Reviews and Overviews
Psychobiological Mechanisms of Resilience
and Vulnerability: Implications for Successful
Adaptation to Extreme Stress
Dennis S. Charney, M.D.
Objective: Most research on the effects
ience or vulnerability. The neural mecha- of severe psychological stress has focused nisms of reward and motivation (hedonia, on stress-related psychopathology. Here, optimism, and learned helpfulness), fear the author develops psychobiological responsiveness (effective behaviors despite models of resilience to extreme stress.
fear), and adaptive social behavior (altru- Method: An integrative model of resil-
ism, bonding, and teamwork) were found ience and vulnerability that encompasses to be relevant to the character traits associ- the neurochemical response patterns to ated with resilience.
acute stress and the neural mechanismsmediating reward, fear conditioning and Conclusions: The opportunity now exists
extinction, and social behavior is proposed.
to bring to bear the full power of advances Results: Eleven possible neurochemical,
in our understanding of the neurobiologi- neuropeptide, and hormonal mediators of cal basis of behavior to facilitate the dis- the psychobiological response to extreme coveries needed to predict, prevent, and stress were identified and related to resil- treat stress-related psychopathology.
(Am J Psychiatry 2004; 161:195–216)
The adaptive physiological response to acute stress in- logical responses that relate to stress-related disorders, volves a process, initially referred to as allostasis by Ster- such as posttraumatic stress disorder (PTSD) and major ling and Eyer (1), in which the internal milieu varies to depression. Surprisingly, there has been little attention di- meet perceived and anticipated demand. McEwen (2) ex- rected toward the question of which neurobiological re- tended this definition to include the concept of a set point sponses are related to resilience to psychological stress in that changes because of the process of maintaining ho- general and to specific forms of psychopathology.
meostasis (2). The responses to severe stress that promote Identification of responses that relate to psychobiologi- survival in the context of a life-threatening situation may cal allostasis and reduced psychobiological allostatic load be adaptive in the short run. However, if recovery from the may provide clues toward discovering improved methods acute event is not accompanied by an adequate homeo- to prevent and treat disorders such as PTSD and major de- static response to terminate the acute adaptive response pression. For example, which aspects of the acute neuro- of stress mediators, the deleterious effects on psychologi- chemical response to traumatic stress promote behaviors cal and physiological function, termed the "allostatic that facilitate an effective survival reaction and may ac- load," occur. The allostatic load is the burden borne by a count for instances of highly effective action while experi- brain and body adapting to challenges, both physiological encing fear? What psychobiological responses serve to and psychological. The concepts of allostasis and allo- maintain neural systems regulating reward and motiva- static load link the protective and survival values of the tion in the face of an unrewarding environment? What al- acute response to stress to the adverse consequences that terations in neural systems regulating fear conditioning result if the acute response persists (3).
and extinction serve to maintain low levels of anxiety, Much of the research on allostasis and allostatic load has despite an uncontrollable stress environment? Which focused on the negative effects of physiological stress on changes in the neural systems involved in learning and the brain and body. The present discussion will consider memory can affect the encoding, consolidation, reconsol- allostasis and allostatic load from the perspective of the ef- idation, and retrieval of memories of trauma so that nor- fects of extreme psychological stress on the complex regu- mal psychological function can be maintained and re- lation of emotion by the brain and the consequences of experiencing symptoms minimized? How can neural sys- such changes on human psychological resilience on one tems regulating social behavior respond to persistent hand, and vulnerability to psychopathology on the other.
abuse and neglect to avoid a sense of hopelessness and in- Most of the neurobiological research on the consequences terpersonal withdrawal? The answers to such questions of severe psychological stress has focused on psychopatho- may provide a greater understanding of why some individ- Am J Psychiatry 161:2, February 2004 ADAPTATION TO EXTREME STRESS
uals are able to cope with extreme stress with minimal lites of DHEA in the hippocampus interfere with the nor- mal uptake of activated glucocorticoid receptors (15) and A number of neurotransmitters, neuropeptides, and may confer neuroprotection (16, 17). DHEA also restores hormones have been linked to the acute psychobiological cortisol-induced suppression of long-term potentiation in response to stress and the long-term psychiatric outcome.
hippocampal neurons (18).
The roles of those neurotransmitters, neuropeptides, and A negative correlation between DHEA reactivity to adre- hormones that have been shown to be significantly altered nal activation and the severity of PTSD has been reported, by psychological stress, have important functional inter- suggesting that enhanced DHEA release in response to actions, and mediate the neural mechanisms and neural prolonged stress may be protective in persons with PTSD circuits relevant to the regulation of reward, fear condi- (unpublished work by Rasmusson et al.). This is consistent tioning, and social behavior will be reviewed. An attempt with recent observations in a study of elite special opera- will be made to identify a putative neurochemical profile tions soldiers that revealed negative correlations between that characterizes psychobiological resilience and has ratios of DHEA to cortisol and dissociation during pro- predictive value regarding successful adaptation to ex- longed and extreme training stress and between DHEA treme stress.
and DHEA-S ("S" stands for sulfate) levels in the recoveryperiod and better overall performance (unpublished work Cortisol and Dehydroepiandrosterone
by Morgan et al.). Other evidence that suggests that DHEApromotes psychological resilience includes several studies There is consistent evidence that many forms of psy- reporting negative associations between plasma DHEA chological stress increase the synthesis and release of cor- levels and depressive symptoms and the antidepressant tisol. Cortisol serves to mobilize and replenish energy effects of DHEA (19–22). Aside from the antiglucocorticoid stores; it contributes to increased arousal, vigilance, fo- actions of DHEA, effects on γ-aminobutyric acid (GABA)A cused attention, and memory formation; inhibition of the receptors (23) and N-methyl-D-aspartic acid (NMDA)- growth and reproductive system; and containment of the based neurotransmission (24) may be involved in the be- immune response. Cortisol has important regulatory ef- havioral effects of DHEA.
fects on the hippocampus, amygdala, and prefrontal cor-tex (4). Glucocorticoids can enhance amygdala activity, in- crease corticotropin-releasing hormone (CRH) mRNAconcentrations in the central nucleus of the amygdala (5– CRH is one of the most important mediators of the 7), increase the effects of CRH on conditioned fear (8), and stress response, coordinating the adaptive behavioral and facilitate the encoding of emotion-related memory (9).
physiological changes that occur during stress (25). Re- Adrenal steroids such as cortisol have biphasic effects on lease of CRH from the hypothalamus into the hypotha- hippocampal excitability and cognitive function and lamic-pituitary portal circulation occurs in response to memory (10). These effects may contribute to adaptive al- stress, resulting in activation of the hypothalamic-pitu- terations in behaviors induced by cortisol during the acute itary-adrenal (HPA) axis and the increased release of corti- response to stress.
sol and DHEA. Equally important are the extrahypotha- It is key, however, that the stress-induced increase in lamic effects of CRH. CRH-containing neurons are located cortisol ultimately be constrained through an elaborate throughout the brain, including the prefrontal and cingu- negative feedback system involving glucocorticoid and late cortices, the central nucleus of the amygdala, the bed mineral corticoid receptors. Excessive and sustained corti- nucleus of the stria terminalis, the nucleus accumbens, sol secretion can have serious adverse effects, including the periaqueductal gray matter, and the brainstem nuclei, hypertension, osteoporosis, immunosuppression, insulin such as the major norepinephrine-containing nucleus, resistance, dyslipidemia, dyscoagulation, and, ultimately, the locus coeruleus, and the serotonin (5-HT) nuclei in the atherosclerosis and cardiovascular disease (11).
dorsal and median raphe (26).
Another adrenal steroid released under stress is dehy- Increased activity of amygdala CRH neurons activates droepiandrosterone (DHEA). DHEA is secreted episodi- fear-related behaviors, while cortical CRH may reduce re- cally and synchronously with cortisol in response to fluc- ward expectation. CRH also inhibits a variety of neuroveg- tuating ACTH levels (12). DHEA has been shown to have etative functions, such as food intake, sexual activity, and antiglucocorticoid and antiglutamatergic activity in sev- endocrine programs for growth and reproduction. It ap- eral tissues, including the brain (13), mediated by compli- pears that early-life stress can produce long-term eleva- cated mechanisms distinct from classical glucocorticoid tion of brain CRH activity and that individual response to receptor antagonism. Peripherally produced DHEA is heightened CRH function may depend upon the social thought to be a major source of brain DHEA. Within the environment, past trauma history, and behavioral domi- brain, regionally specific metabolism of DHEA may ulti- nance (27). Persistent elevation of hypothalamic and mately control the nature of DHEA's effects on cognition extrahypothalamic CRH contributes mightily to the psy- and behavior (14). For instance, 7-hydroxylated metabo- chobiological allostatic load. Increased CSF levels of CRH Am J Psychiatry 161:2, February 2004 DENNIS S. CHARNEY
have been linked to PTSD and major depression (28–30).
autonomic centers, resulting in increased activity of the Psychobiological resilience may be related to an ability to HPA and locus coeruleus. These feedback loops among the restrain the initial CRH response to acute stress.
prefrontal cortex, amygdala, hypothalamus, and brain- Both CRH-1 and CRH-2 receptors are found in the pi- stem noradrenergic neurons contain the elements for a tuitary and throughout the neocortex (especially in the sustained and powerful stress response (4). If unchecked, prefrontal, cingulate, striate, and insular cortices), the persistent hyperresponsiveness of the locus coeruleus- amygdala, and the hippocampal formation in the primate norepinephrine system will contribute to chronic anxiety, brain. The presence of CRH-1 (but not CRH-2) receptors fear, intrusive memories, and an increased risk of hyper- within the locus coeruleus, the nucleus of the solitary tension and cardiovascular disease. In some patients with tract, the thalamus, the striatum, CRH-2 (but not CRH-1) panic disorder, PTSD, and major depression, there is evi- receptors in the choroid plexus, certain hypothalamic nu- dence of heightened locus coeruleus-norepinephrine clei, the nucleus prepositus, and the bed nucleus of the activity (36–40).
stria terminalis suggests that each receptor subtype hasdistinct roles within the primate brain (31).
