ISRN PhysiologyVolume 2013 (2013), Article ID 806104, 23 pageshttp://dx.doi.org/10.1155/2013/806104

Review Article

Brain Physiology and Pathophysiology in Mental Stress

Karim Alkadhi

Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA

Received 23 April 2013; Accepted 15 May 2013

Academic Editors: J. Cannon, Y. Ootsuka, and K. Sakuma

Copyright © 2013 Karim Alkadhi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Exposure to various forms of stress is a common daily occurrence in the lives of most individuals, with both positive and negative effects on brain function. The impact of stress is strongly influenced by the type and duration of the stressor. In its acute form, stress may be a necessary adaptive mechanism for survival and with only transient changes within the brain. However, severe and/or prolonged stress causes overactivation and dysregulation of the hypothalamic pituitary adrenal (HPA) axis thus inflicting detrimental changes in the brain structure and function. Therefore, chronic stress is often considered a negative modulator of the cognitive functions including the learning and memory processes. Exposure to long-lasting stress diminishes health and increases vulnerability to mental disorders. In addition, stress exacerbates functional changes associated with various brain disorders including Alzheimer’s disease and Parkinson’s disease. The primary purpose of this paper is to provide an overview for neuroscientists who are seeking a concise account of the effects of stress on learning and memory and associated signal transduction mechanisms. This review discusses chronic mental stress and its detrimental effects on various aspects of brain functions including learning and memory, synaptic plasticity, and cognition-related signaling enabled via key signal transduction molecules.

1. Introduction

Although stress is a necessary mechanism for survival, severe and/or long-term stress disrupts normal brain structure and function [1–4]. Mental stress, which may range in intensity from mild to severe posttraumatic stress disorder (PTSD), has been reported to impair memory [5–15] possibly by elevating excitatory amino acid and glucocorticoid levels, which in turn induce excitotoxicity and hippocampal atrophy [16].

The endocrinologist, Selye [17], defined “stress” as “the non-specific response of the body to any demand placed on it.” The body’s principal physiological responses to stressful stimuli are mediated by the sympathoadrenal system and the hypothalamic pituitary adrenocortical (HPA) axis, which are, in turn, mediated by the hippocampus [18–21]. Stress stimulates the release of corticotropin-releasing factor (CRF), from the hypothalamic paraventricular nucleus (PVN), into the hypophysial-portal circulation, where it induces the release of adrenocorticotropin hormone (ACTH) from the anterior pituitary and glucocorticoids (cortisol in humans; corticosterone in rodents) from the adrenal glands [22].

The magnitude of the HPA stress response elicited by PVN neurons is limited by neuronal and hormonal mechanisms, which work together to maintain glucocorticoid levels within tolerable limits [23]. Three feedback loops prevent overshooting of the HPA axis: (a) the negative feedback of glucocorticoids to the anterior pituitary, hypothalamus, and hippocampus, (b) the ACTH feedback to the hypothalamus, and (c) the direct feedback of CRF to the hypothalamus.

Mental stress impairs cognitive function in animals and humans [6, 15, 24–32]. It is postulated that mental stress impairs learning and memory through the high adrenal glucocorticoid output known to occur during stressful episodes [33–35]. In humans and animals, the effects of glucocorticoids on memory are dose dependent [11, 36, 37] and determined by the binding of corticosteroids to two receptors in the brain: the type-1, high affinity, mineralocorticoid receptor and type-2, glucocorticoid receptor [38–40]. The mineralocorticoid receptors are mostly restricted to the hippocampus, but the glucocorticoid receptors are ubiquitously expressed in the brain, with high densities in the hippocampus, amygdala, and prefrontal cortex, where they mediate the feedback action of glucocorticoids on stress-activated brain processes [41, 42]. Whereas mineralocorticoid receptors play an important role in the feedback control of the HPA axis, promoting maintenance of basal HPA activity, glucocorticoid receptors directly or indirectly regulate genes controlling development, metabolism, and immune function [39]. Thus, a balance in the expression of mineralocorticoid receptors and glucocorticoid receptors is necessary for maintaining cellular metabolism and cognitive functions, such as learning and memory [21]. Under normal conditions, selective activation of type-1 receptors by mild or moderate glucocorticoid levels enhances memory and increases long-term potentiation (LTP) [41]. However, during stress, activation of type-2 receptors by high glucocorticoid levels impairs memory [9, 32, 43] and suppresses LTP [24, 25, 28, 31, 32, 44–46].

Chronic stress influences the onset and/or severity of cognitive decline in various disorders [47], including Cushing’s syndrome [48], posttraumatic stress disorder [49], hypothyroidism [28, 45], Alzheimer’s disease [50–52], and depression [16, 53]. The physiological consequences of stress depend on the intensity and duration of the stressor and upon how an organism perceives and reacts to the noxious stimulus [54–56].

While acute stress-induced activation of mineralocorticoid receptors enhances LTP and memory consolidation, chronic stress-induced activation of glucocorticoid receptors inhibits LTP and impairs memory [57, 58]. The distinct responses induced by acute or chronic stress are due to a shift in the balance of mineralocorticoid receptor-glucocorticoid receptor occupation [55, 59]. In general, activation of mineralocorticoid receptors by low levels of corticosteroids produces low amplitude Ca²⁺ currents, which have an excitatory effect on hippocampal CA1 pyramidal cells, whereas activation of glucocorticoid receptors by high levels of corticosteroids enhances Ca²⁺ influx and inhibits CA1 pyramidal cell excitability [59].

The hippocampal formation, an important brain structure in learning and memory, is particularly vulnerable to stress hormones due to its high density of glucocorticoid receptors, in spite of its remarkable plasticity [16, 60]. Stress mediates a variety of effects on neuronal excitability, neurochemistry, and structural plasticity of the hippocampus [16]. For example, excessive glucocorticoids are associated with deleterious changes in hippocampal excitability, LTP, and cognitive abilities [61, 62]. The harmful effects of stress on memory have been confirmed by several studies in rodents and humans. Chronic psychosocial stress has been shown to impair hippocampus-dependent learning and memory in animal models [12, 15, 31, 50, 63, 64] and humans [64]. In addition, electrophysiological studies have shown that stress significantly impairs synaptic plasticity in the CA1 region of the hippocampus in urethane-anesthetized rats [30–32, 50] and in hippocampal slices [26]. Furthermore, other studies have shown that stress facilitates the induction of long-term depression (LTD) [29, 65].

The mechanisms mediating stress-induced impairment of cognition and synaptic plasticity are largely unknown. However, advances in animal and human studies have resulted in the establishment of various hypotheses. Based on studies in adult and older animals and humans, a “glucocorticoid cascade” hypothesis is introduced, which suggests that there is a relationship between cumulative exposures to high glucocorticoid levels and hippocampal atrophy [66]. This is supported by findings of studies in aged rats in which glucocorticoid hypersecretion is correlated with memory impairment and reduced hippocampal volume [67]. Furthermore, middle-aged rats exposed to high levels of glucocorticoids also developed memory impairment and hippocampal atrophy [68]. In an attempt to clarify the mechanism by which glucocorticoid levels correlate with hippocampal atrophy, a “neurotoxicity hypothesis” was developed [69]. This hypothesis suggests that prolonged exposure to glucocorticoids reduces the ability of neurons to resist insults, thus increasing the rate at which they are damaged.

2. The Stress Response

The physiologic response to stress consists of a rapid component and a slower one, acting in a coordinated temporal manner to reestablish homeostasis [70–72]. The rapid response is the activation of the sympathetic nervous system, which increases the levels of circulating norepinephrine and epinephrine and elevates the levels of norepinephrine in the brain. This is referred to as the “sympathetic-adrenomedullary system.” The slower, longer-lasting response is activation of the HPA axis that begins with the release of CRF into the circulation from the paraventricular nucleus of the hypothalamus, which then stimulates the pituitary to release ACTH into the bloodstream. The released ACTH accelerates the discharge of glucocorticoids from the adrenal cortex.

The type-2 glucocorticoid receptors bind glucocorticoids at tenfold lower affinity than type-1 receptors. At the circulating low-basal glucocorticoid levels, type-1 receptors are already activated to a large extent. However, when the circulating glucocorticoid levels are elevated after stressful events, type-2 receptors are also activated. Glucocorticoid receptors are abundant throughout the brain. However, both receptor types are highly expressed in the hippocampus making it a target for stress hormone actions [72]. These nuclear receptors can act as transcription factors by binding to the DNA thus regulating gene expression [56]. In addition, glucocorticoids mobilize peripheral energy stores, diminish the immune response, and mediate the negative feedback control of the HPA axis [73]. Both the HPA axis and sympathetic-adrenomedullary system work in concert to coordinate adaptive responses to stressors. Regulation of the HPA axis occurs through negative feedback mechanisms in which high levels of glucocorticoids suppress the release of CRF.

In addition to glucocorticoids, other mechanisms are associated with the detrimental effects of stress on the hippocampus including excessive release of glutamate and repeated activation of glutamate NMDA receptors [74–77], modified interneuronal GABA inhibitory tone [78], and increased serotonergic tone [79]. Perception of stress also results in activation of preganglionic sympathetic neurons in the spinal cord, which activates neurons of the prevertebral or paravertebral ganglia that, in turn, project to effector organs, including the blood vessels, heart, and glands including the adrenals. The consequent physiological changes include elevations in epinephrine and norepinephrine levels, peripheral vasoconstriction, increase in heart rate and vagal withdrawal, and increased energy mobilization [80].

3. Animal Models of Stress

Two major classes of experimental stressors have been in use to produce stress in animals. Various animal models have been used to study the two types of stress, physical and psychological, and their effects on brain functions, including learning and memory, have been discussed previously [81–83]. Animal models for physical stress including cold or hot environment, foot shock, noise, body vibration, exposure to high-altitude and immobilization stress are used to simulate physical stressors that are commonly faced by humans such as exposure to hot or cold environment [84–87]. Psychosocial stress models include social isolation by withdrawing the animal from a group housing, intruder aggression, which involves attack within unfamiliar territory by a dominant male, or disruption of social hierarchy by introducing new comers to a socially stable group. Other psychosocial models include maternal deprivation by separation of preweanling pups from their mother and exposure to predator where the subjects (rats or mice) are exposed to the sight and smell of a natural predator [12, 88–93]. Both physical and psychological stresses may be used to induce acute or chronic stress. Due to the social nature of psychosocial stress, the procedures are considered more naturalistic and species-typical than the artificial noxious stimulus procedures associated with physical stress models [86].

