Structural plasticity of the adult brain: how animal models help us understand brain changes in depression and systemic disorders related to depression.

The brain interprets experiences and translates them into behavioral and physiological responses. Stressful events are those which are threatening or, at the very least, unexpected and surprising, and the physiological and behavioral responses are intended to promote adaptation via a process called "allostasis. " Chemical mediators of allostasis include cortisol and adrenalin from the adrenal glands, other hormones, and neurotransmitters, the parasympathetic and sympathetic nervous systems, and cytokines and chemokines from the immune system. Two brain structures, the amygdala and hippocampus, play key roles in interpreting what is stressful and determining appropriate responses. The hippocampus, a key structure for memories of events and contexts, expresses receptors that enable it to respond to glucocorticoid hormones in the blood, it undergoes atrophy in a number of psychiatric disorders; it also responds to stressors with changes in excitability, decreased dendritic branching, and reduction in number of neurons in the dentate gyrus. The amygdala, which is important for "emotional memories, " becomes hyperactive in posttraumatic stress disorder and depressive illness, in animal models of stress, there is evidence for growth and hypertrophy of nerve cells in the amygdala. Changes in the brain after acute and chronic stressors mirror the pattern seen in the metabolic, cardiovascular, and immune systems, that is, short-term adaptation (allostasis) followed by long-term damage (allostatic load), eg, atherosclerosis, fat deposition obesity, bone demineralization, and impaired immune function. Allostatic load of this kind is seen in major depressive illness and may also be expressed in other chronic anxiety and mood disorders.

When we experience a stressful event, the initial response of the brain, body, and behavior is a protective one, and hormones, cytokines, and other mediators, such as the neurotransmitters, are used to survive and adapt to the challenge. However, repeated stressful experiences have deleterious effects, in part because the very same mechanisms that help protect in the short term are now either mismanaged and/or overused.[1] And, over weeks, months, and years, the dysregulation and overactivity of these systems can promote changes that appear to be deleterious, and stressful experiences have been reported to be a major risk factor in the occurrence of depressive disorders. For example, in the brain, the overactivity of stress hormones in the blood and endogenous excitatory amino acid neurotransmitters in the brain suppress neurogenesis in dentate gyrus (DG) and causes debranching of dendrites in hippocampus and medial prefrontal cortex, whereas chronic stress causes neurons in amygdala to show dendritic growth.[2-5] The hippocampus contains receptors for adrenal steroids, which regulate excitability and morphological changes ( Along with many other brain regions, the amygdala also contains adrenal steroid receptors, which influence function in this structure as well (Table I).

Acute stress induces formation of spine synapses in CA1 region of hippocampus[6] and chronic stress also increases spine synapse formation in hippocampus and amygdala.[7] The contrasting changes of dendrites in amygdala and hippocampus after chronic restraint stress (CRS) offers an unprecedented opportunity for understanding underlying mechanisms, as will be discussed below.

CRS for 21 days or longer impairs hippocampal-dependent cognitive function[8,9] and enhances amygdala -dependent unlearned fear and fear conditioning,[10] which are consistent with the opposite effects of stress on hippocampal and amygdala structure. CRS also increases aggression between animals living in the same cage (Table II).[ Psychosocial stress suppresses neurogenesis and causes dendritic shrinkage,[12-15] and one of these stress models, the tree shrew, is considered to be a model of human depressive illness.[16]

Indeed, in major depression and a number of other mood and anxiety disorders, there are reports of hippocampal volume loss and enlargement of the amygdala.[17,18] Studies in the tree shrew have shown that treatment with anti-depressant, antiseizure, and mood-stabilizing drugs prevents stress-induced hippocampal structural changes.[14,15,19]

Besides reduced neurogenesis in DG, there is also evidence for reduced size of principal neuron cell bodies in hippocampus, which is consistent with reduced size of the dendritic tree.[20] Synaptic reorganization is also a likely consequence of these rather drastic structural changes, and the animal models cited above provide evidence that synapses can be rapidly formed as a result of stress. Taken together, such structural changes seem likely to play a major role in the volume loss in the human hippocampus and the related effects on cognitive function and affect.[18]

This article will review underlying mechanisms and consider their applicability to furthering our understanding of the pathophysiology of mood and anxiety disorders.