CRH-1-deficient mice display decreased anxiety-like behavior and an impaired stress response (32). In contrast, Neuropeptide Y is a highly conserved 36 amino acid CRH-2-deficient mice display increased anxiety-like be- peptide, which is among the most abundant peptides havior and are hypersensitive to stress (33, 34). Thus, evi- found in the mammalian brain. There are five brain areas dence exists in favor of opposite functional roles for the in which neurons containing neuropeptide Y are densely two known CRH receptors; activation of CRH-1 receptors concentrated: the locus coeruleus (41), the paraventricu- may be responsible for increased anxiety-like responses, lar nucleus of the hypothalamus (42), septohippocampal and stimulation of CRH-2 may produce anxiolytic-like re- neurons (43), the nucleus of the solitary tract, and the ven- sponses. Regulation of the relative contribution of the two tral lateral medulla (44). Moderate levels are found in the CRH receptor subtypes to brain CSF pathways may be es- amygdala, hippocampus, cerebral cortex, basal ganglia, sential to coordinating psychological and physiological re- and thalamus (45).
sponses to stressors (32). Thus far, it has not been possible Evidence suggesting the involvement of the amygdala to evaluate CRH-1 and CRH-2 receptors in living human in the anxiolytic effects of neuropeptide Y is robust and subjects, although efforts are ongoing to develop CRH re- probably occurs by means of the neuropeptide Y-Y1 re- ceptor positron emission tomography ligands.
ceptor (46–48). Microinjection of neuropeptide Y into thecentral nucleus of the amygdala reduces anxious behav- Locus Coeruleus-Norepinephrine System
iors. The up-regulation of amygdala neuropeptide Y mRNAlevels after chronic stress suggests that neuropeptide Y Stress activates the locus coeruleus, which results in in- may be involved in the adaptive responses to stress expo- creased norepinephrine release in projection sites of the sure (49). Neuropeptide Y may also be involved in the con- locus coeruleus, including the amygdala, the prefrontal solidation of fear memories; injection of neuropeptide Y cortex, and the hippocampus. The locus coeruleus is acti- into the amygdala impairs memory retention in a foot- vated by a variety of stressors, both intrinsic (hypoglyce- shock avoidance paradigm (50). The anxiolytic effects of mia, decreased blood volume, decreased blood pressure,altered thermoregulation, and distention of the colon and neuropeptide Y also involve the locus coeruleus, possibly bladder) and extrinsic (environmental stress or threat) to by means of the neuropeptide Y-Y2 receptor. Neuropep- the animal. Such activation is adaptive to survival from a tide Y reduces the firing of neurons in the locus coeruleus life-threatening situation and serves as a general alarm (51). Neuropeptide Y also has behaviorally relevant effects function. Activation of the locus coeruleus also contrib- on the hippocampus. Transgenic rats with hippocampal utes to the sympathetic nervous system and HPA axis neuropeptide Y overexpression have attenuated sensitiv- stimulation. Coincidentally, activation of the locus coer- ity to the behavioral consequences of stress and impaired uleus inhibits parasympathetic outflow and neurovegeta- spatial learning (52).
tive function, including eating and sleep. A high level of There are important functional interactions between activation of the locus coeruleus-norepinephrine system neuropeptide Y and CRH (53, 54). Neuropeptide Y counter- inhibits function of the prefrontal cortex, thereby favoring acts the anxiogenic effects of CRH, and a CRH antagonist instinctual responses over more complex cognition (35).
blocks the anxiogenic effects of a neuropeptide Y-Y1 an- The ability of acute stress to coactivate the HPA and tagonist (55). Thus, it has been suggested that the balance locus coeruleus-norepinephrine systems facilitates the between neuropeptide Y and CRH neurotransmission is encoding and relay of aversively charged emotional mem- important to the emotional responses to stress (54). In gen- ories, beginning at the amygdala. The amygdala also in- eral, brain regions that express CRH and CRH receptors hibits the prefrontal cortex (such as the locus coeruleus) also contain neuropeptide Y and neuropeptide Y receptors, and stimulates hypothalamic CRH release and brainstem and the functional effects are often opposite (56), espe- Am J Psychiatry 161:2, February 2004 ADAPTATION TO EXTREME STRESS
cially at the level of the locus coeruleus (57, 58), amygdala receptors are involved. Galanin-1 receptor mRNA levels (59, 60), and the periaqueductal gray matter (61, 62).
are high in the amygdala, hypothalamus, and bed nucleus These data suggest an important role for an up-regu- of the stria terminalis (76), and galanin-1 receptor-defi- lated neuropeptide Y system in the psychobiology of resil- cient mice show increased anxiety-like behavior (77).
ience. Neuropeptide Y has counterregulatory effects on These results suggest that the noradrenergic response to both the CRH and locus coeruleus-norepinephrine sys- stress can recruit the release of galanin in the central nu- tems at brain sites that are important in the expression of cleus of the amygdala and prefrontal cortex, which then anxiety, fear, and depression. Preliminary studies in spe- buffers the anxiogenic effects of norepinephrine. Thus, cial operations soldiers under extreme training stress indi- the net behavioral response due to stress-induced norad- cate that high neuropeptide Y levels are associated with renergic hyperactivity may depend upon the balance be- better performance (63). Patients with PTSD have been tween norepinephrine and neuropeptide Y and galanin shown to have reduced plasma neuropeptide Y levels and neurotransmission. This hypothesis is consistent with ev- a blunted yohimbine-induced neuropeptide Y increase idence that release of neuropeptides preferentially occurs (64). Additionally, low levels of neuropeptide Y have been under conditions of high neurotransmitter activity (78, found in depressed patients, and a variety of antidepres- 79). To our knowledge, galanin function has not been sant drugs increase neuropeptide Y levels (65).
studied in patients exposed to traumatic stress or patientswith PTSD or major depression. Galanin and neuropep- tide Y receptor agonists may be novel targets for the devel-opment of antianxiety drugs (71).
Galanin is a peptide that, in humans, contains 30 amino acids. It has been demonstrated to be involved in a num- ber of physiological and behavioral functions, includinglearning and memory, pain control, food intake, neuroen- Uncontrollable stress activates dopamine release in the docrine control, cardiovascular regulation, and, most re- medial prefrontal cortex (80) and inhibits dopamine re- cently, anxiety (66).
lease in the nucleus accumbens (81, 82). Lesions of the Galanin is closely associated with ascending monoam- pretraining and posttraining amygdala in a conditioned ine pathways. Approximately 80% of noradrenergic cells in stress model block stress-induced dopamine metabolic the locus coeruleus co-express galanin. A dense galanin activation in the medial prefrontal cortex, suggesting immunoreactive fiber system originating in the locus amygdala control of stress-induced dopamine activation coeruleus innervates forebrain and midbrain structures, and a role for integrating the behavioral and neuroendo- including the hippocampus, hypothalamus, amygdala, crine components of the stress response (83). There is pre- and prefrontal cortex (67–69). Neurophysiological studies clinical evidence that the susceptibility of the mesocorti- have shown that galanin reduces the firing rate of the lo- cal dopamine system to stress activation may be in part cus coeruleus, possibly by stimulating the galanin-1 re- genetically determined. It has been suggested that exces- ceptor, which acts as an autoreceptor (70, 71).
sive mesocortical dopamine release by stressful events Studies in rats have shown that galanin administered may represent a vulnerability to depression and favor centrally modulates anxiety-related behaviors (72, 73).
helpless reactions through an inhibition of subcortical Galanin-overexpressing transgenic mice do not exhibit an dopamine transmission (80, 82). These observations may anxiety-like phenotype when tested under baseline (non- be due to the effect of dopamine on reward mechanisms.
challenged) conditions. However, these mice are unre- On the other hand, lesions of dopamine neurons in the sponsive to the anxiogenic effects of the alpha-2 receptor medial prefrontal cortex delay extinction of the condi- antagonist yohimbine. Consistent with this observation, tioned fear stress response (no effect on acquisition), indi- galanin administered directly into the central nucleus of cating that prefrontal dopamine neurons are involved in the amygdala blocked the anxiogenic effects of stress, facilitating extinction of the fear response. This suggests which is associated with increased norepinephrine release that reduced prefrontal cortical dopamine results in the in the central nucleus of the amygdala. Yohimbine in- preservation of fear produced by a conditioned stressor, a creases galanin release in the central nucleus of the amyg- situation hypothesized to occur in PTSD (84). One way to dala (74). Galanin administration and galanin overex- reconcile these two sets of data is to suggest that there is pression in the hippocampus result in deficits in fear an optimal range for stress-induced increases in cortical conditioning (75).
dopamine released in the medial prefrontal cortex to facil- The mechanism by which galanin reduces norepineph- itate adaptive behavioral responses. Too much dopamine rine release at locus coeruleus projections to the amyg- release in the medial prefrontal cortex produces cognitive dala, hypothalamus, and prefrontal cortex may be a direct impairment; an inhibition in dopamine activity in the nu- action of galanin on these brain regions by means of gala- cleus accumbens results in abnormalities in motivation nin-synthesizing neurons or by stimulating galanin recep- and reward mechanisms. Insufficient prefrontal cortical tors in these regions (71, 74). It is not known which galanin dopamine release delays extinction of conditioned fear.