4. Effect of Stress on Structure and Function of the Brain

Stress has profound effects on the structure and function of the brain at the cellular and subcellular levels. The impact of stress on brain structure and function is influenced by a variety of factors including the duration and type of the stressor as well as age and sex of the animal [94–99]. The major areas of the brain most affected by stress are the hippocampus, prefrontal cortex, and amygdala, probably because these areas contain abundant glucocorticoid receptors. Additionally, neurons in these regions are known to be highly plastic, both functionally and structurally, in response to repetitive activation [100, 101]. Hence, neurons in the hippocampus, prefrontal cortex, and amygdala are highly sensitive to stressful stimuli, resulting in significant changes in their structure and function even at the molecular level [102, 103].

Most of the stress-induced structural changes involve the neuronal dendrites and synaptic spines. The stress-induced structural modification of dendrites and synaptic spines in neurons of certain regions of the brain may include cytoskeletal alteration involving actin filaments and microtubules [104–106]. Synaptic spines are specialized protrusions arising mostly from dendrite and are sites of synaptic connections. The number of synaptic spines reflects the extent of connectivity among neurons and may determine the amount of neurotransmitters released during activity in a particular brain region. With activity, branching of dendrites can proliferate and their spines increase in number, enlarge, and change shape forming strong synapses with larger postsynaptic densities indicating more receptor insertion [107]. Additionally, the presynaptic nerve terminals may change shape and increase in size. These changes can occur very quickly (in seconds); thus, dendrites and spines are vital agents for effecting immediate and long-term functional synaptic plasticity [77, 105, 108, 109].

Stress induces similar changes in structure and function of neurons in the hippocampus and prefrontal region but affects neurons of the amygdala differently. Even different areas in the hippocampus (e.g., area CA1 and dentate gyrus) may respond to stress differently [27, 45, 110–112]. The following is a brief discussion of the effect of stress on structural and functional synaptic plasticity in each of the three regions of the brain but with particular emphasis on the hippocampus. It is important to note that acute stress may have different effects on neuronal structures than chronic stress. In fact, chronic stress starts initially as acute stress, but then it is repeated for a long periods of time. This allows the system response to change significantly and, in some cases, even disappear [77].

4.1. Structure and Function of the Hippocampus during Stress

Chronic stress in experimental animals reversibly reduces branching of neurons, decreases densities of dendrites, and affects growth and shape of synaptic spines in neurons of various hippocampal regions [1, 74, 97, 110–119]. Similar structural changes have been reported in CA3 area of brains of humans who experience intense psychosocial stress [120].

Chronic psychosocial stress applied daily for 4–6 weeks in rats impairs spatial short-term memory but has no significant effect on learning or long-term memory [28, 31, 50, 121–123]. However, longer periods of psychosocial stress (>12 weeks) seem to adversely affect short-term as well as long-term memory [124, 125]. In correlation with memory impairment, chronic (4–6 weeks) psychosocial stress caused significant suppression of stimulation-evoked early phase long-term potentiation (E-LTP) of hippocampal area CA1, a cellular correlate of short-term memory [5, 15, 24, 31, 45, 50, 122, 125]. In contrast, the late phase LTP (L-LTP), which is believed to be the cellular correlate of long-term memory, was not significantly affected by chronic stress [126]. However, chronic stress facilitated the induction and markedly enhanced the magnitude of long-term depression (LTD) in area CA1 [29, 65, 122, 126–129]. Chronic stress, however, did not affect basal synaptic transmission of area CA1 as indicated by analysis of input/output (I/O) curves [29].

Investigation of the effect of chronic stress at the subcellular level has been accomplished by analyzing the molecular cascade involved in the expression of memory and synaptic plasticity. Chronic psychosocial stress severely diminished the basal levels of calcium calmodulin kinase II (CaMKII), which is the principal protein kinase essential for LTP maintenance [130]. Both total CaMKII and phosphorylated- (P-) CaMKII levels were decreased in the CA1 region of the hippocampus of chronically stressed rats. The finding that P-CaMKII/CaMKII ratio in CA1 of chronically stressed rats was not changed suggested that the major cause of the decrease in P-CaMKII level might be an overall decrease in the total CaMKII protein levels. Alternatively, the decrease in basal levels of P-CaMKII in stressed rats could have resulted from a decrease of calmodulin level, a decrease of protein kinase-C (PKC) level, and/or an increase in the levels of calcineurin, a phosphatase essential for deactivation (dephosphorylation) of CaMKII [15, 31, 50]. These effects of signaling molecules are discussed further in later sections of this review.

Interestingly, the same protocol of chronic psychosocial stress that markedly impaired short-term memory and suppressed E-LTP of the hippocampal area CA1 did not block E-LTP of the dentate gyrus region of the same hippocampus [27, 45]. This could be due to two major findings; the first is the significantly decreased basal levels of calcineurin in the dentate gyrus of stressed rats, which as a consequence meant a reduction in the dephosphorylation of P-CaMKII in the LTP cascade of the dentate gyrus region. The other finding is that P-CaMKII levels remained unaffected despite the marked decrease in the total CaMKII level in the dentate gyrus region of chronically stressed rats. The decreased dephosphorylation resulting from the reduced calcineurin level was most probably responsible for maintaining adequate levels of P-CaMKII, which may explain the normal E-LTP seen in the dentate gyrus of chronically stressed rats [45].

Another critical molecule in the hippocampus that is negatively affected by chronic psychosocial stress is brain-derived neurotropic factor (BDNF) [32, 131]. The importance of BDNF in the expression of LTP has been demonstrated by the impairment of LTP in the presence of BDNF antibodies or BDNF scavenging protein [132–135]. Furthermore, a number of other factors are involved in modulating hippocampal dendritic and spine plasticity during chronic stress; they include the transmembrane glycoprotein M6a, the stress-related neuropeptide CRF, and the extracellular protease tissue plasminogen activator (tPA) [77, 112, 136–140].

4.2. Stress and the Prefrontal Cortex

The prefrontal cortex neurons appear to respond to stress in a sexually dimorphic manner. In the female, stress increases dendritic density, whereas in the male stress decreases branching and length of dendrites and causes loss of dendritic spines of pyramidal neurons of the medial prefrontal cortex (mPFC) [111, 141–152]. Interestingly, chronic stress-induced spine loss seems to be dependent on the type of spine where large, mushroom shaped spines are decreased but thin spines are increased [111, 146, 153]. These changes in the mPFC are seen in young rats but not in middle aged and aged animals [153].

Excitability of the mPFC neurons is altered as a result of stress-induced atrophy of apical dendrites, which correlates with deficits in the excitatory responses to inputs targeted at those dendrites [154]. It has been reported that chronic stress impacts synaptic plasticity by decreasing the magnitude of LTP in the mPFC [155]. Chronic stress impairs synaptic plasticity by reducing LTP magnitude in the hippocampal-PFC connection thus severely disrupting working memory and behavioral flexibility [147].

Certain morphological changes in the PFC can be seen with repeated exposure to mild stressors and also after acute but intense stress [156–158] indicating that this region is sensitive to both chronic and acute types of stress. Interestingly, while rats of all ages exhibit dendritic retraction with stress in the mPFC, these effects are reversible after a stress-free recovery period in young rats but not in old rats [151].

4.3. Structure and Function of the Amygdala in Stress

Interestingly, chronic stress increases length and number of spines, augments dendritic length, and increases branching points of dendrites of the basolateral complex (BLA) neurons without affecting those in the central nucleus of the amygdala [115, 159–164]. Acute stress, in contrast, does not affect the dendrites but may promote formation of new spines in the amygdalar neurons [162]. Another interesting difference between the amygdala and hippocampus and PFC is while the stress-induced structural atrophy in the hippocampus and mPFC is reversible, the stress-induced dendritic hypertrophy in the amygdala is persistent and remains a long time after termination of stress [165].

The stress-induced hypertrophy and hyperexcitability seen in the amygdalar neurons after stress indicate a strong correlation between structural and functional synaptic plasticity in the amygdala [166]. Intensely emotional experiences are generally thoroughly remembered through a process in which the amygdala plays a vital role [167, 168]. Such memory enhancement is encountered in both unpleasant and pleasurable events [167].

4.4. Interaction among Brain Regions

The stress-induced structural changes most likely contribute to changes in the electrical properties of neurons within the region as well as interactions among these regions. For example, stress inhibits the generation of LTP in the pathway between the hippocampus and the mPFC as well as in the pathway connecting the amygdala to the mPFC [169–172]. Furthermore, stress impacts the reciprocal pathway between the mPFC and the amygdala, such that there is inhibition of LTD and facilitation of LTP of this pathway [173].

Repetitive stimulation, which produces LTP, also swiftly promotes the formation of new spines and spine shape modification in contrast with LTD, which is associated with shrinkage or loss of spines [108]. Therefore, stress-induced changes in functional synaptic plasticity may be influenced by and may in turn impact structural plasticity. For example, by weakening hippocampal structure, stress may diminish activity in hippocampal afferents to the mPFC, which could in turn lead to fewer mPFC dendritic spines.

4.5. Molecular Mechanisms

Chronic stress is known to alter the levels of essential signaling molecules in the molecular cascades implicated in memory and LTP. Alterations in the levels and activities of these signaling molecules disrupt synaptic plasticity and memory and may be important in the pathogenesis of various disorders including stress. The impact of stress on signaling molecules critically important for both synaptic plasticity and memory is discussed in the following.