Allostasis and mechanisms for behavioral adaptation

The amygdala and hippocampus are both involved in contextual fear conditioning and in passive avoidance learning. In fear conditioning, glucocorticoids enhance learned fear[21] and they play an important role in forming the memory of context in contextual fear conditioning, but not of the actual effect of footshock in rats that are already familiar with the context where the shock is administered.[22,23]

This suggests that the hippocampal role in contextual fear conditioning is enhanced by moderate levels of glucocorticoids, but the fear conditioning is either not so dependent on glucocorticoids or is so strong that glucocorticoid influences are hard to demonstrate. Yet there is evidence for an influence of glucocorticoids on the flow of information within the amygdala.

Glucocorticoids potentiate serotonin inhibition of the processing of excitatory input to the lateral amygdala from the thalamus, suggesting that there is a mechanism for containing, or limiting, the sensory input that is important for fear conditioning.[24] Thus, adrenal steroids may regulate the nature of the signals that reach the amygdala and allow for greater discrimination of the most salient cues for learning. Moreover, in passive avoidance, both catecholamines and glucocorticoids play a role in facilitating learning.[25,26]

Catecholamines work outside of the blood–brain barrier and their effects can be blocked by β-adrencrgic–blocking agents, which do not cross the blood–brain barrier.[26] Glucocorticoids enter the brain, and local implants of exogenous corticosterone into hippocampus, amygdala, and nucleus tractus solitarii arc all able to enhance passive avoidance learning.[25]

Adrenal steroids also play a supporting role in the learning of a spatial navigation task in mice.[27] Adrenalectomy impairs the acquisition of the memory of hidden platform location in the Morris water maze, and glucocorticoid administration restores the normal learning curve; however, in mice in which the glucocorticoid receptor (GR) is deleted and replaced with a GR that lacks the UNA binding domain, glucocorticoids do not improve task acquisition.[27] This finding illustrates a role for GRs acting upon the genome in a task that is known to depend on the hippocampus. Interestingly, other actions of glucocorticoids via GRs are known to involve the protein–protein interactions that are not prevented in mice carrying the GR defective in the DNA binding domain.[28]

Other evidence for glucocorticoid actions supports an inverted U-shaped dose–response curve in which low to moderate levels of adrenal steroids enhance acquisition of tasks that involve the hippocampus, whereas high levels of glucocorticoids disrupt task acquisition.[22,29-31] Adrenal steroids have biphasic effects upon excitability of hippocampal neurons, which may underlie their biphasic actions on memory and recall.[30,32,34]

Adaptive structural plasticity

One of the ways that stress hormones modulate function within the brain is by changing the structure of neurons. Within the hippocampus, the input from the entorhinal cortex to the DG is ramified by the connections between the DG and the CA3 pyramidal neurons. One granule neuron innervates, on average, 12 CA3 neurons; and each CA3 neuron innervates, on the average, 50 other CA3 neurons via axon collaterals, as well as 25 inhibitory cells via other axon collaterals ( The net result is a 600-fold amplification of excitation as well as a 300-fold amplification of inhibition, which provide some degree of control of the system. As to why this system exists, the DG-CA3 system is believed to play a role in the memory of sequences of events, although long-term storage of memory occurs in other brain regions.[36,37]

Neurogenesis in the DG

There is structural plasticity within the DG-CA3 system, in that new neurons continue to be produced in the DG throughout adult life[38] and CA3 pyramidal cells undergo remodeling of their dendrites,[2] as will be discussed further below.[39]

The subgranular layer of the DG contains cells that have properties of astrocytes (eg, expression of glial fibrillary acidic protein) and give rise to granule neurons.[40] After administration of bromodcoxyuridine (BrdU) to label DNA of dividing cells, these newly born cells appear as clusters in the inner part of the granule cell layer, where a substantial number of them will go on to differentiate into granule neurons within as little as 7 days. The new granule neurons appear to be quite excitable and capable of participating in long-term potentiation. In the adult rat, 9000 new neurons are born per day and survive with a half-life of 28 days.[41]

There are many hormonal and neurochemical modulators of neurogenesis and cell survival in the DG.[15,38,42-44]