Am J Psychiatry 161:2, February 2004 DENNIS S. CHARNEY
There has been little clinical research regarding dopamine density of 5-HT1A receptors is reduced in depressed pa- function as it pertains to stress-related psychopathology.
tients when they are depressed as well as in remission (98).
Several clinical investigations have reported increased uri- It has been recently demonstrated that 5-HT1A receptor nary and plasma dopamine concentrations (85, 86) in density is also decreased in patients with panic disorder PTSD. In contrast, reduced dopamine metabolism has (99). Examination of 5-HT1A receptor density in patients been demonstrated in depressed patients (87).
with anxiety disorders is indicated.
Different types of acute stress result in increased 5-HT Animals exposed to chronic inescapable stress develop turnover in the prefrontal cortex, nucleus accumbens, behaviors that are consistent with excessive fear and anxi- amygdala, and lateral hypothalamus (88). Serotonin re- ety, such as increased fearfulness, increased defecation, lease may have both anxiogenic and anxiolytic effects, de- and avoidance of novel situations (e.g., an open field). Ex- pending on the region of the forebrain involved and the re- posure to inescapable stressors produce decreases in ben- ceptor subtype activated. For example, anxiogenic effects zodiazepine receptor binding in the cortex, with some are mediated by means of the 5-HT2A receptor, whereas studies showing a decrease in the hippocampus (100, 101).
stimulation of 5-HT1A receptors are anxiolytic and may Exposure to stress has no effects on benzodiazepine re- even relate to adaptive responses to aversive events (89).
ceptor binding in the pons, striatum, thalamus, cerebel- Understanding the function of the 5-HT1A receptor is lum, midbrain, or occipital cortex. These data support a probably most pertinent to the current discussion. The 5- role for alterations in benzodiazepine binding in anxiety, HT1A receptors are found in the superficial cortical layers, with a specific decrease in the frontal cortex and, although the hippocampus, the amygdala, and the raphe nucleus not as consistently, a decrease in the hippocampus (101).
(primarily presynaptic) (90, 91). The behavioral phenotype Neuroimaging studies reveal reduced cortical and sub- of 5-HT1A knockout mice includes increases in anxiety-like cortical benzodiazepine receptor binding in patients with behaviors (92, 93). These behaviors are mediated by post- PTSD and panic disorder (102–104). The findings could be synaptic 5-HT1A receptors in the hippocampus, amygdala, related to a down-regulation of benzodiazepine receptor and cortex (94). Of great interest is the recent finding that binding after exposure to stress. Other possible explana- embryonic and early postnatal shutdown of expression of tions are that stress results in changes in receptor affinity, 5-HT1A receptors produces an anxiety phenotype that can- changes in an endogenous benzodiazepine ligand (the ex- not be rescued with restoration of 5-HT1A receptors. How- istence of which is controversial), and stress-related alter- ever, when 5-HT1A receptor expression is reduced in adult- ations in GABAergic transmission or neurosteroids that af- hood and then reinstated, the anxiety phenotype is no fect benzodiazepine receptor binding. A preexisting low longer present. These results suggest that altered function level of benzodiazepine receptor density may be a genetic of 5-HT1A receptors early in life can produce long-term ab- risk factor for the development of stress-related anxiety normalities in the regulation of anxiety behaviors (94).
Postsynaptic 5-HT1A receptor gene expression is under tonic inhibition by adrenal steroids such as in the hippo- campus, apparently mostly by means of activation of min-eral corticoid receptors. 5-HT 1A receptor density and mRNA levels decrease in response to stress, which is pre- Testosterone has been among the most studied of all vented by adrenalectomy (95).
hormones in terms of its relationships to specific behav- There may also be important functional interactions be- iors. Aggression is the aspect of human behavior most tween 5-HT1A and benzodiazepine receptors. In one study often linked to testosterone concentrations (105). Preclin- of 5-HT1A knockout mice, a down-regulation of benzodi- ical studies consistently show that low levels of testoster- azepine GABA α1 and α2 receptor subunits, as well as ben- one are associated with submissive behavior. In mandrils zodiazepine-resistant anxiety in the elevated-plus maze and squirrel monkeys, social rank correlates with tes- was reported (96). However, a subsequent study did not tosterone levels (105, 106). In human subjects, the per- replicate these results using mice with a different genetic sonal experience of success, as well as the feeling of domi- background (97), raising the possibility that genetic back- nance in a competitive situation, is associated with higher ground can affect functional interplay between 5-HT1A testosterone levels (107, 108). Increased levels of testoster- and benzodiazepine systems.
one have been found in male prison inmates with fre- These results suggest a scenario in which early-life quent episodes of violent behavior (109–111). Psychologi- stress increases CRH and cortisol levels, which, in turn, cal stress is associated with decreases in testosterone down-regulate 5-HT1A receptors, resulting in a lower levels. For example, elite soldiers participating in a physi- threshold for anxiogenic stressful life events. Alternatively, cally and psychologically stressful training exercise show a 5-HT1A receptors may be decreased on a genetic basis. The lowering of their testosterone levels (63).
Am J Psychiatry 161:2, February 2004 ADAPTATION TO EXTREME STRESS
TABLE 1. The Neurochemical Response Patterns to Acute Stress
Association With Resilience Mobilized energy, increased Prefrontal cortex, Increases amygdala Stress-induced increase arousal, focused attention, fear hippocampus, amygdala, constrained by negative memory formation, fear learning releasing hormone feedback by means of (CRH), increases glucocorticoid receptor and mineral corticoid receptors Counteracts deleterious effects of Largely unknown; Antiglucocorticoid High DHEA-cortisol ratios may high cortisol neuroprotection; have preventive effects has positive mood effects regarding PTSD and depression Activated fear behaviors, increased Prefrontal cortex, cingulate Reduced CRH release, arousal, increased motor activity, cortex, amygdala, nucleus anxiogenic, CRH-2 adaptive changes in CRH-1 inhibited neurovegetative accumbens, hippocampus, receptor anxiolytic, and CRH-2 receptors function, reduced reward hypothalamus, bed increases cortisol nucleus of the stria and DHEA, activates terminalis, periaqueductal gray matter, locus coeruleus, dorsal raphe General alarm function activated Prefrontal cortex, amygdala, Activates sympathetic Reduced responsiveness of by extrinsic and intrinsic threat; increased arousal, increased norepinephrine system attention, fear memory outflow, stimulates formation, facilitated motor Anxiolytic; counteracts the stress- Amygdala, hippocampus, Reduces CRH-related Adaptive increase in amygdala related effects of CRH and the hypothalamus, septum, actions at amygdala, neuropeptide Y is associated locus coeruleus-norepinephrine periaqueductal gray reduces rate of firing with reduced stress-induced system; impairs fear memory matter, locus coeruleus of locus coeruleus anxiety and depression Anxiolytic; counteracts the stress- Prefrontal cortex, amygdala, Reduces the Adaptive increase in amygdala induced effects of the locus anxiogenic effects of galanin is associated with hypothalamus, locus reduced stress-induced system; impairs fear anxiety and depression system activation High prefrontal cortex and low Prefrontal cortex, nucleus Cortical and subcortical nucleus accumbens dopamine accumbens, amygdala dopamine systems remain levels are associated with between cortical and in optimal window of anhedonic and helpless activity to preserve functions involving reward and extinction of fear Mixed effects: 5-HT stimulation of Prefrontal cortex, amygdala, High levels of cortisol High activity of postsynaptic 5-HT2 receptors is anxiogenic; 5- hippocampus, dorsal decrease in 5-HT1A 5-HT1A receptors may HT stimulation of 5-HT1A facilitate recovery receptors is anxiolytic Acute stress down-regulation of Prefrontal cortex, May be relationship Resistance to stress-induced cortical benzodiazepine between decreased down-regulation of benzodiazepine receptors decreased benzodiazepine receptor function Stress-induced decrease in Increase in testosterone may assertive behavior and increase testosterone levels promote increased energy and active coping and reduce depression symptoms Acute increases in estrogen may Estrogen increases Short-term increases in estrogen may attenuate adrenal (HPA) and effects of stress-induced HPA norepinephrine responses axis and noradrenergic decreases function system activation of 5-HT1A receptors The mechanism by which testosterone is reduced by lar pathway that is independent of the pituitary but travels physical and psychological stress remains to be eluci- through the spinal cord. This pathway appears to mediate dated. It is unclear whether the decrease in testosterone the effect of CRH to decrease testosterone levels. Thus, hy- from exposure to mental stress is caused by decreased leu- pothalamic increases in CRH produced by psychological teinizing hormone-releasing hormone (LH-RH) synthesis stress may be associated with decreased testosterone by at the hypothalamus or leuteinizing hormone (LH) secre- stimulating the neural pathway that interferes with Leydig tion in the pituitary (105). Perhaps a more likely mecha- cell function independently of the pituitary. It is important nism involves a recently identified hypothalamic-testicu- to establish the relative role of the LH-RH/LH axis and the Am J Psychiatry 161:2, February 2004 DENNIS S. CHARNEY
Depressed men have been found to have decreased se- rum or plasma testosterone in some studies (115), but not Association With Psychopathology all, because of confounding factors. Hypogonadal men of- Unconstrained release leads to hypercortisolemia-depression, ten experience depressive symptoms, which are improved hypertension, osteoporosis, insulin resistance, coronary vascular by testosterone-replacement therapy (116). Clinical trials disease; overconstrained release leads to hypocortisolemia, seen in some PTSD patients of depressed men with decreased testosterone have pro-duced contradictory results. However, a recent placebo- Low DHEA response to stress may predispose to PTSD and controlled study (115) found testosterone gel to be effec- depression and the effects of hypercortisolemia tive for men with treatment-resistant depression and lowtestosterone levels when added to an existing antidepres- Persistently increased CRH concentration may predispose to PTSD sant regimen. Testosterone administration may be helpful and major depression; may relate to chronic symptoms of anxiety, fear, and anhedonia for patients with low testosterone secondary to chronicsevere psychological stress.