4.5.1. Calcium Calmodulin-Dependent Protein Kinase II (CaMKII)

CaMKII is the most abundant protein kinase in the brain. Comprising up to 1% of total brain protein, CaMKII plays an essential role in the regulation of neuronal excitability and synaptic transmission as well as induction and maintenance of hippocampal LTP [174–176]. Elevation of the Ca²⁺ concentration in the postsynaptic region, as a result of glutamate NMDA receptor activation, stimulates several kinases, including CaMKII, which is critical for spatial memory and LTP [177–180]. Activation of CaMKII in the process of LTP induction is necessary and sufficient to generate LTP. The essential role of CaMKII in cognitive abilities and synaptic plasticity is indicated by a number of experiments. For example, CaMKII inhibitors (e.g., H-7) impair memory [181] and block LTP in hippocampal area CA1 [177, 182]. Additionally, CaMKII null mice exhibit significant deficits in memory and LTP, compared to wild-type animals [183, 184]. The activation of CaMKII persists even when Ca²⁺ reverts back to the normal physiological levels, due to its ability of autophosphorylation at amino acid Thr286. Thus, CaMKII has several features that make it an appealing candidate as a memory molecule: its ability to autophosphorylate and remain active even after the decline in intracellular Ca²⁺ concentrations, its abundance in the brain, and its wide spectrum of substrates.

Previous findings in this laboratory showed that chronic stress reduces the basal levels of P-CaMKII and the ratio of P-CaMKII/total CaMKII in the CA1 region of the hippocampus [32, 50]. In order for LTP to be properly maintained, the rate of autophosphorylation must exceed the rate of dephosphorylation. The basal levels of both total CaMKII and P-CaMKII are reduced after chronic stress in the CA1 region of the hippocampus [15]. Stress also blocks the high-frequency stimulation (HFS)-induced LTP and the attended increase in P-CaMKII, which confirms the critical role of P-CaMKII in the expression of LTP. This decrease of P-CaMKII in stressed rats could result from a decrease in calmodulin, PKCγ and/or an increase in calcineurin basal levels in the hippocampal area CA1 of stressed rats [15].

The significant impairment of learning, memory, and synaptic plasticity observed in behavioral and electrophysiological studies may also be associated with the failure of HFS to increase P-CaMKII production in stressed rats. Coupled with the reduced phosphorylation in the stressed animals, indicated by the decreased ratio of P-CaMKII/total CaMKII, the observed cognitive deficits may be due, at least partly, to curtailed CaMKII phosphorylation.

Stress, by social isolation, decreased phosphorylation at Thr286, thus, limiting CaMKII activity. Synaptosomal fraction from cortex of socially isolated animals exhibited decreased phosphorylation at Ser831 relative to that of control animals [185]. This effect, which lasted to a later developmental age, was prevented by RU486, an antagonist of glucocorticoid receptor [185]. Neonatal social isolation that caused downregulation of CaMKII activity is in line with the attenuation of LTP at age of 27 days by early life social isolation. Ser831 of GluR1 subunit of AMPA receptor is a target of CaMKII and is known to be phosphorylated during LTP [186]. Interestingly, certain forms of stress may upregulate CaMKII expression. For example, postnatal maternal deprivation and pubertal immobilization stress upregulate CaMKII [187]. The reason for this differential response is not well understood.

Stress seems to affect levels of CaMKII differently in distinct brain regions. For example, recently, we have shown that predator exposure stress in rats did not significantly change the P-CaMKII levels in the hippocampus, but markedly increased its levels in the amygdala (BLA region) and decreased its levels in the mPFC [92]. In other reports, we showed that psychosocial stress significantly decreased CaMKII levels in hippocampal area CA1 but not in the dentate gyrus area [27, 45, 50].

4.5.2. Calcineurin (PP2B)

Protein phosphatases are responsible for the dephosphorylation and inactivation of previously phosphorylated protein molecules. Several protein phosphatases exist in hippocampal neurons, including calcineurin. The effects of calcineurin on learning and memory are said to be largely regulatory so as to limit the saturation of learning and its underlying synaptic processes. It has been reported that overexpression of calcineurin in the hippocampus results in detrimental effects on cognitive abilities. For instance, overexpression of calcineurin in the hippocampus attenuates hippocampus-dependent memory formation [188]. There are three major types of protein phosphatases in hippocampal neurons: PP1, PP2A, and PP2B (also known as calcineurin). Phosphatases PP1 and PP2A are very effective in dephosphorylating CaMKII at Thr286, thus reversing its constitutive activity to basal levels. Calcineurin is not only a potent inhibitor of postsynaptic activity in the hippocampus [127] but also is responsible for the expression of LTD. Activation of calcineurin by calcium-calmodulin (Ca²⁺-CaM) leads to the activation of PP1, which in turn inactivates P-CaMKII [189, 190]. Additionally, despite the fact that much of the literature classifies phosphatases as a generic “off” switch that equilibrates the cellular environment after kinase activity is finished, calcineurin has been shown to both increase and decrease synaptic efficacy by modulating ion channels (e.g., L-type Ca²⁺ channels) and receptors (e.g., AMPA receptors) in addition to kinases (CaMKII, MAPK), transcription factors (e.g., CREB), and other phosphatases (e.g., PP1) [191].

Chronic psychosocial stress causes overexpression of calcineurin in area CA1 of the hippocampus [27, 32, 50, 192]. Interestingly, within the hippocampal formation, the dentate gyrus area seems to be relatively immune to the effect of moderately chronic stress in that chronic stress produced a significant decrease, rather than increase, in calcineurin levels. Thus, the dentate gyrus of chronically stressed rats seems to have a compensatory mechanism whereby calcineurin levels are reduced in order to maintain normal P-CaMKII levels, which may be responsible for the normal early LTP of the dentate gyrus in chronically stressed rats [27].

Other types of stressors may have different effects on the levels of calcineurin. For example, predator exposure stress produced no significant effect on the expression of calcineurin in hippocampal area CA1, amygdala, or mPFC of rats [92]. Interestingly, calcineurin expression in the hippocampus of maternally deprived rats seems to be sex specific in that it is decreased in male but not female animals [193].

4.5.3. Brain-Derived Neurotrophic Factor (BDNF)

The neurotrophic factor (BDNF) promotes various aspects of plasticity and survival of existing as well as newly born neurons in the central nervous system. This protein factor is expressed not only in brain tissue but also locally in exercised skeletal muscle [52, 194]. In addition to its action on neuronal survival and differentiation, BDNF has a role in the regulation of synaptic strength. It can act as an activity-dependent modulator of neuronal structure, and its release after tetanic stimulation modulates the induction and maintenance phase of LTP in the hippocampus [195, 196]. Experimental evidence supports the role of BDNF in memory processes. It has been shown that memory acquisition and consolidation are accompanied by an increase in BDNF mRNA expression and the activation of its receptor TrkB in the hippocampus [197]. Thus, BDNF plays a prominent role in learning and memory and synaptic plasticity [198].

Two major families of neurotrophic factors have been identified: the neurotrophins family and the glial cell line-derived neurotrophic factor (GDNF) family. The latter includes four members that have been identified so far: GDNF, neurturin, artemin, and persephin, all of which function through activation of receptor tropomyosin kinases (Trk). The neurotrophin family in mammals includes four members that have similar structure and biochemical characteristics and activate one or more of the three members of the TrK family of receptors. The four members are the nerve growth factor (NGF), which activates TrkA receptor, BDNF and neurotrophin-4/5 (NT-4/5), both of which selectively activate TrkB receptor, and neurotrophin-3 (NT-3) with high affinity for TrkC receptor. In addition, all neurotrophins activate, with low affinity, the tumor necrosis factor receptor, p75 neurotrophin receptor (p75(NTR)) [199–202].

Based on the observed changes in the hippocampus in response to stress, a “neurotrophic hypothesis” has been formulated to explain the mechanism of mood disorders due to a lack of trophic support in certain areas of the brain [203, 204]. BDNF is the major neurotrophin thought to be involved in this hypothesis. In general, evidence indicates reductions in BDNF protein level or its mRNA level in the hippocampus after acute and chronic stress [32, 205, 206]. Further, a similar decrease of BDNF in the dentate gyrus is seen after corticosterone administration [205]. Parallel reductions in BDNF levels are reported in the hippocampus [207–209] and PFC [208] of brains of depressed patients.

The trophic influence of glucocorticoids on the brain is related to the previous discussion. The complexity of the neurotrophins system is suggested by the finding that TrkB phosphorylation can also be induced by glucocorticoids in neurons [210] and that both BDNF and glucocorticoids can also regulate the release of CRF [211]. It is well known that prolonged glucocorticoid exposure is associated with dendritic atrophy and synaptic spine loss in adult brains. Although glucocorticoids are maligned because they are the hormones that initiate the stress responses, at normal circulating levels they have trophic effects on neurons [212]. Removing circulating glucocorticoids by adrenalectomy resulted in reduced dendritic density and even neuronal death. These changes in neuronal morphology were prevented when the adrenalectomized rats were treated with corticosterone. This suggests a trophic influence of glucocorticoids on the hippocampus. It has been shown that the trophic effects of glucocorticoids are due to activation of the specific BDNF TrkB receptor [211]. However, BDNF and glucocorticoids have different time courses in acting on the TrKB receptor in that BDNF causes immediate activation of the receptor, whereas glucocorticoids response is smaller but longer lasting [211].

Recent evidence revealed an important role for glucocorticoids in synaptic modulation to improve learning and memory. A single behavioral stressor improved performance in working memory tasks in rats, and short-term corticosterone treatment in vitro induced long-lasting potentiation of synaptic responses, which could be blocked with a glucocorticoid receptor antagonist [213, 214]. Additionally, corticosteroids are said to be involved in structural plasticity of neurons. In vivo studies showed that corticosterone administration enhanced dendritic spine formation in cortical regions and this effect was blocked by corticosterone deprivation [215].

It has been demonstrated by several studies that exposure to a variety of stressors both acute [216–218] and chronic [131, 219–221] can significantly downregulate both BDNF mRNA expression and protein levels in the hippocampus. However, in adrenalectomized animals restoration of basal levels of circulating corticosterone restores the stress-mediated repression of BDNF expression [205] suggesting a role for the basal circulating glucocorticoids in the effects of stress on hippocampal BDNF expression.

