic drugs. Brain Res. 1998; 808(2):134-40. DOI: NA.
  16. 16. Tanaka M, Kohno Y, Nakagawa R, Ida Y, Iimori K, Hoaki Y, Tsuda A, Nagasaki N. Time-related differences in noradrenaline turnover in rat brain regions by stress. Pharmacol Biochem Behav. 1982; 16(2):315-319. DOI: 10.1016/0091-3057(82)90166-6
  17. 17. Tanaka M, Kohno Y, Nakagawa R, Ida Y, Iimori K, Hoaki Y, Tsuda A, Nagasaki N. Naloxone enhances stress-induced increases in noradrenaline turnover in specific brain regions in rats. Life Sci. 1982;30(19):1663-1669. DOI: 10.1016/0024-3205(82)90499-4
  18. 18. Tanaka M, Kohno Y, Tsuda A, Ida Y, Iimori K, Hoaki Y, Nagasaki N. Differential effects of morphine on noradrenaline release in brain regions of stressed and non-stressed rats. Brain Res. 1983A; 275(1):105-115. DOI: 10.1016/0006-8993(83)90422-5.
  19. 19. Ida Y, Tanaka M, Tsuda A, Tsujimaru S, Nagasaki N. Attenuating effect of diazepam on stress-induced increases in noradrenaline turnover in specific brain regions of rats: antagonism by Ro 15-1788. Life Sci. 1985; 37(26):2491-2498. DOI:10.1016/0024-3205(85)90606-X
  20. 20. Tanaka M; Tsuda A, Yokoo H; Yoshida M, Ida Y, Nishimura H. Involvement of the brain noradrenaline system in emotional changes caused by stress in rats. Neurobiology of stress ulcers. Ann N Y Acad Sci. 1990; 597:159-174. DOI: 10.1111/j.1749-6632.1990.tb16165.x
  21. 21. Tanaka T, Yokoo H, Mizoguchi K, Yoshida M, Tsuda A, Tanaka M. Noradrenaline release in the rat amygdala is increased by stress: studies with intracerebral microdialysis. Brain Res. 1991; 544(1):174-176. DOI: 10.1016/0006-8993(91)90902-8.
  22. 22. Sadikot AF, Parent A. The monoaminergic innervation of the amygdala in the squirrel monkey: an immunohistochemical study. Neuroscience. 1990; 36(2):431-447. DOI: 10.1016/0306-4522(90)90439-B
  23. 23. Roder S, Ciriello J. Innervation of the amygdaloid complex by catecholaminergic cell groups of the ventrolateral medulla. J Comp Neurol. 1993;332(1):105-122. DOI: 10.1002/cne.903320108
  24. 24. Feldman S, Conforti N, Saphier D. The preoptic area and bed nucleus of the stria terminalis are involved in the effects of the amygdala on adrenocortical secretion. Neuroscience. 1990; 37: 775-779. DOI: http://dx.doi.org/10.1016/0306-4522(90)90107-F.
  25. 25. Bedse G, Romano A, Tempesta B, Lavecchia MA, Pace L, Bellomo A, Duranti A, Micioni Di Bonaventura MV, Cifani C, Cassano T, Gaetani S. Inhibition of anandamide hydrolysis enhances noradrenergic and GABAergic transmission in the prefrontal cortex and basolateral amygdala of rats subjected to acute swim stress. J Neurosci Res. 2015; 93(5):777-787. DOI: 10.1002/jnr.23539
  26. 26. Khoshboue H, Cecchi M, Dove S, Javors M, Morilak DA. Behavioral reactivity to stress: amplification of stress-induced noradrenergic activation elicits a galanin-mediated anxiolytic effect in central amygdala. Pharmacol Biochem Behav. 2002; 71(3):407-417. DOI: 10.1016/S0091-3057(01)00683-9
  27. 27. Tanaka T, Yoshida M, Yokoo H, Tomita M, Tanaka M. Expression of aggression attenuates both stress-induced gastric ulcer formation and increases in noradrenaline release in the rat amygdale assessed by intracerebral microdialysis. Pharmacol Biochem Behav. 1998; 59(1):27-31. DOI: 10.1016/S0091-3057(97)00312-2
  28. 28. Ray A, Henke PG, Sullivan RM. Noradrenergic mechanisms in the central amygdalar nucleus and gastric stress ulcer formation in rats. Neurosci Lett. 1990; 110(3):331-336. DOI: 10.1016/0304-3940(90)90869-B
  29. 29. Chalmers DT, Watson S.J. Comparative anatomical distribution of 5-HT1A receptor in RNA and 5-HT1A binding in rat brain: a combined in situ hybridization and in vitro receptor autoradiography study. Brain Res. 1991; 561(1):51-60. DOI: 10.1016/0006-8993(91)90748-K
  30. 30. Duxon MS, Flanigan TP, Reavley AC, Baxter GS, Blackburn TP, Fone KC. Evidence for expression of the 5-hydroxytryptamine-2B receptor protein in the rat central nervous system. Neuroscience. 1997; 76(2):323-329. DOI: 10.1016/S0306-4522(96)00480-0
  31. 31. Waeber C, Sibben M, Neioullon A, Bokaert J, Dumais A. Regional distribution and ontogeny of 5-HT4 binding sites in rodent brain. Neuropharmacology. 1994; 33(3-4):527-541. DOI: 10.1016/0166-4328(96)00108-8
  32. 32. Wright DE, Seroogy KB, Lundgren KH, Davis BM, Jennes L. Comparative localization of serotonin 1A, 1C, and 2 receptor sub-type mRNAs in rat brain. J Comp Neurol. 1995; 351(3):357-373. DOI: 10.1002/cne.903510304
  33. 33. Ma QT, Yin GF, Ai MK, Han JS. Serotonergic projections from the nucleus raphe dorsalis to the amygdala in the rat. Neurosci Lett. 1991; 134(1):21-24. DOI: 10.1016/0304-3940(91)90499-J