Neurogenesis in the adult DG is enhanced by the hormone insulin-like growth factor–1 (IGF-1) and by serotonin and a number of antidepressant drugs. Estradiol accelerates cell proliferation in female rats. IGF-1 is the mediator of the ability of exercise to increase cell proliferation in the DG. Lack of IGF-1 and insulin in diabetes has the opposite effect and decreases cell proliferation. Neurogenesis and/or survival of newly born cells is increased by putting mice in a complex (”enriched“) environment.[45] It is also increased by a form of classical conditioning that activates the hippocampus (”trace conditioning“) prolongs the survival of newly born DG neurons.[46,47] On the other hand, certain types of acute stress and many chronic stressors suppress neurogenesis or cell survival in the DG, and the mediators of these inhibitor effects include excitatory amino acids acting via N-methyl-D-aspartate (NMDA) receptors and endogenous opioids.[2,48-50] Chronic stress has even more potent effects on neurogenesis and neuronal survival. CRS for 21 days suppressed neurogenesis and CRS for 42 days causes the number of DG neurons to decrease along with total DG volume (

A single restraint stress does not suppress cell proliferation. Repeated restraint stress for 21 days suppresses cell proliferation. Repeated restraint stress for 42 days reduces volume of the dentate gyrus (DG) and the number of neurons in the DG.

Reproduced from reference 51 with permission: Pham K, Nacher J, Hof PR, McEwen BS. Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur J Neurosci. 2003;17:879-886. Copyright © 2003, Biackwell Publishing, Inc.

Remodeling of dendrites

Another form of structural plasticity is the remodeling of dendrites in the hippocampus.[39] CRS causes retraction and simplification of dendrites in the CA3 region of the hippocampus ( [2] Such dendritic reorganization can also be seen in rats undergoing adaptation of psychosocial stress in the visible burrow system (VBS).The VBS is an apparatus with an open chamber where there is a food and water supply and several tunnels and chambers.[52] Rats can be observed from above by a video camera in this apparatus. In the VBS, male rats housed with several females establish a dominance hierarchy within several days. Over the course of the next week, a few subordinate males may die and others (showing scars from bite marks) will show enlarged adrenals, low testosterone, and many changes in brain chemistry. The dominant shows the fewest scars and has the highest level of testosterone, but also has somewhat larger adrenal glands than cage control rats.

Regarding changes in brain structure, it was the dominant rats that had a more extensive pattern of debranching of the apical dendrites of the CA3 pyramidal neurons in the hippocampus, compared with the subordinate rats, which showed reduced branching compared with the cage controls.[53] What this result emphasizes is that it is not adrenal size or presumed amount of physiological stress per se that determines dendritic remodeling, but a complex set of other factors that modulate neuronal structure. We refer to the phenomenon as “dendritic remodeling” and we generally find that it is a reversible process. In hibernating hamsters, it occurs in a matter of hours and reverses itself just as quickly when hibernating animals are aroused from torpor (A. M. Magarinos, B. S. McEwen, R Pevet, unpublished data). Below we consider mechanisms involved in structural remodeling.

The role of adrenal steroids in the structural remodeling described above reflects may interactions with neurochemical systems in the hippocampus, including serotonin, γ-aminobutyric acid (GABA), and excitatory amino acids ( [2] Probably the most important interactions are those with excitatory amino acids such as glutamate. Excitatory amino acids released by the mossy fiber pathway play a key role in the remodeling of the CA3 region of the hippocampus, and regulation of glutamate release by adrenal steroids may play an important role.[54-57] We have found that the glutamate transporter, Glt-1, is elevated by CRS in hippocampus, particularly in the CA3 region, providing another indication that elevated glutamate levels arc an important component of structural plasticity. We previously showed that NMDA receptor blockade and the Na/Ca channel blocker, phenytoin, both block CRS- and glucocorticoid-induced remodeling of dendrites in CA3.[58-60] Recent evidence indicates that presynaptic receptors containing kainate receptor subunits such as GluR6 are important for the feed-forward actions of glutamate on mossy fiber terminals,[61] and one study showed that a number of kainate receptor subunit mRNAs are regulated biphasically by adrenal steroids.[57] In particular, preferential mineralocorticoid receptor (MR) occupancy by low corticosterone (CORT) levels enhanced mRNA levels for KAR2, GluR6, and GluR7.[57] This agrees with our finding that MR activation by aldosterone in adrenalectomized (ADX) rats restored levels of [3H]kainate binding in the mossy fiber region of CA3.[56] However, further studies are needed.