This decrease in BDNF expression is seen predominantly in the dentate gyrus and CA3 hippocampal areas [216, 219]. However, the duration of stress differentially influences BDNF expression with short-duration stressors of less than 60 min causing an increase in hippocampal BDNF expression and protein levels [222–224].

In contrast to its effects on the hippocampus, stress has been shown to cause an increase in BDNF expression in the frontal cortex [225–227], PVN [216], and amygdala [137, 227]. This differs from reports following glucocorticoids administration, which is largely associated with a decline in BDNF expression in cortical brain regions, including the frontal cortex [207, 228]. This suggests that stress effect may not be due to increased glucocorticoids levels alone.

4.5.4. Cyclic-AMP Response Element Binding Protein (CREB)

CREB, a transcription factor that regulates the expression of CRE-containing genes, plays an essential role in the molecular mechanisms underlying synaptic plasticity processes, and regulates adaptive responses including memory consolidation, addiction, and synaptic refinement [229–231]. CREB signaling may play a central role in mediating the effects of chronic stress on neurogenesis, LTP, and calcium currents in the dentate gyrus area [232, 233].

The transcriptional activity of CREB occurs upon phosphorylation of the regulatory Ser133 residue by key protein kinases [234, 235]. In nerve cells, the depolarization-induced phosphorylation of Ser133 of CREB is critically dependent on Ca²⁺ influx-mediated activation of calcium calmodulin kinase IV (CaMKIV) [236]. Whereas activation of CREB is necessary and sufficient to generate L-LTP and long-term memory [237, 238], inactivation or blocking of CREB impairs synaptic plasticity, learning, and long-term memory [239–241]. For example, mice with mutations in CREB exhibit normal E-LTP and short-term memory but deficient L-LTP and long-term memory [239].

Reports on the impact of stress on CREB are inconsistent. For example, in chronically stressed rats, CREB phosphorylation has been reported to be significantly reduced in several brain regions, including the hippocampus [242, 243]. In mice, however, chronic psychosocial stress has been shown to stimulate CREB transcriptional activity in the brain [24]. Findings from this laboratory consistently showed that chronic psychosocial stress in rats did not significantly affect the basal expression of p-CREB or total CREB [52, 123, 244]. The contradictory findings are most probably the consequences of using different species of animals, different stress paradigms, and whether the analysis was done in a specific area of the brain or the whole brain tissue.

4.5.5. Calcium Calmodulin-Dependent Protein Kinase IV (CaMKIV)

The transcriptional activator, CaMKIV, is expressed in the nuclei and cytosol of neurons in several brain regions, including the cortex, cerebellum, hippocampus, and amygdala [245–249]. CaMKIV activates several transcription factors, including CREB, and phosphorylates and regulates the function of a number of synaptic proteins, including synapsin 1 [250]. Induction of LTP by multiple-high-frequency stimulation causes an increase in the level of CaMKIV leading to phosphorylation and activation of CREB [251, 252]. Therefore, CaMKIV plays a modulatory role along with other signaling pathways to ultimately ensure activation of CREB. Indeed, mice with mutation in CaMKIV showed impaired late phase LTP, long-term memory, and CREB phosphorylation in the hippocampus but intact early phase LTP and short-term memory [253, 254].

The role of CaMKIV in mediating anxiety and stress-related behavior is suggested by examining CaMKIV knockout mice. These animals exhibit decreased anxiety-like behaviors and develop less stress-induced analgesia [255]. However, chronic psychosocial stress in rats produced no significant effect on the expression of CaMKIV [256].

5. Stress and Central Nervous System Disorders

Psychological stress is a major risk factor for the development and progression of a variety of diseases. Chronic exposure to stress diminishes health and increases susceptibility to mental disorders [257]. Moreover, stress aggravates existing functional deficits and structural alterations associated with various brain disorders including schizophrenia [258], Cushing’s disease [259], hypothyroidism [15], Alzheimer’s disease [50, 51], and cardiovascular disease [260, 261]. Long-term high concentrations of glucocorticoids will have indirect detrimental effects on the neurons, by engendering a metabolically adverse cellular environment, which increases their vulnerability to existing or impending insults such as Alzheimer’s disease and Parkinson’s disease [51, 262].

Severe and/or protracted stress causes overactivation and dysregulation of the HPA axis and induces negative effects on the brain morphology and chemistry [263] with serious consequences. The entire vast literature on the role of stress in various disorders is beyond the scope of this report; however, this section briefly reviews the effect of stress on selected brain disorders.

The effects of chronic stress on brain structure and function are similar to those of a variety of brain disorders including Alzheimer’s’ disease and Parkinson’s disease. For example, stress or chronic corticosterone administration in animals compromised normal motor function [264] and exaggerated motor deficits in a rat model of Parkinson’s disease [256] and exasperated or precipitated Alzheimer’s disease phenotype [51, 52, 122, 192].

5.1. Stress-Dependent Cardiovascular Disorders

A growing body of literature suggests that chronic stress-induced activation of the sympathetic nervous system and the HPA axis may lead to inflammation, which plays an important role in the pathophysiology of a number of diseases including cardiovascular disorders. Tonic activation of the sympathetic nervous system may cause overt arterial hypertension and contribute to a high risk of cardiovascular diseases particularly in subjects with high-normal blood pressure [265].

Association between stress and hypertension and other cardiovascular diseases has been thoroughly investigated both in humans and in experimental animals. Even the fetus may suffer from consequences of psychosocial stresses during pregnancy. For example, it has been reported that stressors during pregnancy predispose the child at age 5–7 to higher blood pressure [266]. Psychosocial stressors enhance autonomic stimulation via the HPA axis, which increases circulating catecholamines and cortisol in humans. These heightened autonomic responses are associated with increased risk of hypertension and proinflammatory state and, consequently, development of coronary heart disease.

Hyperactivity of the sympathetic cardiovascular control is believed to contribute to high blood pressure in patients. Chronic psychosocial stress is associated with the onset and aggravation of ischemic heart disease and produces a greater increase in blood pressure in patients with labile hypertension than in normotensive subjects [267, 268]. Although stress-induced hypertension returns to normal within a few days of termination of stress, prolonged mild-moderate hypertension may contribute to atherosclerotic cardiovascular diseases [269] in addition to causing cognitive impairment [27]. Both genetic and stress-induced experimental forms of hypertension are known to include a significant neural component that contributes to the development and maintenance of this disease [260, 270].

We have proposed that the stress-induced sustained increase in central sympathetic outflow to sympathetic ganglia may provide the repeated presynaptic activity required to express LTP in sympathetic ganglia, which in turn leads to a sustained increase in sympathetic tone to blood vessels, causing elevation of blood pressure [91] (see Figure 1).

Figure 1: Chronic mental stress supplies the repetitive stimulation required for induction of ganglionic long-term potentiation (gLTP), which enhances impulses to blood vessels leading to vasoconstriction and hypertension. Treatment with 5-HT3 receptor antagonists normalizes blood pressure in chronically stressed animals. It is noteworthy to mention that such mechanism may be only one of several other contributing mechanisms in the development of hypertension.

Similar to the LTP of the hippocampus, ganglionic LTP has been demonstrated both in vitro and in situ, in a number of autonomic ganglia from vertebrates including mammalian, amphibian, and avian species [271]. Ganglionic LTP of the nicotinic pathway is an enduring increase in synaptic effectiveness that can be induced in ganglia following a short train of relatively high-frequency stimulation of the preganglionic nerve. As in LTP of the hippocampus, the expression of ganglionic LTP is thought to be the product of a complex set of events that involve several enzymes, modulators, and second messengers, involving both the postsynaptic and presynaptic regions [271].

The cardiovascular centers in the brain stem region are regulated by higher centers in the hippocampus, amygdala, and prefrontal lobe of the brain, which are said to have a profound impact on autonomic functions [272, 273]. Stress perception involves participation of the PFC, which consequently alters the cardiovascular functions by influencing the autonomic regulatory systems. The ability of the prefrontal cortex to influence the cardiovascular system response to stress has been demonstrated in pigs, where blocking the frontocortical-brain stem pathways prevents the development of lethal arrhythmias in psychosocially stressed pigs [274].

In vivo expression of LTP in autonomic ganglia is expected to enhance tonic efferent signals to an array of effector organs, including the heart, blood vessels, and glands, which result in modulation of the normal physiology of these organs. We have shown that expression of ganglionic LTP, which enhances activity of the sympathetic nervous system, may be responsible for the development and/or aggravation of stress-induced hypertension in animal models (Figure 2) [91, 126, 260, 271, 275–277]. Sustained elevation of sympathetic tone to the blood vessels and the heart may also lead to increased heart rate (clinically presents as palpitation) and arrhythmias, which may lead to death [277]. The function of the stress-induced elevation of blood pressure is unclear. We suggest that it may be involved in an adaptive mechanism to compensate for reduced blood perfusion reported in certain areas of the brain during stressful conditions [260, 278, 279].

Figure 2: Chronic psychosocial stress caused elevation of blood pressure in normal animals and exacerbates existing hypertension in rat models of hypertension (spontaneous hypertensive rat “SHR” and obese Zucker rat). Note that treatment with 5-HT3 receptor antagonists, which block ganglionic LTP, inhibits the stress-induced component of hypertension. * and # indicate significant difference from the other two groups ().

5.2. Alzheimer’s Disease

Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disease that was first characterized by the Bavarian psychiatrist Alois Alzheimer who published two seminal articles titled “A Characteristic Disease of the Cerebral Cortex” [280] and “On Certain Peculiar Diseases of Old Age” [281], which detailed the biographical, clinical, and neuropathological history of two patients with severe cognitive deficits and proteinaceous deposits as classic hallmarks of AD. The disorder was subsequently named after Alois Alzheimer [282, 283].

Alzheimer’s disease is a multifactorial disease with both familial and sporadic forms. Familial AD is an autosomal dominant hereditary disorder with early onset before the age of 65. A three-gene mutation has been identified as the cause of the familial form of the disease. A common feature of the disease-causing mutations in these genes is that they all involve the metabolism or stability of amyloid-beta (Aβ) protein believed to be a causing factor for AD. Fortunately, the familial AD is relatively rare with a frequency of less than 1% of total AD cases [284, 285]. In addition to age and genetic factors, chronic stress is a risk factor for AD [286, 287], since elevated glucocorticoid levels are correlated with increased Aβ deposition, enhanced Aβ-mediated neurotoxicity, and accelerated cognitive decline [21, 288–290].