  34. 34. Funada M, Hara C. Differential effects of psychological stress on activation of the 5-hydroxytryptamine-and dopamine-containing neurons in the brain of freely moving rats. Brain Res. 2001; 901(1-2):247-251. DOI: 10.1016/S0006-8993(01)02160-6
  35. 35. Amat J, Matus-Amat P, Watkins LR, Maier SF. Escapable and inescapable stress differentially alter extracellular levels of 5-HT in the basolateral amygdale of the rat. Brain Res. 1998; 812(1-2):113-120. DOI: 10.1016/S0006-8993(98)00960-3
  36. 36. Higgins G, Jones B, Oakley N, Tyers M. Evidence that the amygdala is involved in the disinhibitory effects of 5-HT3 receptor antagonists. Psychopharmacology. 1991; 104(4):545-551. DOI: 10.1007/BF02245664
  37. 37. Hodges H, Green S, Glenn B. Evidence that the amygdala is involved in benzodiazepine and serotonergic effects on punished responding but not on discrimination. Psychopharmacology. 1987; 92(4)491-504. DOI: 10.1007/BF00176484
  38. 38. Maier SF, Watkins LR. Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci Biobehav Rev. 2005; 29:829-841. DOI: 10.1016/j.neubiorev.2005.03.021
  39. 39. Southwick SM, Vythilingam M, Charney DS. The psychobiology of depression and resilience to stress: implications for prevention and treatment. Annu Rev Clin Psychol. 2005; 1:255-291. DOI: 10.1146/annurev.clinpsy.1.102803.143948
  40. 40. Foa EB, Zinbarg R, Rothbaum BO. Uncontrollability and unpredictability in post-traumatic stress disorder: an animal model. Psychol Bull. 1992; 112(2):218-238. DOI: 10.1037/0033-2909.112.2.218
  41. 41. Christianson JP, Ragole T, Amat J, Greenwood BN, Strong PV, Paul ED, Fleshner M, Watkins LR, Maier SF. 5-Hydroxytryptamine 2C receptors in the basolateral amygdale are involved in the expression of anxiety after uncontrollable traumatic stress. Biol Psychiatry. 2010; 67(4):339-345. DOI: 10.1016/j.biopsych.2009.09.011.
  42. 42. Mitsushima D, Yamada K, Takase K, Funabashi T, Kimura F. Sex differences in the basolateral amygdala: the extracellular levels of serotonin and dopamine, and their responses to restraint stress in rats. Eur J Neurosci. 2006; 24(11):3245-3254. DOI: 10.1111/j.1460-9568.2006.05214.x
  43. 43. Sheng Z, Kawano J, Yanai A, Fujinaga R, Tanaka M, Watanabe Y, Sinoda K. Expression of estrogen receptors (a, b) and androgen receptor in serotonin neurons of the rat and mouse dorsal raphe nuclei; sex and species differences. Neurosci Res. 49(2):185-96. DOI: http://dx.doi.org/10.1016/j.neures.2004.02.011
  44. 44. McCormick CM, Mathews IZ. HPA function in adolescence: role of sex hormones in its regulation and the enduring consequences of exposure to stressors. Pharmacol Biochem Behav.; 2007; 86(2):220-33. DOI: http://dx.doi.org/10.1016/j.pbb.2006.07.012.
  45. 45. Petrov T, Krukoff TL, Jhamandas JH. Chemically defined collateral projections from the pons to the central nucleus of the amygdala and hypothalamic paraventricular nucleus in the rat. Cell Tissue Res. 1994; 277(2):289-295. DOI: 10.1007/BF00327776
  46. 46. Fisher PM, Meltzer CC, Ziolko SK, Price JC, Moses-Kolko EL, Berga SL, Hariri AR. Capacity for 5-HT-1A-mediated autoregulation predicts amygdala reactivity. Nat Neurosci. 2006; 9(11):1362-1363. DOI: 10.1038/nn1780
  47. 47. Adell A, Casanovas JM, Artigas F. Comparative study in the rat of the actions of different types of stress on the release of 5-HT in raphe nuclei and forebrain areas. Neuropharmacology. 1997; 36(4-5):735-41. DOI: NA
  48. 48. Feldman S, Newman ME, Gur E, Weidenfeld J. Role of serotonin in the amygdala in hypothalamopituitary-adrenocortical responses. Neuroreport. 1998; 9(9):2007-2009. DOI: 10.1097/00001756-199806220-00017
  49. 49. Feldman S, Newman ME, Weidenfeld J. Effects of adrenergic and serotonergic agonists in the amygdala on the hypothalamo-pituitary-adrenocortical axis. Brain Res Bull. 2000; 52(6):531-536. DOI: 10.1016/S0361-9230(00)00292-6
  50. 50. Feldman S and Conforti N. Amygdalectomy Inhibits adrenocortical responses to somatosensory and olfactory stimulation. Neuroendocrinology. 1981; 32(6):330-4. DOI:NA
  51. 51. Feldman S, Conforti N, Itzik A, Weidenfeld J. Differential effect of amygdaloid lesions on CRF-41, ACTH and corticosterone responses following neural stimuli. Brain Res. 1994; 658(1-2):21-6. DOI: NA
  52. 52. Feldman S, Conforti N and Weidenfeld J. Limbic pathways and hypothalamic neurotransmitters mediating adrenocortical responses to neural stimuli. Neurosci Biobehav Rev. 1995; 19(2):235-40. DOI: http://dx.doi.org/10.1016/0149-7634(94)00062-6
  53. 53. Gray TS. Stress, neuropeptides and systemic disease. London: Academic Press, 1991: 37-53.