Because excitatory amino acids play a key role along with circulating glucocorticoids, the activation of the CREB (cyclic adenosine monophosphate response element–binding protein) system is a likely candidate mediator, and recent evidence indicates that phosphorylation of CREB is chronically activated in rats subjected to CRS. CREB has been linked to regulation of synaptic plasticity and particularly neurogenesis.[62] It is possible that CREB is involved in activity-dependent synapse formation, which is evident as a result of long-term potentiation.[63,64]

However, the role of glucocorticoids in activation of the CREB system has not been thoroughly investigated. Nevertheless, treatment with the mood stabilizer lithium prevented CRS-induced structural remodeling of the stress-induced elevation of Glt-1 and CREB phosphorylation (G. E. Wood, L. T. Young, B. S. McEwen, unpublished data), providing further evidence that CRS-induced structural plasticity and the molecular markers Glt-1 and phosphoCREB arc useful in study of psychiatric illnesses. Structural changes in dendrites and spine synapses are the result of modifications in the microtubule system of the cytoskeleton,[65] and new evidence shows that posttranslational modification of tubulin[65] and phosphorylation of the microtubule associated protein tau[66] take place along with changes in the actin cytoskeleton,[67] under conditions in which reorganization of dendrites and synaptic connections occur. Overall, cytoskeletal changes, such as increased paired-helical-like phosphorylation of tau[66] and reduced tyrosinated tubulin,[65] are consistent with increased cytoskeletal rigidity. However, this needs much careful study.

The Rac/Rho guanosine triphosphatases (GTPases) and related proteins such as the guanosine triphosphate (GTP) exchange factor, kalirin, have been shown to play a key regulatory role in cytoskeletal modifications in developing and adult neurons.[67,68] Except for one relevant study on seizures,[65] there are no studies thus far of the effects of chronic stress on these pathways or of the modifications of the cytoskeleton itself.

Besides glucocorticoids and excitatory amino acids, neurotrophins and gp130 cytokines are implicated in structural plasticity along with extracellular proteases such as tissue plasminogen activator (tPA) and neuropsin. Brainderived neurotrophic factor (BDNF) plays a major role in activity-dependent synaptic and dendritic remodeling,[69-73] and is implicated in hippocampal-dependent memory formation.[74] BDNF also regulates tPA release from neurons[75] and tPA is released from nerve terminals in hippocampus and other brain areas such as amygdala.[76-78] It has been suggested that tPA may play a role in the processing of proBDNF into active forms.[79] The activity of tPA is associated with structural plasticity and increased fear,[77] motor learning,[80] and enhancement of long-term potentiation.[81] Activity of tPA is an important mediator of structural plasticity and enhanced fear in the amygdala resulting from acute restraint stress. For example, plasminogen (inactive zymogen) leads to plasmin (active serine protease). Using tPA knockout mice, we have found that in medial and central amygdala[77]:

tPA is released under stress and initiates neural remodeling.

This release is plasminogen-independent (extracellular signal–regulated kinase [ERK1/2]; guanosine triphosphate–activating protein [GAP-43]).

tPA induces termination of its own action via plasminogen-activator inhibitor–1 (PAI-1).

tPA activity is required for increased anxiety in the elevated plus maze.

We are presently studying the long-term effects of stress. Neuropsin is another protease that is induced in hippocampus by NMDA-mediated excitation in seizures and leads to proteolysis of the presynaptic adhesion molecule, L1.[82]

The gp130 cytokines are expressed in hippocampus under stimulation by seizures, along with their receptors, which are constitutive]}' expressed.[83] Leukemia inhibitor}' factor (LIF) is particularly interesting because it interferes with neurotrophin signaling[84] and causes dendritic retraction in cell culture.[85] However, it has not yet been determined whether acute or chronic stress increases LIF expression, and it is conceivable that increased expression of LIF might play a role in dendritic shortening.

The ability of neuronal processes to expand or contract, and newly formed neurons to make connections, is dependent on the extracellular environment in which polysialated neural cell adhesion molecule (PSA-NCAM) plays an important role.[86] PSA-NCAM is associated with regions of the brain that show structural plasticity such as the inner granule cell layer of the DG and the mossy fiber terminals of CA3.[87] CRS for 21 days causes increased PSA-NCAM. expression in the DG proliferative zone even though cell proliferation is suppressed, and these changes have disappeared after CRS for 42 days.[51] This raised questions about the role of PSA-NCAM in adaptive structural plasticity, which need to be investigated. Removal of the PSA residue by endoneuraminidase (EndoN)[88] is a powerful tool for manipulating this system, since PSA removal abolishes plasticity of suprachiasmatic neurons to environmentally induced phase shifting of the diurnal rhythm.[89]

We now turn to the important question of whether chronic stress increases or decreases vulnerability of the hippocampus to damage from other insults.