The hippocampal complex of the brain is a particularly susceptible target in AD where early symptoms include significant impairment of the hippocampus-dependent cognitive abilities. Accumulating evidence suggests that elevation of glucocorticoid levels, as in chronic stress, increases neuronal vulnerability to age-related damages hence speeding up the progression of aging of the brain [291]. A possible explanation for this increased vulnerability is that age-associated deterioration of the hippocampal neurons may interfere with the negative feedback inhibition of the HPA axis and consequently result in elevated plasma glucocorticoid levels. Such enhanced levels of glucocorticoids have been observed in Alzheimer’s patients [292, 293].

Furthermore, genetic studies indicate a link between glucocorticoids function and the risk for developing AD [294]. Studies in transgenic mice demonstrate that acute corticosterone treatment increased soluble and insoluble Aβ protein production in vivo [21]. Additional data from in vitro studies found that corticosterone treatment increased steady-state levels of amyloid precursor protein (APP) and β-APP cleaving enzyme (BACE). This increase was blocked by glucocorticoid antagonists indicating selective activation of glucocorticoid type-2 receptors [21]. Studies in animal models of AD provide corroborative evidence of stress-induced changes in AD. For example, exposure to chronic stress results in an increase in the levels of Aβ and/or Aβ-related proteins suggesting that stress may drive the APP enzymatic processing cascade to favor the amyloidogenic pathway [50, 295]. This prompted the proposition that stress may contribute to the development and/or maintenance of AD. Further support of this hypothesis comes from an epidemiological report that suggests stress as a risk factor for AD because elderly individuals who suffer psychological distress are more likely to develop the disorder than their age-matched, nonstressed individuals [21].

My laboratory group has conducted extensive studies on the impact of chronic psychosocial stress in rat models of AD phenotype at the behavioral, cellular, and subcellular levels [50, 192, 253, 296]. Particularly interesting is our novel subclinical or “at-risk” rat model of AD. This model was obtained by 14-day intracerebroventricular infusion of subpathogenic doses of Aβ protein by osmotic pumps. Treated rats were not different from control rats in every test conducted; thus the model was assumed to mimic preclinical, symptomless condition in humans. However, when these rats were subjected to chronic psychosocial stress before and during amyloids infusion, they exhibited clear AD phenotypes, including impaired learning and memory, suppressed LTP, and deficit of cognition-related molecular cascades similar to those seen in rats infused with full pathogenic doses of Aβ proteins (Table 1) (reviewed in [244]).

Table 1: Effects of chronic psychosocial stress on cellular and molecular neuronal functions in at-risk AD model in rats. Sub-Aβ (160 pmol/day; subpathogenic dose); Full Aβ (300 pmol/day; pathogenic dose) in CA1 area of the hippocampus; decreased; increased; no change compared to the control. Note that Sub-Aβ values are identical to control values (not shown) and that the presence of stress in sub-Aβ rats revealed full AD phenotype seen in Full Aβ.

Stress
Sub-A
Str/sub-A
Full A

P-CaMKII

t-CaMKII

Calcineurin

BDNF

P-CREB

t-CREB

CaMKIV

Learning

Short-term memory

Long-term memory

Early LTP magnitude

Late LTP magnitude

LTD magnitude

A number of reports have demonstrated that patients with AD exhibit HPA axis abnormalities [29–303]. In AD patients, the concurrent age-associated loss of hippocampal neurons and downregulation of glucocorticoid receptors cause severe dysregulation of the HPA system [304]. With aging, progressive failure of the negative feedback regulation of the HPA axis allows continued glucocorticoid release [68, 305, 306], which promotes hippocampal atrophy [307], excitotoxicity and neurotoxicity, [3, 306]. The combination of these adverse effects may reduce the ability of neurons to survive concurrent insults, thus exacerbating Aβ-mediated neurotoxicity and/or impairment of memory and LTP [24, 28, 55, 308, 309].

5.3. Parkinson’s Disease

The impact of overactive HPA axis on various neurodegenerative diseases including Parkinson’s disease (PD) is well known [310–313]. Parkinson’s disease is a progressive neurodegenerative disorder with complex, multifactorial etiology, affecting around 1% of individuals over the age of 65, and hallmarked by loss of dopaminergic neurons of the nigrostriatal pathway and debilitating motor dysfunction [262, 314, 315]. Additionally, neuronal loss that occurs in other brain areas and protein accumulation could play a prominent role in the pathogenesis of PD. While the serious motor symptoms (rigidity, bradykinesia, resting tremor, and postural instability) are the obvious manifestations of the disease, a variety of nonmotor symptoms may also be present and together they can negatively affect the quality of life of patients. Depression seems to be one of the most common PD comorbidities, which may be masked by the psychomotor symptoms [316, 317].

The majority (90%) of cases of PD are sporadic with the remaining 10% may be due to a genetic origin (familial) [314]. In addition to aging, it is believed that a combination of genetic vulnerability and environmental factors, including stress, may be involved in the expression of the disease. Parkinsonism can also be precipitated by toxins, certain medications, central nervous system infection, and other disorders. Recently, inhibitors of the ubiquitin-proteasome system, including some environmental toxins, have been identified as possible factors for this disease [318].

While acute stress increases dopamine release as an essential measure to promote adaptation and survival, chronic stress decreases dopaminergic tone in various regions of the brain including PFC, striatum, nucleus accumbens, and frontal cortex [319, 320]. However, the effect of stress in the presence of already impaired dopaminergic system, as in PD, may have serious implications for the disease [315].

Unfortunately, the exact etiology of PD is currently unclear, but the primary risk factor for PD is aging, which may be accompanied by elevated levels of cortisol [321]. Interestingly, cortisol level is elevated in PD patients relative to healthy age-matched controls [322], which is an indication of the presence of stress. Plasma cortisol levels in PD patients can be lowered by acute treatment with levodopa, the drug of choice for treatment of PD [323], suggesting that stress is not merely a psychological reaction to being diagnosed with the disease and implying an association between dopaminergic system dysfunction and HPA axis hyperactivity [315]. Stress can transiently increase motor symptoms of PD, but it is unclear whether other behavioral changes associated with PD are also affected.

Severe stressors may bring about the development of PD later in life. For example, thirty-five years after release, prisoners of war showed a higher incident rate of PD development [324]. This, however, may be the product of the continuous form of traumatic stress, PTSD. It is believed that prolonged stress episodes may cause permanent damage to brain structure [325]. Accordingly, emergence of the PD clinical symptoms during a stressful period may indicate a preexisting subthreshold damage to the nigrostriatal system that has been intensified by stress. These neurological impairments were linked both to the degree of dopamine depletion and to the intensity of the stress [312].

High cortisol levels accelerate PD progression [262]. Pleasure responses were further reduced in PD patients after exposure to emotional stress, even though stress did not affect certain motor symptoms [326]. However, corticosteroids may also have neuroprotective effects by curbing harmful microglial reactivity [327].

5.4. Epilepsy

Epilepsy is a brain disorder characterized by periods of abnormal intense neuronal repetitive activity resulting in recurrent seizure episodes. The paroxysmal nature of epilepsy suggests the involvement of triggering factors. Stress is consistently identified as the most common trigger of seizures in patient perception studies, independent of the subtype of epilepsy reported [328–334]. In fact, one proposed theory for the etiology of epilepsy is that it is due to psychological causes such as stress, psychic trauma, and shock. Although the mechanism(s) by which stress causes or triggers epilepsy remained obscure, a number of theories have been proposed (reviewed in [335]).

Seizures can originate from different regions of the brain and can be generalized or localized (focal) depending on the type of epilepsy. The disease is frequently comorbid with other disorders, including anxiety, depression and cognitive and memory problems. In epilepsy the brain can undergo various changes at the cellular level including cell loss and widespread circuit abnormalities, alterations of synaptic properties, aberrant ion channels, inflammation, and changes in glial cell function [336].

Because of the subjective perception of stress, self-report studies in humans are not very reliable. However, correlational studies explored the relationship between stress and occurrence of seizures in populations affected by a common stressor. For example, investigation of the effect of a controlled evacuation from a flooded area in the Netherlands on patients with epilepsy revealed a strong relationship between the stressful situation and the frequency of seizures in the evacuated patients [337]. Similarly, during the 1991-1992 Croatian war, Bosnjak and colleagues [338] compared epileptic children with other epileptic children but from areas unaffected by war and reported a strong association between stress and seizure frequency.

Although human data on the association between stress and epilepsy are limited, a wealth of data from animal experiments on the effects of stress or glucocorticoids, albeit sometimes contradictory, exists in the literature. Experiments on the effect of corticosterone in various experimental epilepsy models yielded conflicting results. With so many different experimental variables, the contradictory findings are not surprising (reviewed in [334]).

With acute stress, the results have been variable depending on the epilepsy model and are, to some extent, sex dependent [334]. Depending on the seizure induction method and type of acute stressor used, acute stress is reported to both enhance and reduce seizure susceptibility [334]. Emotional stress is considered the most frequent self-reported seizure trigger [332]. For example, acute stress has been reported to exacerbate or even trigger an epileptic episode [329] as patients recount that the frequency of their seizures increases if they are exposed to stress [330, 339].

In contrast to acute stress, the results of the effects of chronic stress and early life stress on seizure susceptibility in experimental animals have been more consistent. Early life stress can result in lasting vulnerability to epileptogenesis in adult animals [340–342]. Various forms of psychiatric disorder have been reported in humans as a product of stress in early life, they include mood and anxiety disorders, schizophrenia and even dementia [71] in addition to increased vulnerability to limbic epilepsy in adult life [343–345].