  54. 54. Cassell MD, Freedman LJ, Shi C. The intrinsic organization of the central extended amygdala. Ann N Y Acad Sci. 1999; 877:217-241. DOI: 10.1111/j.1749-6632.1999.tb09270.x
  55. 55. Davis M, Rainnie D, Cassell M. Neurotransmission in the rat amygdala related to fear and anxiety. Trends Neurosci. 1994; 17(5):208-214. DOI: 10.1016/0166-2236(94)90106-6
  56. 56. Woodruff AR, Monyer H, Sah P. GABAergic excitation in the basolateral amygdala. J Neurosci. 2006; 26(46):11881-11887. DOI: 10.1523/JNEUROSCI.3389-06.2006
  57. 57. Reznikov LR, Reagan LP, Fadel JR. Effects of acute and repeated restraint stress on GABA efflux in the rat basolateral and central amygdala. Brain Res. 2009; 1256:61-68. DOI: 10.1016/j.brainres.2008.12.022.
  58. 58. Andolina D, Maran D, Valzania A, Conversi D, Puglisi-Allegra S. Prefrontal/amygdalar system determines stress coping behavior through 5-HT/GABA connection. Neuropsychopharmacology. 2013; 38(10):2057-2067. DOI: 10.1038/npp.2013.107
  59. 59. Andolina D, Maran D, Viscomi MT, Puglisi-Allegra S. Strain-dependent variations in stress coping behavior are mediated by a 5-HT/GABA interaction within the prefrontal corticolimbic system. Int J Neuropsychopharmacol. 2014; 18(3) pii: pyu074. DOI: 10.1093/ijnp/pyu074
  60. 60. Andolina D, Di Segni M, Bisicchia E, D'Alessandro F, Cestari V, Ventura A, Concepcion C, Puglisi-Allegra S, Ventura R. Effects of lack of microRNA-34 on the neural circuitry underlying the stress response and anxiety. Neuropharmacology. 2016; 107:305-316. DOI: 10.1016/j.neuropharm.2016.03.044
  61. 61. Rodríguez Manzanares PA, Isoardi NA, Carrer HF, Molina VA. Previous stress facilitates fear memory, attenuates GABAergic inhibition, and increases synaptic plasticity in the rat basolateral amygdala. J Neurosci. 2005; 25(38):8725-8734. DOI: 10.1523/JNEUROSCI.2260-05.2005
  62. 62. Rainnie DG, Bergeron R, Sajdyk TJ, Patil M, Gehlert DR, Shekhar A. Corticotrophin releasing factor-induced synaptic plasticity in the amygdala translates stress into emotional disorders. J Neurosci. 2004; 24(14):3471-3479. DOI: 10.1523/JNEUROSCI.5740-03.2004
  63. 63. Ursin H, Olff M. Aggression, defense, and coping in humans. Aggress Behav. 1995; 21(1):13-19. DOI: 10.1002/1098-2337(1995)21:1<13::AID-AB2480210104>3.0.CO;2-Z
  64. 64. Puglisi-Allegra S, Andolina D. Serotonin and stress coping. Behav Brain Res. 2015; 5:277:58-67. doi: 10.1016/j.bbr.2014.07.052.
  65. 65. Lehner M, Taracha E, Turzyńska D, Sobolewska A, Hamed A, Kołomańska P, Skórzewska A, Maciejak P, Szyndler J, Bidziński A, Płaźnik A. The role of the dorsomedial part of the prefrontal cortex serotonergic innervations in rat responses to the aversively conditioned context: behavioral, biochemical and immunocytochemical studies. Behav Brain Res. 2008; 192(2):203-215. DOI: 10.1016/j.bbr.2008.04.003.