Permanent damage as a result of stress

The remodeling of the hippocampus in response to stress is largely reversible if the CRS is terminated at the end of 3 weeks.[10] After 3 weeks of CRS, neurogenesis is reduced in DG and dendrites are shorter and less branched,[51,59,60] and there is an increase in PSA-NCAM expression in the DG that is consistent with increased mobility of neuronal processes even in the face of reduced DG neuron production. Continuation of CRS for a total of 6 weeks abolishes the upregulation of PSA-NCAM and results in a significant 6% reduction in DG volume and 13% reduction in granule neuron number.[51] We do not yet know whether structural changes occurring after 6 weeks of CRS are reversible or whether they can be accelerated by antidepressant or antiepilcptic drugs that block the effects of stress and glucocorticoids on remodeling. Nor do we know whether the structural changes occurring with CRS increase or decrease the vulnerability of the hippocampus to damage by excitotoxicity.

It is well established that glucocorticoids exacerbate damage to the hippocampus caused by ischemia[90] and seizures.[91,92] Glucocorticoids exacerbate excitotoxic damage and do so, at least in part, by facilitating trafficking of immune cells to the injury site,[93] and, there, cytotoxic T cells are able to produce cytotoxic death of neurons.[94] However, the phenomenon of ischemic preconditioning[95] reveals that prior stimulation of the hippocampus can induce a protective mechanism that may reduce the damage produced by a full-scale ischemic event. It is not clear whether the same mechanisms might be operative when stress is applied and whether they might affect the response to excitotoxicity in response to seizures, but this possibility needs to be kept in mind if it turns out that prior CRS has a protective effect on subsequent responses to excitotoxic challenge.

Protective agents may also involve substances that are upregulated in the brain in response to damage or threat of damage. One of the prominent features of excitotoxic damage or removal of adrenal steroids is the robust induction of calcitonin gene–related peptide (CGRP) in terminals and cell bodies in hippocampus and in mossy cells. The increased expression of CGRP in mossy cells is especially prominent after bilateral ADX under conditions in which there is apoptosis of granule cells, and the CGRP immunoreactivity is enhanced within the inner third of the molecular layer of the DG. The neuroimmune peptide, CGRP, is one of the most diverse and influential immunoregulators of the periphery. This important neuropeptide has multiple functions including: its actions as a potent vasodilator[96] and an immune modulator,[97 -102] as well as a neural and immune developmental regulator, a modulator of hormone release involved in growth and development, and a stimulator of sympathetic outflow, which is mediated by CRF and an inducer of apoptosis (reviewed in reference 103). Some of the different functional roles for CGRP may not be independent, but may be part of a cascade of events that constitute the healing response to injury. A number of studies have shown that CGRP is expressed following various kinds of trauma and plays an important role in the acute phase response that may be of particular relevance to the outcome of the regional injury response in the central nervous system (CNS).[103,104]

In recent studies, the expression of CGRP within the hippocampus increases in four separate models of CNS injury: ADX,[105] intrahippocampal colchicine injection,[105] trimethyltin ingestion,[106] and kainic acid injections. In each case, the expression of this peptide was limited to the specific region of damage and in association with the surviving neuronal population. Although the upregulation of CGRP may be associated with neuronal cell survival,[107] other studies have shown that both microglia and astrocytes express CGRP receptors and that exposure to physiological levels of CGRP induces c-fos in microglia and astrocytes and increases plasminogen activators.[108]

The role of CGRP may then not only protect against immune system damage to neurons, but may also participate in plasticity and healing.