Prenatal stresses and exposure to elevated corticosteroid blood levels impair hippocampal synaptic function and increase the rate of severe seizure and may enhance later seizure susceptibility in infant rats. In animal experiments, early life stress results in long-lasting augmentation of HPA axis responses to limbic seizures, in addition to cell loss in hippocampal area CA3 and enhanced neurogenesis, in a sex-dependent fashion [345]. This may represent possible mechanisms by which early life stress promotes susceptibility to limbic epileptogenesis in rats and possibly to human mesial temporal lobe epilepsy and its associated psychiatric comorbidities. This most common form of focal epilepsy in adults [346] arises from limbic structures, including the hippocampus, which are vulnerable to the effects of stress [254, 347].

Accumulating evidence supports the role of stress hormones in the effect of stress on epilepsy. For example, administering exogenous corticosterone exacerbates the kindling model of epilepsy [348–350]. The involvement of stress hormones was indicated by the findings that glucocorticoid and mineralocorticoid receptors antagonists [349] as well as adrenalectomy or hypophysectomy reversed or slowed the effect on kindling in rats [351–354]. It appears that even CRF has proconvulsive activity. It has been reported that intracerebroventricular injections of CRF produced spontaneous seizures in rats [355–359].

Neurogenesis is important for hippocampal functions (for review see [360]). Chronic stress and depression are known to cause decreased granule cell neurogenesis in the dentate gyrus, whereas neurogenesis initially increases during the development of epilepsy but then decreases later in the disease. However, the majority of these nascent granule cells that are generated early in epilepsy assimilate abnormally [361]. Aberrant integration of new cells during the development of epilepsy may interfere with the ability of the dentate gyrus to curtail excessive excitatory activity from reaching hippocampal pyramidal cells, thus furthering seizure activity (Figure 3). Therefore, in spite of the opposing effects of stress and epilepsy on neurogenesis, both disorders may be epileptogenic. Because of these marked changes in dentate gyrus granule cell neurogenesis, it has been suggested that temporal lobe epilepsy develops when large numbers of granule cells integrate abnormally into the dentate gyrus [362] (reviewed in [363]).

Figure 3: Chronic stress lowers seizure threshold in epileptic patients (DG = dentate gyrus).

6. Concluding Remarks

This paper reviews the current state of knowledge regarding the impact of mental stress on brain structure and function. The reader will see relatively more emphasis put on how chronic stress affects synaptic plasticity and its underlying molecular cascades. The review also discusses the effect of stress on certain disease conditions. The discussion of how stress impacts health conditions is obviously not comprehensive as chronic stress negatively impacts a wide variety of other disorders that are not discussed here due to space limitation. It is well known that chronic stress negatively impacts patients suffering from schizophrenia [364], Cushing’s syndrome [365], thyroid hormone disorders [15, 366, 367], sleep disorders [368], Huntington’s disease [369], and bipolar disorder [370, 371] among others.

References

A. M. Magarinos, J. M. Verdugo, and B. S. McEwen, “Chronic stress alters synaptic terminal structure in hippocampus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, pp. 14002–14008, 1997.

B. S. McEwen, C. D. Conrad, Y. Kuroda, M. Frankfurt, A. Maria Magarinos, and C. McKittrick, “Prevention of stress-induced morphological and cognitive consequences,” European Neuropsychopharmacology, vol. 7, supplement 3, pp. S323–S328, 1997.

B. S. McEwen, “The neurobiology of stress: from serendipity to clinical relevance,” Brain Research, vol. 886, no. 1-2, pp. 172–189, 2000.

B. S. McEwen, “Protective and damaging effects of stress mediators: the good and bad sides of the response to stress,” Metabolism, vol. 51, no. 6, pp. 2–4, 2002.

D. M. Diamond and G. M. Rose, “Stress impairs LTP and hippocampal-dependent memory,” Annals of the New York Academy of Sciences, vol. 746, pp. 411–414, 1994.

V. Luine, M. Villegas, C. Martinez, and B. S. McEwen, “Repeated stress causes reversible impairments of spatial memory performance,” Brain Research, vol. 639, no. 1, pp. 167–170, 1994.

V. Luine, M. Villegas, C. Martinez, and B. S. McEwen, “Stress-dependent impairments of spatial memory. Role of 5-HT,” Annals of the New York Academy of Sciences, vol. 746, pp. 403–404, 1994.

C. D. Conrad, L. A. M. Galea, Y. Kuroda, and B. S. McEwen, “Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine pretreatment,” Behavioral Neuroscience, vol. 110, no. 6, pp. 1321–1334, 1996.

D. M. Diamond, N. Ingersoll, M. Fleshner, and G. M. Rose, “Psychological stress impairs spatial working memory: relevance to electrophysiological studies of hippocampal function,” Behavioral Neuroscience, vol. 110, no. 4, pp. 661–672, 1996.

C. Kirschbaum, O. T. Wolf, M. May, W. Wippich, and D. H. Hellhammer, “Stress- and treatment-induced elevations of cortisol levels associated with impaired declarative memory in healthy adults,” Life Sciences, vol. 58, no. 17, pp. 1475–1483, 1996.

S. J. Lupien, S. Gaudreau, B. M. Tchiteya et al., “Stress-induced declarative memory impairment in healthy elderly subjects: relationship to cortisol reactivity,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 7, pp. 2070–2075, 1997.

D. M. Diamond, C. R. Park, K. L. Heman, and G. M. Rose, “Exposing rats to a predator impairs spatial working memory in the radial arm water maze,” Hippocampus, vol. 9, pp. 542–552, 1999.

C. Hölscher, “Stress impairs performance in spatial water maze learning tasks,” Behavioural Brain Research, vol. 100, no. 1-2, pp. 225–235, 1999.

C. R. Park, A. M. Campbell, and D. M. Diamond, “Chronic psychosocial stress impairs learning and memory and increases sensitivity to yohimbine in adult rats,” Biological Psychiatry, vol. 50, no. 12, pp. 994–1004, 2001.

N. Z. Gerges, K. H. Alzoubi, C. R. Park, D. M. Diamond, and K. A. Alkadhi, “Adverse effect of the combination of hypothyroidism and chronic psychosocial stress on hippocampus-dependent memory in rats,” Behavioural Brain Research, vol. 155, no. 1, pp. 77–84, 2004.

B. S. McEwen, “Stress and hippocampal plasticity,” Annual Review of Neuroscience, vol. 22, pp. 105–122, 1999.

H. Selye, “A syndrome produced by diverse nocuous agents,” Nature, vol. 138, articl 32, 1936.

C. Hoschl and T. Hajek, “Hippocampal damage mediated by corticosteroids—a neuropsychiatric research challenge,” European Archives of Psychiatry and Clinical Neuroscience, vol. 251, supplement 2, pp. II81–II88, 2001.

R. Kurukulasuriya, B. K. Sorensen, J. T. Link et al., “Biaryl amide glucagon receptor antagonists,” Bioorganic and Medicinal Chemistry Letters, vol. 14, no. 9, pp. 2047–2050, 2004.

R. E. Tanzi and L. Bertram, “Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective,” Cell, vol. 120, no. 4, pp. 545–555, 2005.

K. N. Green, L. M. Billings, B. Roozendaal, J. L. McGaugh, and F. M. LaFerla, “Glucocorticoids increase amyloid-β and tau pathology in a mouse model of Alzheimer's disease,” Journal of Neuroscience, vol. 26, no. 35, pp. 9047–9056, 2006.

M. J. Owens, D. H. Overstreet, D. L. Knight et al., “Alterations in the hypothalamic-pituitary-adrenal axis in a proposed animal model of depression with genetic muscarinic supersensitivity,” Neuropsychopharmacology, vol. 4, no. 2, pp. 87–93, 1991.

M. E. Keller-Wood and M. F. Dallman, “Corticosteroid inhibition of ACTH secretion,” Endocrine Reviews, vol. 5, no. 1, pp. 1–24, 1984.

M. R. Foy, M. E. Stanton, S. Levine, and R. F. Thompson, “Behavioral stress impairs long-term potentiation in rodent hippocampus,” Behavioral and Neural Biology, vol. 48, no. 1, pp. 138–149, 1987.

D. M. Diamond, M. Fleshner, and G. M. Rose, “Psychological stress repeatedly blocks hippocampal primed burst potentiation in behaving rats,” Behavioural Brain Research, vol. 62, no. 1, pp. 1–9, 1994.

J. J. Kim, M. R. Foy, and R. F. Thompson, “Behavioral stress modifies hippocampal plasticity through N-methyl-D-aspartate receptor activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 10, pp. 4750–4753, 1996.

N. Z. Gerges, A. M. Aleisa, L. A. Schwarz, and K. A. Alkadhi, “Chronic psychosocial stress decreases calcineurin in the dentate gyrus: a possible mechanism for preservation of early LTP,” Neuroscience, vol. 117, no. 4, pp. 869–874, 2003.

N. Z. Gerges, A. M. Aleisa, L. A. Schwarz, and K. A. Alkadhi, “Reduced basal CaMKII levels in hippocampal CA1 region: possible cause of stress-induced impairment of LTP in chronically stressed rats,” Hippocampus, vol. 14, no. 3, pp. 402–410, 2004.

A. M. Aleisa, K. H. Alzoubi, N. Z. Gerges, and K. A. Alkadhi, “Nicotine blocks stress-induced impairment of spatial memory and long-term potentiation of the hippocampal CA1 region,” International Journal of Neuropsychopharmacology, vol. 9, no. 4, pp. 417–426, 2006.

A. M. Aleisa, K. H. Alzoubi, and K. A. Alkadhi, “Chronic but not acute nicotine treatment reverses stress-induced impairment of LTP in anesthetized rats,” Brain Research, vol. 1097, no. 1, pp. 78–84, 2006.

A. M. Aleisa, K. H. Alzoubi, and K. A. Alkadhi, “Nicotine prevents stress-induced enhancement of long-term depression in hippocampal area CA1: electrophysiological and molecular studies,” Journal of Neuroscience Research, vol. 83, no. 2, pp. 309–317, 2006.

A. M. Aleisa, K. H. Alzoubi, N. Z. Gerges, and K. A. Alkadhi, “Chronic psychosocial stress-induced impairment of hippocampal LTP: possible role of BDNF,” Neurobiology of Disease, vol. 22, no. 3, pp. 453–462, 2006.