  66. 66. Cabib S, Puglisi-Allegra S. Genotype-dependent effects of chronic stress on apomorphine-induced alterations of striatal and mesolimbic dopamine metabolism. Brain Res. 1991; 542(1):91-96. DOI: 10.1016/0006-8993(91)91002-I
  67. 67. Alcaro A, Cabib S, Ventura R, Puglisi-Allegra S. Genotype and experience dependent susceptibility to depressive-like responses in the forced-swimming test. Psychopharmacology. 2002; 164(2):138-143. DOI: 10.1007/s00213-002-1161-8
  68. 68. Ventura R, Cabib S, Puglisi-Allegra S. Genetic susceptibility of mesocortical dopamine to stress determines liability to inhibition of mesoaccumbens dopamine and to behavioral ‘despair’ in a mouse model of depression. Neuroscience. 2002; 115(4):999-1007. DOI: 10.1016/S0306-4522(02)00581-X
  69. 69. LeDoux JE, Farb C, Ruggiero DA. Topographic organization of neurons in the acoustic thalamus that project to the amygdala. J Neurosci. 1990;10(4):1043-1054. DOI: 0270-6474/90/041043-12$02.00/0
  70. 70. Turner BH, Herkenham M. Thalamo amygdaloid projections in the rat: a test of the amygdala’s role in sensory processing. J Comp Neurol. 1991; 313(2):295-325. DOI: 10.1002/cne.903130208
  71. 71. McDonald AJ, Shammah-Lagnado SJ, Shi C, Davis M. Cortical afferents to the extended amygdala. Ann N Y Acad Sci. 1999; 877:309-338. DOI: 10.1111/j.1749-6632.1999.tb09275.x
  72. 72. Reznikov LR, Grillo CA, Piroli GG, Pasumarthi RK, Reagan LP, Fadel J. Acute stress-mediated increases in extracellular glutamate levels in the rat amygdala: differential effects of antidepressant treatment. Eur J Neurosci. 2007; 25(10):3109-3114. DOI: 10.1111/j.1460-9568.2007.05560.x
  73. 73. Skórzewska A, Bidziński A, Hamed A, Lehner M, Turzyńska D, Sobolewska A, Szyndler J, Maciejak P, Wisłowska-Stanek A, Płaźnik A. The effect of CRF and alpha-helical CRF((9-41)) on rat fear responses and amino acids release in the central nucleus of the amygdala. Neuropharmacology. 2009; 57(2):148-156. DOI: 10.1016/j.neuropharm.2009.04.016.
  74. 74. Reaga LP, Reznikov LR, Evans AN, Gabriel C, Mocaër E, Fadel JR. The antidepressant agomelatine inhibits stress-mediated changes in amino acid efflux in the rat hippocampus and amygdala. Brain Res. 2012; 1466:91-98. DOI: 10.1016/j.brainres.2012.05.039.
  75. 75. Gabr RW, Birkle DL, Azzaro AJ. Stimulation of the amygdala by glutamate facilitates corticotropin-releasing factor release from the median eminence and activation of the hypothalamic-pituitary-adrenal axis in stressed rats. Neuroendocrinology. 1995;62(4):333-339. DOI: 10.1159/000127022
  76. 76. Herman JP, Cullinan WE. Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci. 1997; 20(2):78-84. DOI: 10.1016/S0166-2236(96)10069-2
  77. 77. Venton BJ, Robinson TE, Kennedy RT, Maren S. Dynamic amino acid increases in the basolateral amygdala during acquisition and expression of conditioned fear. Eur J Neurosci. 2006; 23(12):3391-3398. DOI: 10.1111/j.1460-9568.2006.04841.x
  78. 78. Grillo CA, Risher M, Macht VA, Bumgardner AL, Hang A, Gabriel C, Mocaër E, Piroli GG, Fadel JR, Reagan LP. Repeated restraint stress-induced atrophy of glutamatergic pyramidal neurons and decreases in glutamatergic efflux in the rat amygdale are prevented by the antidepressant agomelatine. Neuroscience. 2015; 284:430-443. DOI: 10.1016/j.neuroscience.2014.09.047.
  79. 79. Piroli GG, Reznikov LR, Grillo CA, Hagar JM, Fadel JR, Reagan LP. Tianeptine modulates amygdalar glutamate neurochemistry and synaptic proteins in rats subjected to repeated stress. Exp Neurol. 2013; 241:184-93. doi: 10.1016/j.expneurol.2012.12.005.
  80. 80. Mancuso JJ, Chen Y, Li X, Xue Z, Wong ST. Methods of dendritic spine detection: from Golgi to high-resolution optical imaging. Neuroscience. 2013; 251:129-140. DOI: 10.1016/j.neuroscience.2012.04.010.
  81. 81. Holtmaat A, Svoboda K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci. 2009; 10(9):647-658. DOI: 10.1038/nrn2699.