Protective and damaging effects of the mediators of adaptation

Individual differences in the progression of a number of disorders that accumulate with time can be conceptualized as an accumulation of wear and tear of daily experiences, lifestyle, and major life stressors, which interact with the genetic constitution and predisposing early life experiences.[109-111] 'Ihc neuroendocrine system, autonomic nervous system, and immune system are mediators of adaptation to the challenges of daily life, referred to as “allostasis,” meaning “maintaining stability through change.”[112] Physiological mediators, such as adrenalin from the adrenal medulla, glucocorticoids from the adrenal cortex, and cytokines from cells of the immune system, act upon receptors in various tissues and organs to produce effects that are adaptive in the short term, but can be damaging if the mediators are not shut off when no longer needed. When release of the mediators is not efficiently terminated, their effects on target cells are prolonged, leading to other consequences that may include receptor desensitization and tissue damage. This process has been named “allostatic load,”[113]-[114] which refers to the price the tissue or organ pays for an overactive or inefficiently managed allostatic response. Therefore, allostatic load refers to the “cost” of adaptation.

The brain is the master controller of the three systems noted above and is also a target of these systems, subject to both protection and damage. Allostasis also applies not only to circulating hormones, but also to organs and tissues of the body. In the nervous system, neurotransmitters are released by neuronal activity, and they produce effects locally to cither propagate or inhibit further neural activity. Neurotransmitters and hormones are usually released during a discrete period of activation and then are shut off, and the mediators themselves are removed from the intracellular space by reuptake or metabolism in order not to prolong their effects. When that does not happen, however, there is allostatic load and the brain is at increased risk for damage.[115,116]

The processes of allostasis and allostatic load have been described and measured for metabolic and cardiovascular changes that are associated with obesity, type 2 diabetes, and cardiovascular disease.[117] However, the same type of elevated and prolonged secretion of glucocorticoids during aging has also been associated with impairment of cognitive function in rodents[118-120] and humans.[121-123] Moreover, the endogenous excitatory amino acid neurotransmitters appear to play a major role in these changes,[119] even though they are also an essential part of normal synaptic neurotransmission and plasticity.

Allostatic states in depressive illness

Stress hormones are elevated in major depressive illness. In particular the diurnal rhythm is distorted.[124] Normally low evening levels of Cortisol are increased in a subset of depressed patients[125,126] and the stress hormone axis in major depression is resistant to suppression by the synthetic glucocorticoid dexamethasone.[127] It is also noteworthy that androgen levels are elevated in women with major depression, which undoubtedly reflects adrenal hyperactivity.[128] IGF-1 levels are also reported to be elevated in major depression, and this may reflect elevated growth hormone release as a result of the hypercortisolemia.[129]

Each of these patterns of elevation constitutes an “allostatic state,” and represents a pathway for the development of allostatic load in the brain and in other organs throughout the body. Regarding the brain, we already noted the studies showing that hippocampal volume loss in major depressive illness is related to duration of the depression rather than to age per se of the patients.[130-132] Not all studies report such changes (see, for example, references 133 and 134); the reasons for these different results are beyond the scope of this discussion, but they may be explained by differences in the duration of depression, as well as gender and age. It should be noted that hippocampal size in elderly twins shows only 40% genetic contribution, with the predominant influence being environmental.[135] This emphasizes the importance of experimental factors and allostatic load in determining hippocampal volume.

Hippocampal atrophy has been found in relation to depression in the elderly,[136] with an association detected with presence of the ApoE4 genotype.[137] In subjects with a long-term history of depression, Sheline and colleagues described magnetic resonance imaging (MRI) evidence for discontinuities that might represent sites of damage.[130]

Although some recent postmortem studies on brains from depressed individuals did not show neuron loss in hippocampus,[138,139] the duration of the depression and the subtype of depression were not carefully controlled. Thus, the possibility that neural damage may ultimately occur in major depression cannot be disregarded, particularly when depression lasts a long time. However, in a recent study in young depressed subjects, hippocampal volume was not smaller in first-episode depression, but declined rapidly over several years.[140] 'Ihc key, unanswered question is whether such changes can be prevented or even reversed. It is important to note that other brain regions besides hippocampus are affected in depressive illness and undergo structural changes. One region is the prefrontal cortex, and structural imaging[141] showed loss of volume in familial pure depressive disorder, whereas autopsy studies[142-144] have shown loss of volume and glial cells, as well as neuronal density in both unipolar and bipolar disorder. There is one animal study showing that chronic glucocorticoid treatment induces loss of dendrites in the rat prefrontal cortex.[4] However, much more work needs to be done on this brain region.