E. Fuchs and G. Flügge, “Stress, glucocorticoids and structural plasticity of the hippocampus,” Neuroscience and Biobehavioral Reviews, vol. 23, no. 2, pp. 295–300, 1998.

J. Kim and K. S. Yoon, “Stress: Metaplastic effects in the hippocampus,” Trends in Neurosciences, vol. 21, no. 12, pp. 505–509, 1998.

F. Ohl, T. Michaelis, G. K. Vollmann-Honsdorf, C. Kirschbaum, and E. Fuchs, “Effect of chronic psychosocial stress and long-term cortisol treatment on hippocampus-mediated memory and hippocampal volume: a pilot-study in tree shrews,” Psychoneuroendocrinology, vol. 25, no. 4, pp. 357–363, 2000.

S. J. Lupien and B. S. McEwen, “The acute effects of corticosteroids on cognition: integration of animal and human model studies,” Brain Research Reviews, vol. 24, no. 1, pp. 1–27, 1997.

H. C. Abercrombie, N. H. Kalin, M. E. Thurow, M. A. Rosenkranz, and R. J. Davidson, “Cortisol variation in humans affects memory for emotionally laden and neutral information,” Behavioral Neuroscience, vol. 117, no. 3, pp. 505–516, 2003.

R. M. Sapolsky, H. Uno, C. S. Rebert, and C. E. Finch, “Hippocampal damage associated with prolonged glucocorticoid exposure in primates,” Journal of Neuroscience, vol. 10, no. 9, pp. 2897–2902, 1990.

E. R. De Kloet, W. Sutanto, N. Rots et al., “Plasticity and function of brain corticosteroid receptors during aging,” Acta Endocrinologica, vol. 125, supplement 1, pp. 65–72, 1991.

B. S. McEwen and R. M. Sapolsky, “Stress and cognitive function,” Current Opinion in Neurobiology, vol. 5, no. 2, pp. 205–216, 1995.

J. M. H. M. Reul and E. R. De Kloet, “Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation,” Endocrinology, vol. 117, no. 6, pp. 2505–2511, 1985.

J. M. H. M. Reul and E. R. De Kloet, “Anatomical resolution of two types of corticosterone receptor sites in rat brain with in vitro autoradiography and computerized image analysis,” Journal of Steroid Biochemistry, vol. 24, no. 1, pp. 269–272, 1986.

C. Sandi, “Stress, cognitive impairment and cell adhesion molecules,” Nature Reviews Neuroscience, vol. 5, no. 12, pp. 917–930, 2004.

N. Z. Gerges, K. H. Alzoubi, and K. A. Alkadhi, “Role of phosphorylated CaMKII and calcineurin in the differential effect of hypothyroidism on LTP of CA1 and dentate gyrus,” Hippocampus, vol. 15, no. 4, pp. 480–490, 2005.

N. Z. Gerges, J. L. Stringer, and K. A. Alkadhi, “Combination of hypothyroidism and stress abolishes early LTP in the CA1 but not dentate gyrus of hippocampus of adult rats,” Brain Research, vol. 922, no. 2, pp. 250–260, 2001.

J. J. Kim and D. M. Diamond, “The stressed hippocampus, synaptic plasticity and lost memories,” Nature Reviews Neuroscience, vol. 3, no. 6, pp. 453–462, 2002.

T. B. VanItallie, “Stress: a risk factor for serious illness,” Metabolism: Clinical and Experimental, vol. 51, no. 6, pp. 40–45, 2002.

M. N. Starkman, B. Giordani, S. S. Gebarski, S. Berent, M. A. Schork, and D. E. Schteingart, “Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease,” Biological Psychiatry, vol. 46, no. 12, pp. 1595–1602, 1999.

R. Yehuda, “Biology of posttraumatic stress disorder,” Journal of Clinical Psychiatry, vol. 62, supplement 17, pp. 41–46, 2001.

M. Srivareerat, T. T. Tran, K. H. Alzoubi, and K. A. Alkadhi, “Chronic psychosocial stress exacerbates impairment of cognition and long-term potentiation in beta-amyloid rat model of Alzheimer's disease,” Biological Psychiatry, vol. 65, no. 11, pp. 918–926, 2009.

T. T. Tran, M. Srivareerat, I. A. Alhaider, and K. A. Alkadhi, “Chronic psychosocial stress enhances long-term depression in a subthreshold amyloid-beta rat model of Alzheimer's disease,” Journal of Neurochemistry, vol. 119, no. 2, pp. 408–416, 2011.

K. A. Alkadhi, “Exercise muscles and the brain,” Journal of Clinical & Experimental Pharmacology, vol. 2, article 3, 2012.

S. E. Meyer, G. P. Chrousos, and P. W. Gold, “Major depression and the stress system: a life span perspective,” Development and Psychopathology, vol. 13, no. 3, pp. 565–580, 2001.

P. E. Gold, R. L. Delanoy, and J. Merrin, “Modulation of long-term potentiation by peripherally administered amphetamine and epinephrine,” Brain Research, vol. 305, no. 1, pp. 103–107, 1984.

D. M. Diamond, M. C. Bennett, M. Fleshner, and G. M. Rose, “Inverted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation,” Hippocampus, vol. 2, no. 4, pp. 421–430, 1992.

M. Joëls, “Corticosteroid effects in the brain: U-shape it,” Trends in Pharmacological Sciences, vol. 27, no. 5, pp. 244–250, 2006.

M. Joels, W. Hesen, and E. R. De Kloet, “Mineralocorticoid hormones suppress serotonin-induced hyperpolarization of rat hippocampal CA 1 neurons,” Journal of Neuroscience, vol. 11, no. 8, pp. 2288–2294, 1991.

C. D. Conrad, J. E. LeDoux, A. M. Magariños, and B. S. McEwen, “Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy,” Behavioral Neuroscience, vol. 113, no. 5, pp. 902–913, 1999.

C. Pavlides, Y. Watanabe, A. M. Magariños, and B. S. McEwen, “Opposing roles of type I and type II adrenal steroid receptors in hippocampal long-term potentiation,” Neuroscience, vol. 68, no. 2, pp. 387–394, 1995.

B. S. McEwen, “Plasticity of the hippocampus: adaptation to chronic stress and allostatic load,” Annals of the New York Academy of Sciences, vol. 933, pp. 265–277, 2001.

D. N. Alfarez, O. Wiegert, and H. J. Krugers, “Stress, corticosteroid hormones and hippocampal synaptic function,” CNS and Neurological Disorders, vol. 5, no. 5, pp. 521–529, 2006.

P. J. Lucassen, V. M. Heine, M. B. Muller et al., “Stress, depression and hippocampal apoptosis,” CNS and Neurological Disorders, vol. 5, no. 5, pp. 531–546, 2006.

K. Touyarot, C. Venero, and C. Sandi, “Spatial learning impairment induced by chronic stress is related to individual differences in novelty reactivity: search for neurobiological correlates,” Psychoneuroendocrinology, vol. 29, no. 2, pp. 290–305, 2004.

S. J. Lupien, A. Evans, C. Lord et al., “Hippocampal volume is as variable in young as in older adults: Implications for the notion of hippocampal atrophy in humans,” NeuroImage, vol. 34, no. 2, pp. 479–485, 2007.

L. Xu, R. Anwyl, and M. J. Rowan, “Behavioural stress facilitates the induction of long-term depression in the hippocampus,” Nature, vol. 387, no. 6632, pp. 497–500, 1997.

R. M. Sapolsky, “Glucocorticoids, stress, and their adverse neurological effects: relevance to aging,” Experimental Gerontology, vol. 34, no. 6, pp. 721–732, 1999.

A. M. Issa, W. Rowe, S. Gauthier, and M. J. Meaney, “Hypothalamic-pituitary-adrenal activity in aged, cognitively impaired and cognitively unimpaired rats,” Journal of Neuroscience, vol. 10, no. 10, pp. 3247–3254, 1990.

P. W. Landfield, J. C. Waymire, and G. Lynch, “Hippocampal aging and adrenocorticoids: quantitative correlations,” Science, vol. 202, no. 4372, pp. 1098–1102, 1978.

M. W. Gilbertson, M. E. Shenton, A. Ciszewski et al., “Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma,” Nature Neuroscience, vol. 5, no. 11, pp. 1242–1247, 2002.

C. Tsigos and G. P. Chrousos, “Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress,” Journal of Psychosomatic Research, vol. 53, no. 4, pp. 865–871, 2002.

S. J. Lupien, B. S. McEwen, M. R. Gunnar, and C. Heim, “Effects of stress throughout the lifespan on the brain, behaviour and cognition,” Nature Reviews Neuroscience, vol. 10, no. 6, pp. 434–445, 2009.

Y. M. Ulrich-Lai and J. P. Herman, “Neural regulation of endocrine and autonomic stress responses,” Nature Reviews Neuroscience, vol. 10, no. 6, pp. 397–409, 2009.

E. R. De Kloet, M. Joëls, and F. Holsboer, “Stress and the brain: from adaptation to disease,” Nature Reviews Neuroscience, vol. 6, no. 6, pp. 463–475, 2005.

A. M. Magariños and B. S. McEwen, “Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: Involvement of glucocorticoid secretion and excitatory amino acid receptors,” Neuroscience, vol. 69, no. 1, pp. 89–98, 1995.

A. M. Magariños, B. S. McEwen, G. Flügge, and E. Fuchs, “Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews,” Journal of Neuroscience, vol. 16, no. 10, pp. 3534–3540, 1996.

K. M. Christian, A. D. Miracle, C. L. Wellman, and K. Nakazawa, “Chronic stress-induced hippocampal dendritic retraction requires CA3 NMDA receptors,” Neuroscience, vol. 174, pp. 26–36, 2011.

B. Leuner and T. J. Shors, “Stress, anxiety, and dendritic spines: what are the connections?” Neuroscience. In press

A. M. Magariños, A. Deslandes, and B. S. McEwen, “Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA3 pyramidal neurons after chronic stress,” European Journal of Pharmacology, vol. 371, no. 2-3, pp. 113–122, 1999.