There is abundant preclinical and clinical literature dem- Unrestrained functioning of locus coeruleus-norepinephrine onstrating consistent gender differences in stress respon- system leads to chronic anxiety, hypervigilance, and intrusive memories; some patients with PTSD, panic disorder, and major siveness (117). Most of the work focused on HPA responses depression show evidence of heightened locus coeruleus- to stressors. Female rats consistently show greater increases norepinephrine activity in corticosterone and ACTH in response to acute and Low neuropeptide Y response to stress is associated with increased chronic stressors. These differences have generally been at- vulnerability to PTSD and depression tributed to the activational effects of gonadal steroids on el-ements of the HPA axis in females (118). Several studies Hypothesized low galanin response to stress is associated with suggest that estradiol plays a role in enhanced stress re- increased vulnerability to PTSD and depression sponses in female rats, based upon increased HPA axis re-sponses to stress when ovariectomized rats are treated withestradiol (119). A possible mechanism for these findings is Persistently high levels of prefrontal cortical and low levels of that estrogen (as well as progesterone) produces a relative subcortical dopamine activity are associated with cognitive resistance to glucocorticoid feedback (120).
dysfunction and depression; persistently low levels of prefrontal cortical dopamine are associated with chronic anxiety and fear However, a recent investigation by Young and col- leagues, studying the effects of estrogen antagonists and Low activity of postsynaptic 5-HT1A receptors may predispose to physiological doses of estradiol, found that estradiol re- anxiety and depression duced the ACTH response to restraint stress in female rats(118). The estrogen antagonists had the opposite effect.
Decreased cortical benzodiazepine receptors are associated with These data suggest that physiological doses of estradiol panic disorder and PTSD are inhibitory to stress responsiveness and that blockingestradiol on gonadally intact, normally cycling female ratsleads to exaggerated stress responsiveness. The contrastwith prior studies seems to relate to the dosage of estradiol Decreased CSF testosterone levels are found in PTSD; testosterone and the duration of administration. Considered together, supplementation is helpful for depressed men with low testosterone levels the studies indicate that short-term exposure to low dosesof estrogen can suppress HPA axis responses to stress buthigher doses and more prolonged treatment enhances Long-term increases in estrogen may down-regulate 5-HT1A receptors and increase risk for depression and anxiety HPA axis responses (117, 118). The mechanism underlyingthese effects could be due to enhanced negative feedbackor decreases in the stimulatory aspects of the system, re-lated to either CRH or ACTH. This remains to be eluci-dated, since studies examining the effects of estradiol on hypothalamic testicular axis in modulating the influence mineral corticoid receptor and glucocorticoid receptor of specific stressors on testosterone release (112).
binding and mRNA expression and on CRH have not There is a recent report of reduced CSF testosterone lev- yielded consistent results, perhaps due to variability in els in PTSD patients that was negatively correlated with doses and duration of treatment regimens.
CSF CRH concentrations (113). There was no correlation Studies in human populations suggest that female sub- between plasma and CSF testosterone levels (113). The jects respond with greater HPA activation to stressors in- data from studies measuring plasma testosterone levels in volving interpersonal concerns (social rejection) and male PTSD patients are mixed (114).
subjects to achievement-oriented stressors (117). The role Am J Psychiatry 161:2, February 2004 ADAPTATION TO EXTREME STRESS
of estrogen in these differential responses remains to be may contribute, alone or through functional interactions, studied. Estrogen has been shown to blunt HPA axis re- to resilience or vulnerability (Table 1 and Figure 1). In the sponses to psychological stress in postmenopausal beginning of this article, the concept of allostatic load was women (121, 122) and to blunt the ACTH response to CRH introduced as a measure of the cumulative physiological in postmenopausal women with high levels of body fat. In burden borne by the body from attempts to adapt to stres- addition, 8 weeks of estrogen supplementation to peri- sors and strains of life's demands (137). McEwen and Stel- menopausal women blunted systolic and diastolic blood lar (3) hypothesized that the cumulative impact on health pressure, cortisol, ACTH, plasma epinephrine and norepi- risk from modest dysregulations in multiple systems can nephrine, and norepinephrine responses of the entire be substantial, even if they individually have minimal and body to stress (120).
insignificant health effects. Thus, they defined allostatic Although the mechanisms responsible for the effect of es- load as a cumulative measure of physiological dysregula- trogen on glucocorticoid levels are not fully defined, it ap- tion over multiple systems (3).
pears that it acts by means of ACTH and thus the pituitary The concept of allostatic load has proven to be useful as or hypothalamus rather than directly on the adrenal gland.
a predictor of functional decline in elderly men and This is consistent with evidence obtained from women with women. Seeman and colleagues (138) developed a mea- hypothalamic amenorrhea, in whom a blunted response to sure of allostatic load based on 10 markers reflecting levels CRH administration and increased cortisol levels were ob- of physiological activity across a range of important regu- served (123). These effects could be explained by a direct latory systems, which individually have been linked to dis- action of estrogen on CRH gene expression or glucocorti- ease based upon data from a longitudinal community- coid receptor numbers or function (124).
based study of successful aging (138). The markers were The mechanisms by which estrogens affect catechola- mine levels are also uncertain. The effects of estrogen may 1. Twelve-hour overnight urinary cortisol excretion be due to actions on the adrenal gland or central or periph- 2. Twelve-hour overnight urinary excretion of norepi- eral neuronal pathways. Neuronal pathways seem more likely (125), although several different mechanisms may be 3. Twelve-hour overnight urinary excretion of epinephrine involved, including effects on α1-noradrenergic (126) and 4. Serum DHEA-S level β-noradrenergic (127) receptors and modulation of nor- 5. Average systolic blood pressure epinephrine release. Estrogen has also been shown to up- 6. Average diastolic blood pressure regulate the GABAA benzodiazepine receptor (128).
7. Ratio of waist-hip circumference The effects of estrogen on mood and anxiety may be me- 8. Serum high-density lipid (HDL) cholesterol diated in part by the serotonin system (129). Estrogen has 9. Ratio of total cholesterol to HDL cholesterol complex effects on functioning of the serotonin system, in- 10. Blood-glycosylated hemoglobin cluding increased tryptophan hydroxylase gene and proteinexpression (130), decreased expression of the serotonin For each of the 10 markers, the subjects were classified transporter (131), and increased 5-HT2A binding (132). Per- into quartiles based upon the distribution of scores in the haps most important are studies relevant to the 5-HT1A re- baseline cohort. Allostatic load was measured by summing ceptor. Estrogen in both rats and monkeys decreases 5-HT1A the number of parameters for which the subject fell into in RNA and 5-HT1A binding in both presynaptic (dorsal the highest-risk quartile (top quartile for all markers except raphe) and postsynaptic sites (133). Estrogen also decreases HDL cholesterol and DHEA-S, for which the lowest quartile the inhibitory G proteins involved in intracellular signal corresponds to the highest risk). In two follow-up studies transduction mediated by the 5-HT1A receptor (134, 135).
encompassing 2.5 and 7 years, none of the 10 markers of al- Women appear to be more sensitive to the effects of lostatic load exhibited significant associations on their traumatic stress. One survey found that 31% of women own with health outcomes. However, the summaried mea- and 19% of men develop PTSD when exposed to major sure of allostatic load was found to be significantly associ- trauma (136). However, the role of estrogen in the devel- ated with four major health outcomes: 1) new cardiovascu- opment of PTSD has not been investigated. Based upon lar events, 2) a decline in cognitive functioning, 3) a decline these data, short-term increases in estrogen after expo- in physical functioning, and 4) mortality. Thus, these data sure to stress might be beneficial because of its ability to are consistent with the hypothesis that although modest blunt the HPA axis and noradrenergic response to stress.
abnormalities in a single physiological system may not be However long-term stress-related elevation in estrogen predictive of poor health outcome, the cumulative effect of might be detrimental because of estrogen-induced de- multiple abnormalities in the physiological system is prog- creases in 5-HT1A receptor numbers and function.
nostic of poor physical health (11, 138).