Depressive illness is associated with a hyperactivation of the amygdala,[145,146] and more recently, with an actual enlargement of the amygdala in the first episode of major depression.[147] This is reminiscent of the increased dendritic branching reported in rats after repeated immoblization stress (see above and reference 148). Since the amygdala integrates information related to fear and strong emotions, and also sends outputs via the central nucleus for autonomic arousal and via the basal nucleus for more active aspects of coping,[149] the elevation of amygdala activity may be a first step that leads to overactivation of systems involved in physiological and behavioral coping.

The long-term consequences of this may well be a wear and tear on the body that results in a number of pathophysiological consequences, since the amygdala regulates both autonomic nervous system activity and adrenocorticotropic hormone (ACTH) and Cortisol production through outputs of its central nucleus.[149,150] It is important to note that there are reports that in recurrent major depression of long duration the amygdala may undergo shrinkage.[131,151]

It is thus possible that initial hypertrophy gives way to atrophy in this important brain structure. Besides the brain changes in major depression, there are other changes in the body that reflect dysregulatcd hypothalamopituitary axis (HPA) and autonomic activity, and are slow in developing. These constitute allostatic load that produces cumulative pathophysiology, which may also be reversible if caught in time. Such cumulative, long-term effects include bone mineral loss[152-154] and abdominal fat deposition.[155-157] Moreover, the combination of long-term allostatic load, together with dysregulation of the autonomic nervous system in major depression,[158] is associated with increased blood platelet reactivity[159-161] and increased risk for cardiovascular disease.[162-165]

There are parallels between the story for major depression and what is known about psychiatric and somatic features of Cushing’s disease involving melancholia, depression, abdominal obesity, bone mineral loss, and increased risk for cardiovascular disease.[166-169] In addition, there is evidence for hippocampal atrophy in Cushing’s disease along with memory impairments.[170-172] Interestingly, hippocampal volume loss in Cushing's disease is at least partially reversible over several years after correction of the hypercortisolemia.[173-175]

Finally, a largely unexplored area concerns the effects of antidepressant medication on the brain and body changes associated with depressive illness. On the one hand, certain antidepressants may contribute to some of the associated pathophysiology, such as cardiovascular instability.[176] On the other hand, withdrawal from antidpressant treatment may cause imbalances in neurotransmitter systems, with elevations of excitatory amino acid tone,[177] and contribute to the allostatic load that occurs as the depressive state continues.[178]

Conclusion

Translational studies of brain changes in major psychiatric illnesses such as unipolar and bipolar depression and posttraumatic stress disorder are showing that changes in volume of structures such as hippocampus, prefrontal cortex, and amygdala must be considered as part of the neurobiological consequences of these illnesses.[17,18,140,179,180]

Structural remodeling in these brain regions is important for human psychiatric disorders because the altered circuitry is likely to contribute to impaired cognitive function and affect regulation. Moreover, stress is widely acknowledged as a predisposing and precipitating factor in psychiatric illness.[181,182]

Thus, animal models are relevant to human psychiatric disorders in at least four ways:

First, they have led to―and continue to contribute―basic knowledge to the ongoing studies of how the human brain changes structurally in depression and related psychiatric disorders.

Second, the structural changes that occur with chronic stress appear to be reversible as long as the stress is terminated in time. This suggests the hopeful possibility that brain changes in at least some major psychiatricdisorders may be treatable if we can find the right agents or therapies and intervene in time.

Third, reversible or not, the effects of chronic stress may predispose to greater vulnerability to adverse consequences from other insults.

Fourth, the systemic manifestations of the allostatic load generated by chronic psychiatric disorders affects the metabolic, immune, and cardiovascular systems, leading to systemic disorders that add to the costs of healthcare.

Table I.

Distribution of adrenal steroid receptors in brain regions. GR, glucocorticoid receptor; MR, mineralocorticoid receptor.

Hippocampus	MR and GR
Amygdala	GR and some MR
Septum	GR and some MR
Hypothatamus	GR mostly; low levels of MR
Cerebral cortex	GR mostly; low levels of MR
Midbrain	GR mostly; low levels of MR
Brain stem	GR mostly; patches of MR
Cerebellum	GR mostly

Table II.

Cumulative effects of restraint stress on behavior.

• Cognitive impairment, spatial recognition memory (hippocampus)

• Increased anxiety and enhanced fear conditioning (amygdala)

• Increased aggression (amygdala)