  82. 82. Sousa N, Almeida OFX. Disconnection and reconnection: the morphological basis of (mal) adaptation to stress. Trends Neurosci. 2012; 35(12):742-751. DOI: 10.1016/j.tins.2012.08.006
  83. 83. Vyas A, Mitra R, Shankaranarayana Rao BS, Chattarji S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci. 2002; 22(15):6810-6818. DOI: 20026655
  84. 84. Vyas A, Pillai AG, Chattarji S. Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior. Neuroscience. 2004; 128(4):667-673. DOI: 10.1016/j.neuroscience.2004.07.013
  85. 85. Mitra R, Sapolsky RM. Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy. Proc Natl Acad Sci USA. 2008; 105(14):5573-5578. DOI: 10.1073/pnas.0705615105
  86. 86. Mitra R, Adamec R, Sapolsky R. Resilience against predator stress and dendritic morphology of amygdala neurons. Behav Brain Res. 2009; 205(2):535-543. DOI: 10.1016/j.bbr.2009.08.014
  87. 87. Qin M, Xia Z, Huang T, Smith CB. Effects of chronic immobilization stress on anxiety-like behavior and basolateral amygdala morphology in Fmr1 knockout mice. Neuroscience. 2001; 194:282-290. DOI: 10.1016/j.neuroscience.2011.06.047
  88. 88. Muller JF, Mascagni F, McDonald AJ. Pyramidal cells of the rat basolateral amygdala: synaptology and innervation by parvalbumin-immunoreactive interneurons J Comp Neurol. 2006; 494(4):635-650. DOI: 10.1002/cne.20832
  89. 89. Weinstock M. The long-term behavioural consequences of prenatal stress. Neurosci Biobehav Rev. 2008; 32(6):1073-1086. DOI: 10.1016/j.neubiorev.2008.03.002
  90. 90. Mitra R, Jadhav S, McEwen BS, Vyas A, Chattarji S. Stress duration modulates the spatiotemporal patterns of spine formation in the basolateral amygdale. Proc Natl Acad Sci USA. 2005; 102(26):9371-9376. DOI: 10.1073/pnas.0504011102
  91. 91. Gourley SL, Swanson AM, Koleske AJ. Corticosteroid-induced neural remodeling predicts behavioral vulnerability and resilience. J Neurosci. 2013; 33(7):3107-3112. DOI: 10.1523/JNEUROSCI.2138-12.2013
  92. 92. Grillon C, Duncko R, Covington MF, Kopperman L, Kling MA. Acute stress potentiates anxiety in humans. Biol Psychiatry. 2007;62(10):1183-1186. DOI: 10.1016/j.biopsych.2007.06.007
  93. 93. Haramati S, Navon I, Issler O, Ezra-Nevo G, Gil S, Zwang R, Hornstein E, Chen A. MicroRNA as repressors of stress-induced anxiety: the case of amygdalar miR-34. J Neurosci. 2001; 31(40):14191-14203. DOI: 10.1523/JNEUROSCI.1673-11.2011
  94. 94. Maroun M, Ioannides PJ, Bergman KL, Kavushansky A, Holmes A, Wellman CL. Fear extinction deficits following acute stress associate with increased spine density and dendritic retraction in basolateral amygdale neurons. Eur J Neurosci. 2013; 38(4):2611-2620. DOI: 10.1111/ejn.12259
  95. 95. Rao RP, Anilkumar S, McEwen BS, Chattarji S. Glucocorticoids protect against the delayed behavioral and cellular effects of acute stress on the amygdala. Biol Psychiatry. 2012; 72(6):466-475. DOI: 10.1016/j.biopsych.2012.04.008
  96. 96. Johnson SA, Wang JF, Sun X, McEwen BS, Chattarji S, Young LT. Lithium treatment prevents stress-induced dendritic remodeling in the rodent amygdala. Neuroscience. 2009; 163(1):34-39. DOI: 10.1016/j.neuroscience.2009.06.005
  97. 97. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005; 62(6):593-602. DOI: 10.1001/archpsyc.62.6.593
  98. 98. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995; 52(12):1048-1060. DOI: 10.1001/archpsyc.1995.03950240066012
  99. 99. Stam R. PTSD and stress sensitisation: a tale of brain and body. Part 1: Human studies Neurosci Biobehav Rev. 2007; 31(4):530-557. DOI: 10.1016/j.neubiorev.2006.11.010
  100. 100. Feng J, Fouse S, Fan G. Epigenetic regulation of neural gene expression and neuronal function. Pediatr Res. 2007; 61(5 Pt 2):58R-63R. DOI: 10.1203/pdr.0b013e3180457635
  101. 101. Kim JK, Samaranayake M, Pradhan S. Epigenetic mechanisms in mammals. Cell Mol Life Sci. 2009; 66(4):596-612. DOI: 10.1007/s00018-008-8432-4
  102. 102. Issler O, Chen A. Determining the role of microRNAs in psychiatric disorders. Nat Rev Neurosci. 2015; 16(4):201-212. DOI: 10.1038/nrn3879
  103. 103. Malan-Müller S, Hemmings SM, Seedat S. Big effects of small RNAs: a review of microRNAs in anxiety. Mol Neurobiol. 2013; 47(2):726-739. DOI: 10.1007/s12035-012-8374-6
  104. 104. O'Connor RM, Dinan TG, Cryan JF. Little things on which happiness depends: microRNAs as novel therapeutic targets for the treatment of anxiety and depression. Mol Psychiatry. 2012; 17(4):359-376. DOI: 10.1038/mp.2011.162
  105. 105. Schouten M, Aschrafi A, Bielefeld P, Doxakis E, Fitzsimons CP. microRNAs and the regulation of neuronal plasticity under stress conditions. Neuroscience. 2013; 241:188-205. DOI: 10.1016/j.neuroscience.2013.02.065
  106. 106. Klengel T, Binder EB. Epigenetics of stress related psychiatric disorders and gene × environment interactions. Neuron. 2015; 86(6):1343-57. Doi: 10.1016/j.neuron.2015.05.036.
  107. 107. Kim YK, Kim VN. Processing of intronic microRNAs. EMBO J. 2007; 26(3):775-83. DOI: 10.1038/sj.emboj.7601512
  108. 108. Leung AKL, Sharp PA. MicroRNA functions in stress responses. Mol Cell. 2010; 40(2):205-215. DOI: 10.1016/j.molcel.2010.09.027.