The allostatic load concept has not been used to investi- Resilience and Vulnerability to Stress
gate neurobiological risk factors related to psychopathol- The last section identified 11 possible mediators of the ogy. Perhaps an analogous approach that involves the psychobiological response to extreme stress and how each identification of a group of biological markers that will re- Am J Psychiatry 161:2, February 2004 DENNIS S. CHARNEY
FIGURE 1. Neurochemical Response Patterns to Acute Stressa
Nucleus accumbens Prefrontal cortex Galanin Norepinephrine releasing hormone releasing hormone releasing hormone Galanin Leydig Cells
releasing hormone a This figure illustrates some of the key brain structures involved in the neurochemical response patterns following acute psychological stress.
The functional interactions among the different neurotransmitters, neuropeptides, and hormones are emphasized. It is apparent the func-tional status of brain regions such as the amygdala (neuropeptide Y, galanin, corticotropin-releasing hormone [CRH], cortisol, and norepi-nephrine), hippocampus (cortisol and norepinephrine), locus coeruleus (neuropeptide Y, galanin, and CRH), and prefrontal cortex (dopamine,norepinephrine, galanin, and cortisol) will depend upon the balance among multiple inhibitory and excitatory neurochemical inputs. It isalso noteworthy that functional effects may vary depending on the brain region. Cortisol increases CRH concentrations in the amygdala anddecreases concentrations in the paraventricular nucleus of the hypothalamus. As described in the text, these neurochemical response pat-terns may relate to resilience and vulnerability to the effects of extreme psychological stress.
late to psychobiological allostasis and psychobiological al- neuropeptide Y, galanin, testosterone, and 5-HT1A receptor lostatic load and, consequently, to resilience and vulnera- and benzodiazepine receptor function and the lowest bility to the effects of extreme psychobiological stress will quartile for HPA axis, CRH, and locus coeruleus-norepi- be fruitful. It is in this context that this review of the neuro- nephrine activity (Table 1). The mediators of the stress re- chemical response patterns to stress can provide a frame- sponse identified in this review are not meant to be an ex- work for developing a measure for psychobiological allo- haustive or definitive list. For example, glutamate and static load. The finding that many of these measures have neurotrophic factors, such as brain-derived neurotrophic important functional interactions is supportive of the con- factor, and neuropeptides, such as substance P and chole- cept of developing a more integrative measure. One pre- cystokinin, could have been included. Longitudinal com- diction is that individuals in the highest quartile for mea- munity-based surveys of successful adaptation to extreme sures of HPA axis, CRH, locus coeruleus-norepinephrine, stress should be considered to determine if markers such dopamine, and estrogen activity and the lowest quartile for as these or others can be used to develop a measure of psy- DHEA, neuropeptide Y, galanin, testosterone, and 5-HT1A chobiological allostatic load that will be of predictive value.
receptor and benzodiazepine receptor function will havethe highest index for psychobiological allostatic load and Reward, Fear Conditioning,
an increased risk for psychopathology after exposure to and Social Behavior
stress. It is possible that psychobiological allostatic loadwill relate to vulnerability to the effects of chronic, mild, Most of the research on resilience in the face of adversity intermittent stressors as well as extreme psychological focuses on early childhood and adolescence. Studies of trauma. In contrast, a resilient profile will be characterized children raised in a variety of settings, including war, fam- by individuals in the highest quartile for measures of DHEA, ily violence, poverty, and natural disasters, have revealed a Am J Psychiatry 161:2, February 2004 ADAPTATION TO EXTREME STRESS
TABLE 2. Neural Mechanisms Related to Resilience and Vulnerability to Extreme Stress
Neurochemical Systems Association With Resilience Association With Psychopathology Dopamine, dopamine Medial prefrontal Acute and chronic stress do not Stress-induced reduction in receptors, glutamate, produce impairment in dopamine and increases in cAMP neurochemical or transcription response-element binding factor-mediated reward protein transcription produces a dysfunction in reward circuitry aminobutyric acid leading to anhedonia and (GABA), opioids, cAMP response element binding protein, Medial prefrontal Adaptive association between May account for common clinical receptors; voltage- conditioned stimuli and observation in panic disorder, cortex, anterior unconditioned stimuli does occur; PTSD, and depression that cingulate, dorsal fear responses are circumscribed; overgeneralization of sensory thalamus, lateral this may be due to functional and cognitive stimuli associated differences in NMDA receptors and with or resembling the original voltage-gated calcium channels; trauma elicits panic attacks, treatment with an NMDA receptor flashbacks, and autonomic agonist (memantine) or voltage- gated calcium channel antagonists (verapamil and nimodipine) may attenuate acquisition of fear Medial prefrontal Reduced stress-induced release of CRH, Excessive stress-mediated release adrenergic receptor, cortisol, and norepinephrine of CRH, cortisol, and lateral amygdala decreases fear memory norepinephrine will facilitate consolidation; CRH antagonists and development of indelible fear β-adrenergic receptor antagonists memories; chronic anxiety and may have preventive effects depressive symptoms may result releasing hormone from excessive contextual fear (CRH), GABA, opioid, entorhinal cortex The lability of the memory trace allows Repeated reactivation and a reorganization of original memory reconsolidation may further norepinephrine, β- that is less traumatic and symptom strengthen the memory trace adrenergic receptors, producing; treatment with NMDA and lead to persistence of receptor and β-adrenergic receptor trauma-related symptoms antagonists after memory reactivation may reduce the strength of the original traumatic memory Medial prefrontal An ability to quickly attenuate learned Failure in neural mechanisms of receptors, voltage- fear through a powerful extinction extinction may relate to process and an ability to function persistent traumatic memories, more effectively in dangerous reexperiencing symptoms, situations may be due to inhibition of autonomic hyperarousal, and amygdala activity mediated by the medial prefrontal cortex consistent pattern of individual characteristics associated For example, the original Mercury 7 astronauts reported with successful adaptation. These include good intellec- that they had encountered challenges in which they felt tual functioning, effective self-regulation of emotions and fear but still were able to function effectively (142–144).
attachment behaviors, a positive self-concept, optimism, In recent years, significant advances have been made in altruism, a capacity to convert traumatic helplessness into understanding how the brain regulates reward and moti- learned helpfulness, and an active coping style in con- vation (hedonia, optimism, and learned helpfulness), fronting a stressor (139–141).
learns, remembers, and responds to fear (effective behav- Which adult characteristics are associated with resil- iors despite fear), and develops adaptive social behaviors ience to stress? Most of the data come from studies of men (altruism, bonding, and teamwork). The neural mecha- in combat but are applicable to other professions, such as nisms that mediate these functions are relevant to how an firefighters and police, in which danger is ever-present and individual responds to extreme stress and may account, at effective action under stress is imperative. These include least in part, for the character traits reviewed that relate to an ability to bond with a group with a common mission, a resilience and courage (Table 2).
high value placed on altruism, and the capacity to toleratehigh levels of fear and still perform effectively. Most coura- Regulation of Reward
geous individuals are not fearless but are willing and ableto approach a fear-inducing situation despite the presence The ability to maintain properly functioning reward of subjective fear and psychophysiological disturbance.
pathways and a hedonic tone in the context of chronic Am J Psychiatry 161:2, February 2004 DENNIS S. CHARNEY
stress and an unrewarding environment may be critical to increased sensitivity to aversive stimuli and decreased maintaining optimism, hopefulness, and a positive self- sensitivity to rewarding stimuli. Thus, cAMP response- concept after exposure to extreme stress. Resilient individ- element binding protein in the nucleus accumbens mod- uals may have a reward system that is either hypersensi- ulates behavioral responsiveness to emotional stimuli tive to reward or is resistant to change, despite chronic ex- such that increased cAMP response-element binding pro- posure to neglect and abuse.
tein after stress may contribute to persistent anhedonia in The mesolimbic dopamine pathways are centrally in- patients with PTSD or major depression (145).