  109. 109. Mannironi C, Camon J, De Vito F, Biundo A, De Stefano ME, Persiconi I, Bozzoni I, Fragapane P, Mele A, Presutti C. Acute stress alters amygdale microRNA miR-135a and miR-124 expression: inferences for corticosteroid dependent stress response. PLoS One. 2013; 8(9):e73385. DOI: 10.1371/journal.pone.0073385.
  110. 110. Balakathiresan NS, Chandran R, Bhomia M, Jia M, Li H, Maheshwari RK. Serum and amygdale microRNA signatures of posttraumatic stress: fear correlation and biomarker potential. J Psychiatr Res. 2014; 57:65-73. DOI: 10.1016/j.jpsychires.2014.05.020.
  111. 111. Volk N, Paul ED, Haramati S, Eitan C, Fields BK, Zwang R, Gil S, Lowry CA, Chen A. MicroRNA-19b associates with Ago2 in the amygdale following chronic stress and regulates the adrenergic receptor beta1. J Neurosci. 2014; 34(45):15070-15082. DOI: 10.1523/JNEUROSCI.0855-14.2014.
  112. 112. Wingo AP, Almli LM, Stevens JS, Klengel T, Uddin M, Li Y, Bustamante AC, Lori A, Koen N, Stein DJ, Smith AK, Aiello AE, Koenen KC, Wildman DE, Galea S, Bradley B, Binder EB, Jin P, Gibson G, Ressler KJ. DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression. Nat Commun. 2015; 6:10106. Doi: 10.1038/ncomms10106.
  113. 113. Phillips AG, Ahn S, Howland JG. Amygdalar control of the mesocorticolimbic dopamine system: parallel pathways to motivated behavior. Neurosci Biobehav Rev. 2003; 27(6):543-554. DOI: 10.1016/j.neubiorev.2003.09.002
  114. 114. Phelps EA, Delgado MR, Nearing KI, LeDoux JE. Extinction learning in humans: role of the amygdala and vmPFC. Neuron. 2004; 43(6):897-905. DOI: 10.1016/j.neuron.2004.08.042
  115. 115. Akirav I, Maroun M. The role of the medial prefrontal cortex-amygdala circuit in stress effects on the extinction of fear. Neural Plast. 2007; 2007:30873. DOI: 10.1155/2007/30873
  116. 116. Meaney MJ, Aitken DH. The effects of early postnatal handling on hippocampal glucocorticoid receptor concentrations: temporal parameters. Brain Res. 1985; 354(2):301-304. DOI: 10.1016/0165-3806(85)90183-X
  117. 117. McEwen BS, De Kloet ER, Rostene W. Adrenal steroid receptors and actions in the nervous system. Physiol Rev. 1986; 66(4):1121-1188. DOI: NA
  118. 118. Krettek JE, Price JL. Projections from the amygdaloid complex and adjacent olfactory structures to the entorhinal cortex and subiculum in the rat and cat. J Comp Neurol. 1977; 172(4):723-752. DOI: 10.1002/cne.901720409
  119. 119. Porrino LJ, Crane AM, Goldman-Rakic PS. Direct and indirect pathways from the amygdala to the frontal lobe in rhesus monkeys. J Comp Neurol. 1981; 198(1):121-136. DOI: 10.1002/cne.901980111
  120. 120. Mcdonald AJ, Mascagni F, Guo L. Projections of the medial and lateral prefrontal cortices to the amygdala: a Phaseolus vulgaris leucoagglutinin study in the rat. Neuroscience. 1996; 71(1):55-75. DOI: 10.1016/0306-4522(95)00417-3
  121. 121. Cassell MD, Chittick CA, Siegel MA, Wright DJ. Collateralization of the amygdaloid projections of the rat prelimbic and infralimbic cortices. J Comp Neurol. 1989; 279(2):235-248. DOI: 10.1002/cne.902790207
  122. 122. Amaral DG, Insausti R. Retrograde transport of D-[3H]-aspartate injected into the monkey amygdaloid complex. Exp Brain Res. 1992; 88(2):375-388. DOI: 10.1016/0304-3940(83)90415-9
  123. 123. Berretta S, Pantazopoulos H, Caldera M, Pantazopoulos P, Paré D. Infralimbic cortex activation increases c-Fos expression in intercalated neurons of the amygdala. Neuroscience. 2005; 132(4):943-953. DOI: 10.1016/j.neuroscience.2005.01.020
  124. 124. Quirk GJ, Likhtik E, Pelletier JG, Paré D. Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdale output neurons. J Neurosci. 2003; 23(25):8800-8807. DOI: NA
  125. 125. Rosenkranz JA, Grace AA. Cellular mechanisms of infralimbic and prelimbic prefrontal cortical inhibition and dopaminergic modulation of basolateral amygdala neurons in vivo. J Neurosci. 2002; 22(1):324-337. DOI: 0270-6474/01/220324-14$15.00/0
  126. 126. Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, Zeidan MA, Handwerger K, Orr SP, Rauch SL. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatry. 2009; 66(12):1075-1082. DOI: 10.1016/j.biopsych.2009.06.026
  127. 127. Shvil E, Rusch HL, Sullivan GM, Neria Y. Neural, psychophysiological, and behavioral markers of fear processing in PTSD: a review of the literature. Curr Psychiatry Rep. 2013; 15 (5):358-374. DOI: 10.1007/s11920-013-0358-3.