volved in reward, motivation, and hedonic tone. Subcorti- The amygdala modulates conditioned responses to re- cal structures involved in dopamine signaling include the warding stimuli through circuits formed by the amygdala, dorsal striatum, ventral striatum (i.e., nucleus accum- subiculum, bed nucleus of the stria terminalis, nucleus ac- bens), amygdala, and midbrain ventral tegmental area cumbens, and medial prefrontal cortex. These neural net- (145, 146). The nucleus accumbens and its dopaminergic works establish the emotional value of a reward memory inputs play a central role in reward. The nucleus accum- as well as its strength and persistence. The molecular basis bens is a target of the mesolimbic dopamine system, which for such plasticity is just beginning to be developed—the arises in the ventral tegmental area. The neurons of the cAMP pathway and cAMP response-element binding pro- ventral tegmental area also innervate several other limbic tein in the amygdala promote both aversive and rewarding structures, including the amygdala and the medial pre- associations (151, 152).
frontal cortex. The amygdala sends projections to the ven- Sensitivity to the behavioral effects of dopamine-en- tral tegmental area and nucleus accumbens. Increasing hancing drugs may be heritable. There may be an endo- evidence suggests that similar mechanisms in the ventral phenotype related to resistance to anhedonia and hope- tegmental area and nucleus accumbens mediate responses lessness in the face of stress (153). Subjects with major to natural reinforcers under normal conditions. In nonhu- depression are hyperresponsive to amphetamine such man primates, the firing patterns of dopamine neurons in that the severity of depression in major depression was the ventral tegmental area are sensitive readouts of reward highly correlated with the rewarding effects of amphet- expectations. Dopamine neurons increase their firing amine. The mechanism may be depletion of synaptic relative to the predictability of reward. The dopamine dopamine with up-regulation of dopamine receptors (154, neuronal response is activated when rewards occur with- 155). Increasing dopamine function in the nucleus ac- out being predicted or are better than predicted. The neu- cumbens, the orbital frontal cortex, and the ventral teg- rons show no change when rewards are predicted and de- mental area and NMDA receptor blockade in the nucleus creased activity when rewards are omitted or are less than accumbens and the medial prefrontal cortex may enhance predicted (147, 148).
sensitivity to reward. Therefore, psychostimulants, dopa- The medial prefrontal cortex receives glutamatergic in- mine reuptake inhibitors, monoxamine oxidase-B inhibi- put from the amygdala and sends glutamatergic projec- tors (selegiline), the dopamine receptor agonists (prami- tions to the nucleus accumbens and the ventral tegmental pexole), and NMDA receptor antagonists (memantine) area. Electrical stimulation of the medial prefrontal cortex may be useful for treating anhedonia and hopelessness re- is thought to be rewarding because it causes glutamate re- sulting from traumatic stress exposure.
lease in the ventral tegmental area and dopamine releasein the nucleus accumbens. In contrast, the drug of abuse The Neural Mechanisms
phencyclidine is rewarding because of its antagonism of of Anxiety and Fear
NMDA-type glutamate receptors in the nucleus accum-bens and the medial prefrontal cortex. Functional interac- tions among glutamate, NMDA receptors, dopamine, and Fear conditioning in many patients with PTSD and ma- dopamine receptors are critical to the proper functioning jor depression causes vivid recall of memories of trau- of reward circuits (146, 147, 149). Neurons of the orbital- matic events, autonomic hyperarousal, and even flash- frontal cortex, which receive dopamine projections from backs elicited by sensory and cognitive stimuli associated the ventral tegmental area, have the ability to discriminate with prior traumas. Consequently, patients may begin to different rewards according to their motivational value.
avoid these stimuli in their everyday lives, or a numbing of The preference-related activations may facilitate neuronal general emotional responsiveness may ensue. Resilience mechanisms that lead to behavioral choices favoring the to the effects of severe stress may be characterized by the most rewarding and profitable goals (147, 148).
capacity to avoid overgeneralizing specific conditioned Recent approaches to reward mechanisms include ex- stimuli to a larger context, reversible storage of emotional amination of the molecular and cellular changes in the memories, and facilitated extinction.
ventral tegmental area and nucleus accumbens pathway.
Classical fear conditioning is a form of associative learn- Acute and chronic stress induce transcription in the nu- ing in which subjects come to express fear responses to a cleus accumbens that is mediated by cAMP response- neutral conditioned stimulus that is paired with an aver- element binding protein (150). This is associated with sive unconditioned stimulus. The conditioned stimulus, Am J Psychiatry 161:2, February 2004 ADAPTATION TO EXTREME STRESS
as a consequence of this pairing, acquires the ability to This hypothesis leads to several predictions that may elicit a spectrum of behavioral, autonomic, and endocrine have relevance to psychological responses to stress. It sug- responses that normally would only occur in the context gests that blocking NMDA receptors in the amygdala dur- of danger (156). Fear conditioning can be adaptive and en- ing learning should impair memory of short- and long- able efficient behavior in dangerous situations. The indi- term fear. This has been demonstrated in rodents (160, vidual who can accurately predict threat can engage in ap- 161). Valid human models of fear conditioning and the propriate behaviors in the face of danger. In the clinical availability of the NMDA receptor antagonist memantine situation, specific environmental features (conditioned should permit this hypothesis to be tested clinically (162).
stimuli) may be linked to the traumatic event (uncondi- If memantine impairs the acquisition of fear in humans, it tioned stimuli), such that reexposure to a similar environ- may have use in the prevention and treatment of stress-in- ment produces a recurrence of the symptoms of anxiety duced disorders such as PTSD. Blockade of voltage-gated and fear. Patients often generalize these cues and experi- calcium channels appears to block long-term but not ence a continuous perception of threat to the point that short-term memory (163). Therefore, clinically available they become conditioned to context.
calcium channel blockers such as verapamil and nimodi-pine may be helpful in diminishing the intensity and im- Cue-specific conditioned stimuli are transmitted to the pact of recently acquired fear memory and perhaps in pre- thalamus by external and visceral pathways. Afferents then venting PTSD as well.
reach the lateral amygdala by means of two parallel cir-cuits: a rapid subcortical path directly from the dorsal (sen- This discussion has focused primarily upon the neural mechanisms related to the coincident learning of the un- sory) thalamus and a slower regulatory cortical pathway conditioned stimuli-conditioned stimuli association (i.e., encompassing the primary somatosensory cortices, the Pavlovian fear conditioning) in the lateral amygdala. How- insula, and the anterior cingulate/prefrontal cortex. Con- ever, there is significant evidence that a broader neural cir- textual conditioned stimuli are projected to the lateral cuitry underlies the memory of fear that is modulated by amygdala from the hippocampus and perhaps the bed nu- amygdala activity. The inhibitory-avoidance paradigm is cleus of the stria terminalis. The long loop pathway indi- used to examine memory consolidation for aversively mo- cates that sensory information relayed to the amygdala tivated tasks and involves intentional instrumental choice undergoes substantial higher-level processing, thereby behavior. Studies using inhibitory avoidance learning enabling assignment of significance based on prior ex- procedures have been used to support the view that the perience to complex stimuli. Cortical involvement in fear amygdala is not the sole site for fear learning but, in addi- conditioning is clinically relevant because it provides a tion, can modulate the strength of memory storage in mechanism by which cognitive factors will influence other brain structures (164).
whether symptoms are experienced or not following expo- There is evidence that Pavlovian fear conditioning and sure to stress (157).
inhibitory avoidance involve fundamentally different neu- During the expression of fear-related behaviors, the lat- ral mechanisms. Pavlovian fear conditioning and inhibi- eral amygdala engages the central nucleus of the amyg- tory avoidance are differentially affected by posttraining dala, which, as the principal output nucleus, projects to ar- pharmacological manipulations. The two types of learn- eas of the hypothalamus and brainstem that mediate the ing involve different experimental procedures. In Pavlov- autonomic, endocrine, and behavioral responses associ- ian fear conditioning, the presentation of the conditioned ated with fear (158). The molecular and cellular mecha- stimuli and unconditioned stimuli occurs independent of nisms that underlie synaptic plasticity in amygdala-depen- behavior, whereas with inhibitory avoidance shock, deliv- dent learned fear are an area of active investigation (159).
ery is contingent upon an animal's behavioral response.