  128. 128. Patel R, Spreng RN, Shin LM, Girard TA. Neurocircuitry models of posttraumatic stress disorder and beyond: a meta-analysis of functional neuroimaging studies. Neurosci Biobehav Rev. 2012; 36(9):2130-2142. DOI: 10.1016/j.neubiorev.2012.06.003
  129. 129. Rougemont-Bücking A, Linnman C, Zeffiro TA, et al. Altered processing of contextual information during fear extinction in PTSD: an fMRI study. CNS Neurosci Ther. 2011; 17(4):227-236. DOI: 10.1111/j.1755-5949.2010.00152.x.
  130. 130. Jovanovic T, Norrholm SD. Neural mechanisms of impaired fear inhibition in posttraumatic stress disorder. Front Behav Neurosci. 2011; 5:44. DOI: 10.3389/fnbeh.2011.00044.
  131. 131. Fisher PM, Meltzer CC, Price JC, Coleman RL, Ziolko SK, Becker C, Moses-Kolko EL, Berga SL, Hariri AR. Medial prefrontal cortex 5-HT(2A) density is correlated with amygdala reactivity, response habituation, and functional coupling. Cereb Cortex. 2009;19(11):2499-2507. DOI: 10.1093/cercor/bhp022.
  132. 132. Wellman CL, Izquierdo A, Garrett JE, Martin KP, Carroll J, Millstein R, Lesch KP, Murphy DL, Holmes A. Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice. J Neurosci. 2007;27(3):684-691. DOI: 10.1523/JNEUROSCI.4595-06.2007
  133. 133. Pissiota A, Frans O, Michelgård A, Appel L, Långström B, Flaten MA, Fredrikson M. Amygdala and anterior cingulate cortex activation during affective startle modulation: a PET study of fear. Eur J Neurosci. 2003; 18(5):1325-1331. DOI: 10.1046/j.1460-9568.2003.02855.x
  134. 134. Sehlmeyer C, Dannlowski U, Schöning S, Kugel H, Pyka M, Pfleiderer B, Zwitserlood P, Schiffbauer H, Heindel W, Arolt V, Konrad C. Neural correlates of trait anxiety in fear extinction. Psychol Med. 2011; 41(4):789-798. DOI: 10.1017/S0033291710001248
  135. 135. Etkin A, Klemenhagen KC, Dudman JT, Rogan MT, Hen R, Kandel ER, Hirsch J. Individual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces. Neuron. 2004; 44(6):1043-1055. DOI: 10.1016/j.neuron.2004.12.006
  136. 136. Gaffrey MS, Luby JL, Belden AC, Hirshberg JS, Volsch J, BarchDM. Association between depression severity and amygdala reactivity during sad face viewing in depressed preschoolers: an fMRI study. J Affect Disord. 2010; 129(1-3):364-370. DOI: 10.1016/j.jad.2010.08.031
  137. 137. Bryant RA, Kemp AH, Felmingham KL, Liddell B, Olivieri G, Peduto A, Gordon E, Williams LM. Enhanced amygdala and medial prefrontal activation during nonconscious processing of fear in posttraumatic stress disorder: an fMRI study. Hum Brain Mapp. 2008; 29(5):517-523. DOI: 10.1002/hbm.20415
  138. 138. Evans KC, Wright CI, Wedig MM, Gold AL, Pollack MH, Rauch SL. A functional MRI study of amygdala responses to angry schematic faces in social anxiety disorder. Depress Anxiety. 2008; 25(6):496-505. DOI: 10.1002/da.20347
  139. 139. Rauch SL, Whalen PJ, Shin LM, McInerney SC, Macklin ML, Lasko NB, Orr SP, Pitman RK. Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biol Psychiatry. 2000; 47(9):769-776. DOI: 10.1016/S0006-3223(00)00828-3
  140. 140. Shin LM, Wright CI, Cannistraro PA, Wedig MM, McMullin K, Martis B, Macklin ML, Lasko NB, Cavanagh SR, Krangel TS, Orr SP, Pitman RK, Whalen PJ, Rauch SL. A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry. 2005; 62(3):273-281. DOI: 10.1001/archpsyc.62.3.273
  141. 141. Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007; 164(10):1476-1488. DOI: 10.1176/appi.ajp.2007.07030504
  142. 142. Rauch SL, Shin LM, Wright CI. Neuroimaging studies of amygdala function in anxiety disorders. Ann N Y Acad Sci. 2003; 985:389-410. DOI: 10.1111/j.1749-6632.2003.tb07096.x
  143. 143. Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2010; 35(1):169-191. DOI: 10.1038/npp.2009.83.
  144. 144. Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception II: implications for major psychiatric disorders. Biol Psychiatry. 2003; 54(5):515-528. DOI: 10.1016/S0006-3223(03)00171-9
  145. 145. Drevets WC, Bogers W, Raichle ME. Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism. Eur Neuropsychopharmacol. 2002; 12(6):527-544. DOI: 10.1016/S0924-977X(02)00102-5
  146. 146. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: American Psychiatric Association, 2013.