Long-term potentiation in the lateral amygdala appears to Inhibitory avoidance may involve a more complex neural be a critical mechanism for storing memories of the associ- network because an animal's response is contingent upon ation between conditioned stimuli and unconditioned a number of contextual cues, in contrast to the more spe- stimuli (156). A variety of behavioral and electrophysiolog- cific conditioned stimuli and unconditioned stimuli. The ical data have led LeDoux and colleagues (157, 158) to pro- basal lateral amygdala is the primary amygdala nucleus pose a model to explain how neural responses to the condi- responsible for voluntary emotional behavior based upon tioned stimuli and unconditioned stimuli in the lateral aversive emotional events, whereas the central nucleus of amygdala could influence long-term potentiation-like the amygdala is more involved in Pavlovian responses to changes that store memories during fear conditioning.
fear-inducing stimuli (165). The relevance of the inhibi- This model proposes that calcium entry through NMDA tory-avoidance paradigm to human fear and anxiety rests receptors and voltage-gated calcium channels initiates the on its assessment of a behavioral response to a fear-induc- molecular processes to consolidate synaptic changes into ing context (166).
long-term memory (156). Short-term memory requires Specific drugs and neurotransmitters infused into the calcium entry only through NMDA receptors and not volt- basal lateral amygdala influence consolidation of memory age-gated calcium channels.
for inhibitory avoidance training. Posttraining peripheral Am J Psychiatry 161:2, February 2004 DENNIS S. CHARNEY
or intra-amygdala infusions of drugs affecting GABA, opi- and β-adrenergic receptor antagonists may prevent these oid, glucocorticoid, and muscarinic acetylcholine recep- effects in vulnerable subjects.
tors have dose- and time-dependent effects on memoryconsolidation (164). Norepinephrine infused directly into the basal lateral amygdala after inhibitory avoidance train- Reconsolidation is a process in which old, reactivated ing enhances memory consolidation, indicating that the memories undergo another round of consolidation (171– degree of activation of the noradrenergic system within the 173). The process of reconsolidation is extremely relevant amygdala by an aversive experience may predict the extent to both vulnerability and resiliency to the effects of extreme of the long-term memory for the experience (167).
stress. It is the rule rather than the exception that memories Interactions among CRH, cortisol, and norepinephrine are reactivated by cues associated with the original trauma.
receptors have important effects on memory consolida- Repeated reactivation of these memories may serve to tion, which is likely to be relevant to the effects of traumatic strengthen the memories and facilitate long-term consoli- stress on memory. Extensive evidence indicates that gluco- dation (174, 175). Each time a traumatic memory is re- corticoids influence long-term memory consolidation by trieved, it is integrated into an ongoing perceptual and means of stimulation of glucocorticoid receptors. The glu- emotional experience and becomes part of a new memory.
cocorticoid effects on memory consolidation require acti- Moreover, preclinical studies indicate that consolidated vation of the basal lateral amygdala, and lesions of the memories for auditory fear conditioning, which are stored basal lateral amygdala block retention enhancement of in- in the amygdala (176), hippocampal-dependent contextual trahippocampal infusions of a glucocorticoid receptor ag- fear memory (171), and hippocampal-dependent memory onist. Additionally, the basal lateral amygdala is a critical associated with inhibitory avoidance (172) are sensitive to locus of interaction between glucocorticoids and norepi- disruption upon reactivation by administration of a protein nephrine in modulating memory consolidation (168).
synthesis inhibitor directly into the amygdala and hippo- There is also extensive evidence consistent with a role campus, respectively. The reconsolidation process, which for CRH in mediating the effects of stress on memory con- has enormous clinical implications, results in reactivated solidation. Activation of CRH receptors in the basal lateral memory trace then returns to a state of lability and must amygdala by CRH released from the central nucleus of the undergo consolidation once more if it is to remain in long- amygdala facilitates the effects of stress on memory con- term storage. Some controversies persist regarding the solidation. As reviewed, there are important functional temporal persistence of systems reconsolidation. Debiec interactions between the CRH and norepinephrine sys- and colleagues (171) found that intrahippocampal infu- tems, including a role in memory consolidation. Memory sions of anisomycin caused amnesia for a consolidated enhancement produced by CRH infusions in the hippo- hippocampal-dependent memory if the memory was reac- campus are blocked by propranolol and the noradrenergic tivated, even up to 45 days after training. Milekic and Al- toxin DSP-4 (75-R), suggesting that CRH infusions by berini (172) however, found that the ability of intrahippoc- means of a presynaptic mechanism stimulate norepi- ampal infusion of anisomycin to produce amnesia for an nephrine release in the hippocampus (169).
inhibitory avoidance task was evident only when the mem- Efferent projections from the basal lateral amygdala are ory was recent (up to 7 days old). Further work is needed to also crucial to memory formation. The basal lateral path- resolve this very important question (173).
way of the amygdala stria terminalis is involved, since le- The reconsolidation process involves NMDA receptors sions of the stria terminalis impair the memory-enhanc- and β-adrenergic receptors and requires cAMP response- ing effects of intra-amygdala infusions of norepinephrine element binding protein induction. The cAMP response- and systemic dexamethasone, which are presumably act- element binding protein requirement suggests that nu- ing on the hippocampus. Also, lesions of the nucleus ac- clear protein synthesis is necessary (177). NMDA receptor cumbens block the memory-enhancing effects of intra- antagonists and β receptor antagonists impair reconsoli- amygdala infusions of glucocorticoid receptor agonist.
dation (174, 178). The effect of the β receptor antagonist Finally, the cortex is also a locus for memory consolida- propranolol was greater after memory reactivation than tion, since projections from the basal lateral amygdala are when administered immediately after the initial training.
essential in the modulation of memory by the entorhinal These results suggest that reactivation of memory initiates cortex (165, 170).
a cascade of intracellular events that involve both NMDA These results support the concept that CRH, by means receptor and β receptor activation in a fashion similar to of an interaction with glucocorticoids, interacts with the noradrenergic system to consolidate traumatic memories.
This remarkable lability of a memory trace, which per- Individuals with excessive stress-induced release of CRH, mits a reorganization of an existing memory in a retrieval cortisol, and norepinephrine are likely to be prone to the environment, provides a theoretical basis for both psycho- development of indelible traumatic memories and their therapeutic and pharmacotherapeutic intervention for associated reexperiencing symptoms. Administration of traumatic stress exposure. Administration of β receptor CRH antagonists, glucocorticoid receptor antagonists, and NMDA receptor antagonists shortly after the initial Am J Psychiatry 161:2, February 2004 ADAPTATION TO EXTREME STRESS
trauma exposure as well as after reactivation of memory showed that PTSD patients had increased left amygdala ac- associated with the event may reduce the strength of the tivation during fear acquisition and decreased activity of original traumatic memory.
the medial prefrontal cortex/anterior cingulate during ex-tinction. It has been proposed that potentiating NMDA re- ceptors using the glycine agonist D-cycloserine may facili- When the conditioned stimuli are presented repeatedly tate the extinction process when given in combination with in the absence of the unconditioned stimuli, a reduction behavioral therapy in patients with anxiety disorders (189).
in the conditioned fear response occurs. This process iscalled extinction. It forms the basis for exposure-based The Neural Basis of Social Behavior
psychotherapies for the treatment of a variety of clinicalconditions characterized by exaggerated fear responses.
As noted, a number of scholars have worked to define Individuals who show an ability to attenuate learned fear the psychological characteristics that promote resiliency.
quickly through powerful and efficient extinction pro- These characteristics include being altruistic toward oth- cesses are likely to function more effectively under dan- ers and having the ability to attract and use support (139– gerous conditions. They may also be less susceptible to 141). Therefore, understanding the neural basis of altru- the effects of intermittent exposure to fear stimuli, which ism and other forms of adaptive social behavior may be can reinstate fear-conditioned learning. Highly stress-re- relevant to a better conceptualization of the psychobiol- silient individuals under extreme stress generally experi- ogy of resilience.
ence fear but have the capacity to function well under Preclinical studies have used several rodent model sys- states of high fear. In addition, individuals in positions tems to increase our knowledge of how the brain pro- that regularly cause them to confront danger need to be cesses social information and regulates social behavior able to extinguish learned fears rapidly.
(190). These models include the oxytocin knockout mouse Extinction is characterized by many of the same neural and the study of the neurobiology of social behaviors in mechanisms as in fear acquisition. Activation of amygdala prairie and montane voles. The oxytocin knockout mouse NMDA receptors by glutamate is essential (179), and L- exhibits a specific deficit in social recognition in the con- type voltage-gated calcium channels also contribute to ex- text of intact general cognitive abilities and olfactory tinction plasticity (180). Long-term extinction memory is processing (191). Social recognition is fully restored by altered by a number of different neurotransmitter sys- oxytocin infusion during the initial processing of social in- tems, including GABA, norepinephrine, and dopamine, in formation. Studies measuring C-Fos induction indicate a manner similar to fear acquisition (181, 182).
that the medial amygdala is involved in pathways that dif- Destruction of the medial prefrontal cortex blocks recall ferentially process social and nonsocial information (192).
of fear extinction (183, 184), indicating that the medial Prairie and montane voles are similar genetically but prefrontal cortex might store long-term extinction mem- vary greatly in their social behaviors. The prairie vole is ory. Infralimbic neurons, which are part of the medial pre- highly social, forms long-lasting social attachments, and is frontal cortex, fire only when rats are recalling extinc- monogamous (193), whereas the montane vole avoids so- tion—greater firing correlates with reduced fear behaviors cial contact except for the purpose of mating (194). Oxyto- (185). It has been suggested that the consolidation of ex- cin and vasopressin appear to play crucial roles in the so- tinction involves potentiation of inputs into the medial cial behavior of prairie voles. They increase the amount of prefrontal cortex by means of NMDA-dependent plastic- time a vole spends socially engaged and are involved in ity. The basal lateral amygdala sends direct excitatory the formation of the pair bond. The levels of oxytocin and inputs to the medial prefrontal cortex, and NMDA an- vasopressin are similar in prairie and montane voles. The tagonists infused into the basal lateral amygdala block ex- differences in social behavior are explained by the regional tinction. The ability of the medial prefrontal cortex to expression of these peptides in the brain. Prairie voles modulate fear behaviors is probably related to projections have high levels of oxytocin receptors in the nucleus ac- from the medial prefrontal cortex by means of GABA inter- cumbens and the basal lateral amygdala relative to mon- neurons to the basal lateral amygdala (186).
tane voles (195). Similarly, prairie voles have higher densi- Failure to achieve an adequate level of activation of the ties of the vasopressin-1A receptor on the ventral pallidum medial prefrontal cortex after extinction might lead to per- and the medial amygdala than montane voles. Infusion of sistent fear responses (187). Individuals with the capacity vasopressin has different effects in the two voles; prairie to function well after experiencing states of high fear may voles increase social interaction, and montane voles in- have potent medial prefrontal cortex inhibition of amyg- crease nonsocial behaviors, such as autogrooming (196).
dala responsiveness. In contrast, patients with PTSD ex- The neural mechanisms responsible for the effects of oxy- hibit depressed ventral medial prefrontal cortex activity, tocin and vasopressin on social behavior are thought to in- which correlates with increased autonomic arousal after volve some of the same circuitry (the nucleus accumbens exposure to traumatic reminders (unpublished work by and the ventral pallidum) involved in reward-related be- Bremner et al.). Consistent with this hypothesis, we (188) havior. These brain regions are also components of the Am J Psychiatry 161:2, February 2004 DENNIS S. CHARNEY
FIGURE 2. Neural Circuits Associated With Reward, Fear Conditioning, and Social Behaviora
Medial prefrontal Nucleus accumbens Glucocorticoid receptor β-Adrenergic receptor type I releasing hormone a The figure depicts a simplified summary of some of the brain structures and relevant neurochemistry mediating the neural mechanisms of reward (purple paths), fear conditioning and extinction (yellow paths), and social behaviors (blue paths). Only a subset of the many knowninterconnections among these various regions is shown, and relevant interneurons are not illustrated (see text), yet it can be seen there isconsiderable overlap in the brain structures associated with these neural mechanisms. This suggests that there may be clinically relevantfunctional interactions among the circuits. For example, a properly functioning reward circuit may be necessary for the reinforcement of pos-itive social behaviors. An overly responsive fear circuit or impaired extinction process may negatively influence functioning of the reward sys-tem. The assessment of these neural mechanisms must be considered in the context of their neurochemical regulation. Alterations in oneneurotransmitter, neuropeptide, or hormone system will affect more than one circuit. Several receptors that are related to putative anti-anxiety and antidepressant drug targets are illustrated. The functional status of these circuits has important influences on stress-related psy-chopathology and the discovery of novel therapeutics (see text).
dopamine reward system (197). This suggests that, in prai- altruism. Highly resilient children, adolescents, and adults rie voles, activation of these brain regions during social in- have exceptional abilities to form supportive social at- teractions reinforces social behavior.
tachments. Individuals who demonstrate outstanding Recently, there have been several human studies that leadership ability and courageous acts in the context of bear on the neural basis of social cooperation. Reciprocal great personal danger are frequently characterized by altruism is a core behavioral principle of human social life unique altruism. Clinical studies in such individuals de- and has been related to resilience. Rilling and colleagues signed to examine the neural circuits related to social co- (198) studied social cooperation with the iterated Pris- operation are now indicated.
oner's Dilemma Game. They found that mutual coopera-tion was associated with consistent activation of brain ar- Future Research Directions
eas linked to reward processing, including the nucleusaccumbens, the caudate nucleus, and regions of the me- Examination of the neural circuits of reward, fear condi- dial prefrontal cortex. They hypothesized that this pattern tioning and extinction, and social behavior reveal that sev- of neural activation by means of linkage to reward circuits eral brain structures are involved in more than one circuit sustains cooperative social relationships and inhibits the (Figure 2). This is most striking for the amygdala, the nu- selfish impulse to accept but not to reciprocate an act of cleus accumbens, and the medial prefrontal cortex. The Am J Psychiatry 161:2, February 2004 ADAPTATION TO EXTREME STRESS
amygdala has been most prominently identified as a criti- dence that smaller hippocampal volume may constitute a cal structure in studies of fear conditioning; however, it risk factor for the development of stress-related psycho- also has a major role in reward mechanisms. The nucleus pathology. The recent identification of functional poly- accumbens is implicated in both reward and social behav- morphisms for the glucocorticoid receptor (208), for the iors, and the medial prefrontal cortex is a component of all α2C adrenergic receptor subtype (209), and for neuropep- three circuits.
tide Y synthesis (210) provides opportunities to investigate These observations raise many intriguing questions. For the genetic basis of the neurochemical response pattern to example, does a particular level of amygdala function in fear conditioning relate in a predictable way to its function Work is commencing to examine the genetic basis of the in the reward system? Does the finding of increased amyg- neural mechanisms of reward, fear conditioning, and so- dala responsiveness to fear stimuli in PTSD and depres- cial behavior. There have been several recent advances in sion suggest that amygdala dysfunction will also be appar- understanding the genetic contribution and molecular ent in the study of reward in these disorders? To carry this machinery related to amygdala-dependent learned fear. A a step further, will there be a clinical correlation between gene-encoding gastrin-releasing peptide has been identi- abnormalities in fear regulation and anhedonia? The re- fied in the lateral amygdala. The gastrin-releasing peptide dundancy in the circuits mediating reward and social be- receptor is expressed in GABA-ergic interneurons and me- havior, especially involving the nucleus accumbens, sug- diates their inhibition of principal neurons. In knockout gests a functional interaction between these two circuits.
mice with the gastrin-releasing peptide receptor, this inhi- When both systems are functioning well, positive social bition is reduced and long-term potentiation is enhanced.
behaviors are reinforced. However, an inability to experi- These mice have enhanced and prolonged fear memory ence reward because of an impaired circuit may result in for auditory and contextual cues, indicating that the gas- unrewarding social experiences, deficient social compe- trin-releasing peptide signaling pathway may serve as an tence, and social withdrawal. The medial prefrontal cortex inhibitory feedback constraint on learned fear (159). The is believed to be a critical link between emotional regula- work further supports a role of GABA in fear and anxiety tion and higher-level decision making. Abnormalities in states (211) and suggests the genetic basis of vulnerability functioning of the medial prefrontal cortex could be man- to anxiety may relate to gastrin-releasing peptide, gastrin- ifested by a failure to assess accurately the range of out- releasing peptide receptor, and GABA (212). Other preclin- comes associated with reward or punishment, indicative ical studies indicate that there may be a genetically deter- of a functional relationship between reward and fear cir- mined mesocortical and mesoaccumbens dopamine re- cuits. Moreover, it has been suggested that this region reg- sponse to stress that relates to learned helplessness (80).
ulates social interactions, including the capacity for em- There may be genetic mechanisms affecting social affilia- pathy and altruism (199).
tion behavior that involves the vasopressin-1A receptor To date, most neuroimaging studies have investigated that can be evaluated in clinical populations (213). Re- the functional status of these circuits in isolation and not in cently, it was demonstrated that healthy subjects with the relation to each other. This article suggests that assessment serotonin transporter polymorphism that has been associ- of the functional relationships among these circuits, in- ated with reduced 5-HT expression and function and in- cluding the associated neurochemical modulation, may be creased fear and anxiety behaviors exhibit increased amyg- important in providing a more comprehensive and precise dala neuronal activity in response to fear-inducing stimuli understanding of the contribution of these circuits to resil- (214–216). These preclinical and clinical data suggest that ience and vulnerability to stress.
multidisciplinary studies that use neurochemical, neu- There is emerging evidence indicating that genetic fac- roimaging, and genetic approaches have the potential to tors contribute to the vulnerability to stress-related psy- clarify the complex relationships among genotype, pheno- chopathology, such as in PTSD. An investigation of twin type, and psychobiological responses to stress.
pairs from the Vietnam Twin Registry (200) reported that Philosophers and behavioral scientists have been inter- inherited factors accounted for up to 32% of the variance ested in stress, coping, and resilience since antiquity, such of PTSD symptoms beyond the contribution of trauma se- as when Socrates said to Laches, "Tell me, if you can, what verity. The molecular neurobiological abnormalities that is courage" (217). Epidemiological and phenomenological underlie these findings have not been elucidated. Two rel- investigations reveal specific individual, familial, and atively small association studies (201, 202) that evaluated community characteristics that promote resilience and dopamine D2 receptor polymorphisms in PTSD yielded have even informed social policy. We now have the oppor- contradictory results. A preliminary study (203) found an tunity to bring to bear the full power of advances in our association between the dopamine transporter polymor- understanding of the neurobiological basis of behavior, to phism and PTSD. Volumetric magnetic resonance imaging break down the artificial boundaries of mind-brain and investigations (204–206) demonstrated a smaller hippo- nature-nurture (218), and to create more comprehensive campal volume in PTSD patients. A study of monozygotic psychobiological models of what Ann Masten has termed twins discordant for trauma exposure (207) found evi- the "ordinary magic" of resilience processes (219). Such Am J Psychiatry 161:2, February 2004 DENNIS S. CHARNEY
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A Natural Approach to Menopause Every day, in hundreds of doctors' offices, the same Study (HERS) confirmed that hormones did not reduce the conversation takes place between women going through risk of heart problems in postmenopausal women with heart menopause and their doctors. The doctor writes out disease. In fact, their risk of blood clots doubled and their need

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