  147. 147. Whalen PJ, Shin LM, McInerney SC, Fischer H, Wright CI, Rauch SL. A functional MRI study of human amygdale responses to facial expressions of fear versus anger. Emotion. 2001; 1(1):70-83. DOI: 10.1037/1528-3542.1.1.70
  148. 148. LaBar KS, Gatenby JC, Gore JC, LeDoux JE, Phelps EA. Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study. Neuron. 1998; 20(5):937-945. DOI: 10.1016/S0896-6273(00)80475-4
  149. 149. Phan KL, Wager T, Taylor SF, Liberzon I. Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage. 2002; 16(2):331-348. DOI: 10.1006/nimg.2002.1087
  150. 150. Rauch SL, Shin LM, Phelps EA. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research—past, present, and future. Biol Psychiatry. 2006; 60(4): 376-382. DOI: 10.1016/j.biopsych.2006.06.004
  151. 151. Rauch SL, Van Der Kolk BA, Fisler RE, Alpert NM, Orr SP, Savage CR, Fischman AJ, Jenike MA, Pitman RK. A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery. Arch Gen Psychiatry. 1996; 53(5):380-387. DOI: 10.1001/archpsyc.1996.01830050014003.
  152. 152. Shin LM, Orr SP, Carson MA, Rauch SL, Macklin ML, Lasko NB, Peters PM, Metzger LJ, Dougherty DD, Cannistraro PA, Alpert NM, Fischman AJ, Pitman RK. Regional cerebral blood flow in amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch Gen Psychiatry. 2004; 61(2):168-176. DOI: 10.1001/archpsyc.61.2.168
  153. 153. Liberzon I, Taylor SF, Amdur R, Jung TD, Chamberlain KR, Minoshima S, Koeppe RA, Fig LM. Brain activation in PTSD in response to trauma-related stimuli. Biol Psychiatry. 1999; 45(7):817-826. DOI: 10.1016/S0006-3223(98)00246-7
  154. 154. Pissiota A, Frans O, Fernandez M, von Knorring L, Fischer H, Fredrikson M. Neurofunctional correlates of posttraumatic stress disorder: a PET symptom provocation study. Eur Arch Psychiatry Clin Neurosci. 2002; 252(2):68-75. DOI: 10.1007/s004060200014
  155. 155. Hendler T, Rotshtein P, Yeshurun Y, Weizmann T, Kahn I, Ben-Bashat D, Malach R, Bleich A. Sensing the invisible: differential sensitivity of visual cortex and amygdala to traumatic context. Neuroimage. 2003; 19(3):587-600. DOI: 10.1016/S1053-8119(03)00141-1
  156. 156. Shin LM, McNally RJ, Kosslyn SM, Thompson WL, Rauch SL, Alpert NM, Metzger LJ, Lasko NB, Orr SP, Pitman RK. A positron emission tomographic study of symptom provocation in PTSD. Ann N Y Acad Sci. 1997; 821:521-523. DOI: 10.1111/j.1749-6632.1997.tb48320.x
  157. 157. Protopopescu X, Pan H, Tuescher O, Cloitre M, Goldstein M, Engelien W, Epstein J, Yang Y, Gorman J, LeDoux J, Silbersweig D, Stern E. Differential time courses and specificity of amygdala activity in posttraumatic stress disorder subjects and normal control subjects. Biol Psychiatry. 2005; 57(5):464-473. DOI: 10.1016/j.biopsych.2004.12.026
  158. 158. Gilbert R, Widom CS, Browne K, Fergusson D, Webb E, Janson S. Burden and consequences of child maltreatment in high-income countries. Lancet. 2009; 373(9657):68-81. DOI: 10.1016/S0140-6736(08)61706-7
  159. 159. Dannlowski U, Kugel H, Huber F, Stuhrmann A, Redlich R, Grotegerd D, Dohm K, Sehlmeyer C, Konrad C, Baune BT, Arolt V, Heindel W, Zwitserlood P, Suslow T. Childhood maltreatment is associated with an automatic negative emotion processing bias in the amygdala. Hum Brain Mapp. 2013; 34(11):2899-2909. DOI: 10.1002/hbm.22112
  160. 160. Admon R, Lubin G, Stern O, Rosenberg K, Sela L, Ben-Ami H, Hendler T. Human vulnerability to stress depends on amygdala's predisposition and hippocampal plasticity. Proc Natl Acad Sci USA. 2009;106(33):14120-14125. DOI: 10.1073/pnas.0903183106
  161. 161. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, Egan MF, Weinberger DR. Serotonin transporter genetic variation and the response of the human amygdala. Science. 2002;297(5580):400-403. DOI: 10.1126/science.1071829
  162. 162. Rhodes RA, Murthy NV, Dresner MA, Selvaraj S, Stavrakakis N, Babar S, Cowen PJ, Grasby PM. 2007 Human 5-HT transporter availability predicts amygdala reactivity in vivo. J Neurosci. 27(34):9233-9237. DOI:10.1523/jneurosci.1175-07.2007
  163. 163. Domschke K, Baune BT, Havlik L, Stuhrmann A, Suslow T, Kugel H, Zwanzger P, Grotegerd D, Sehlmeyer C, Arolt V, Dannlowski U. Catechol-O-methyltransferase gene variation: impact on amygdale response to aversive stimuli. Neuroimage. 2012; 60(4):2222-2229. DOI: 10.1016/j.neuroimage.2012.02.039.

Written By

Diego Andolina and Antonella Borreca

Submitted: October 11th, 2016 Reviewed: February 10th, 2017 Published: July 5th, 2017