C. R. McKittrick, A. M. Magarinõs, D. C. Blanchard, R. J. Blanchard, B. S. McEwen, and R. R. Sakai, “Chronic social stress reduces dendritic arbors in CA3 of hippocampus and decreases binding to serotonin transporter sites,” Synapse, vol. 36, pp. 85–94, 2000.

A. Steptoe and M. Kivimäki, “Stress and cardiovascular disease,” Nature Reviews Cardiology, vol. 9, no. 6, pp. 360–370, 2012.

B. Beerda, M. B. H. Schilder, J. A. R. A. M. Van Hooff, H. W. De Vries, and J. A. Mol, “Chronic stress in dogs subjected to social and spatial restriction. I. Behavioral responses,” Physiology and Behavior, vol. 66, no. 2, pp. 233–242, 1999.

V. K. Patchev and A. V. Patchev, “Experimental models of stress,” Dialogues in Clinical Neuroscience, vol. 8, no. 4, pp. 417–432, 2006.

A. S. Jaggi, N. Bhatia, N. Kumar, N. Singh, P. Anand, and R. Dhawan, “A review on animal models for screening potential anti-stress agents,” Neurological Sciences, vol. 32, no. 6, pp. 993–1005, 2011.

E. B. Foa, R. Zinbarg, and B. O. Rothbaum, “Uncontrollability and unpredictability in post-traumatic stress disorder: an animal model,” Psychological Bulletin, vol. 112, no. 2, pp. 218–238, 1992.

S. Bonfils, “‘Restraint ulcer’ as a model of stress-induced gastric lesion. A historical note,” Annals of the New York Academy of Sciences, vol. 697, pp. 229–232, 1993.

S. C. Heinrichs and G. F. Koob, “UNIT 8.4 application of experimental stressors in laboratory rodents,” Current Protocols in Neuroscience, 2006.

T. Buynitsky and D. I. Mostofsky, “Restraint stress in biobehavioral research: recent developments,” Neuroscience and Biobehavioral Reviews, vol. 33, no. 7, pp. 1089–1098, 2009.

J. W. Kim and B. Kirkpatrick, “Social isolation in animal models of relevance to neuropsychiatric disorders,” Biological Psychiatry, vol. 40, no. 9, pp. 918–922, 1996.

S. Bhatnagar and C. Vining, “Facilitation of hypothalamic-pituitary-adrenal responses to novel stress following repeated social stress using the resident/intruder paradigm,” Hormones and Behavior, vol. 43, no. 1, pp. 158–165, 2003.

T. Kikusui and Y. Mori, “Behavioural and neurochemical consequences of early weaning in rodents,” Journal of Neuroendocrinology, vol. 21, no. 4, pp. 427–431, 2009.

K. A. Alkadhi, K. H. Alzoubi, A. M. Aleisa, F. L. Tanner, and A. S. Nimer, “Psychosocial stress-induced hypertension results from in vivo expression of long-term potentiation in rat sympathetic ganglia,” Neurobiology of Disease, vol. 20, no. 3, pp. 849–857, 2005.

P. R. Zoladz, C. R. Park, J. D. Halonen et al., “Differential expression of molecular markers of synaptic plasticity in the hippocampus, prefrontal cortex, and amygdala in response to spatial learning, predator exposure, and stress-induced amnesia,” Hippocampus, vol. 22, no. 3, pp. 577–589, 2012.

H. Miura, Y. Ando, Y. Noda, K. Isobe, and N. Ozaki, “Long-lasting effects of inescapable-predator stress on brain tryptophan metabolism and the behavior of juvenile mice,” Stress, vol. 14, no. 3, pp. 262–272, 2011.

R. D. Romeo and B. S. McEwen, “Stress and the adolescent brain,” Annals of the New York Academy of Sciences, vol. 1094, pp. 202–214, 2006.

K. J. McLaughlin, S. E. Baran, and C. D. Conrad, “Chronic stress- and sex-specific neuromorphological and functional changes in limbic structures,” Molecular Neurobiology, vol. 40, no. 2, pp. 166–182, 2009.

M. Weinstock, “Sex-dependent changes induced by prenatal stress in cortical and hippocampal morphology and behaviour in rats: an update,” Stress, vol. 14, no. 6, pp. 604–613, 2011.

R. Adamec, M. Hebert, J. Blundell, and R. F. Mervis, “Dendritic morphology of amygdala and hippocampal neurons in more and less predator stress responsive rats and more and less spontaneously anxious handled controls,” Behavioural Brain Research, vol. 226, no. 1, pp. 133–146, 2012.

B. S. McEwen, “Brain on stress: how the social environment gets under the skin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, supplement 2, pp. 17180–17185, 2012.

M. M. Miller, J. H. Morrison, and B. S. McEwen, “Basal anxiety-like behavior predicts differences in dendritic morphology in the medial prefrontal cortex in two strains of rats,” Behavioural Brain Research, vol. 229, no. 1, pp. 280–288, 2012.

A. Holtmaat and K. Svoboda, “Experience-dependent structural synaptic plasticity in the mammalian brain,” Nature Reviews Neuroscience, vol. 10, no. 9, pp. 647–658, 2009.

B. Leuner and E. Gould, “Structural plasticity and hippocampal function,” Annual Review of Psychology, vol. 61, pp. 111–140, 2010.

J. J. Radley and J. H. Morrison, “Repeated stress and structural plasticity in the brain,” Ageing Research Reviews, vol. 4, no. 2, pp. 271–287, 2005.

D. J. Christoffel, S. A. Golden, and S. J. Russo, “Structural and synaptic plasticity in stress-related disorders,” Reviews in the Neurosciences, vol. 22, no. 5, pp. 535–549, 2011.

J. Jaworski, L. C. Kapitein, S. M. Gouveia et al., “Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity,” Neuron, vol. 61, no. 1, pp. 85–100, 2009.

V. A. Kulkarni and B. L. Firestein, “The dendritic tree and brain disorders,” Molecular and Cellular Neuroscience, vol. 50, no. 1, pp. 10–20, 2012.

P. Penzes and I. Rafalovich, “Regulation of the actin cytoskeleton in dendritic spines,” Advances in Experimental Medicine and Biology, vol. 970, pp. 81–95, 2012.

H. Kasai, M. Matsuzaki, J. Noguchi, N. Yasumatsu, and H. Nakahara, “Structure-stability-function relationships of dendritic spines,” Trends in Neurosciences, vol. 26, no. 7, pp. 360–368, 2003.

M. Bosch and Y. Hayashi, “Structural plasticity of dendritic spines,” Current Opinion in Neurobiology, vol. 22, no. 3, pp. 383–388, 2012.

G. Tavosanis, “Dendritic structural plasticity,” Developmental Neurobiology, vol. 72, no. 1, pp. 73–86, 2012.

K. J. McLaughlin, S. E. Baran, R. L. Wright, and C. D. Conrad, “Chronic stress enhances spatial memory in ovariectomized female rats despite CA3 dendritic retraction: possible involvement of CA1 neurons,” Neuroscience, vol. 135, no. 4, pp. 1045–1054, 2005.

J. M. Bessa, A. R. Mesquita, M. Oliveira et al., “A trans-dimensional approach to the behavioral aspects of depression,” Frontiers in Behavioral Neuroscience, vol. 3, article 1, 2009.

M. Mucha, A. E. Skrzypiec, E. Schiavon, B. K. Attwood, E. Kucerova, and R. Pawlak, “Lipocalin-2 controls neuronal excitability and anxiety by regulating dendritic spine formation and maturation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 45, pp. 18436–18441, 2011.

Y. Watanabe, E. Gould, and B. S. McEwen, “Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons,” Brain Research, vol. 588, no. 2, pp. 341–345, 1992.

N. Sousa, N. V. Lukoyanov, M. D. Madeira, O. F. X. Almeida, and M. M. Paula-Barbosa, “Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement,” Neuroscience, vol. 97, no. 2, pp. 253–266, 2000.

A. Vyas, R. Mitra, B. S. Shankaranarayana Rao, and S. Chattarji, “Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons,” Journal of Neuroscience, vol. 22, no. 15, pp. 6810–6818, 2002.

C. Sandi, H. A. Davies, M. I. Cordero, J. J. Rodriguez, V. I. Popov, and M. G. Stewart, “Rapid reversal of stress induced loss of synapses in CA3 of rat hippocampus following water maze training,” European Journal of Neuroscience, vol. 17, no. 11, pp. 2447–2456, 2003.

R. Pawlak, B. S. S. Rao, J. P. Melchor, S. Chattarji, B. McEwen, and S. Strickland, “Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 50, pp. 18201–18206, 2005.

M. G. Stewart, H. A. Davies, C. Sandi et al., “Stress suppresses and learning induces plasticity in CA3 of rat hippocampus: a three-dimensional ultrastructural study of thorny excrescences and their postsynaptic densities,” Neuroscience, vol. 131, no. 1, pp. 43–54, 2005.

H. S. Donohue, P. L. A. Gabbott, H. A. Davies et al., “Chronic restraint stress induces changes in synapse morphology in stratum lacunosum-moleculare CA1 rat hippocampus: a stereological and three-dimensional ultrastructural study,” Neuroscience, vol. 140, no. 2, pp. 597–606, 2006.

A. Soetanto, R. S. Wilson, K. Talbot et al., “Association of anxiety and depression with microtubule-associated protein 2- and synaptopodin-immunolabeled dendrite and spine densities in hippocampal CA3 of older humans,” Archives of General Psychiatry, vol. 67, no. 5, pp. 448–457, 2010.

T. T. Tran, M. Srivareerat, and K. A. Alkadhi, “Chronic psychosocial stress accelerates impairment of long-term memory and late-phase long-term potentiation in an at-risk model of Alzheimer's disease,” Hippocampus, vol. 21, no. 7, pp. 724–732, 2011.

T. T. Tran, M. Srivareerat, and K. A. Alkadhi, “Chronic psychosocial stress triggers cognitive impairment in a novel at-risk model of Alzheimer's disease,” Neurobiology of Disease, vol. 37, no. 3, pp. 756–763, 2010.

K. H. Alzoubi, M. Srivareerat, T. T. Tran, and K. A. Alkadhi, “Role of α7- and α4β2-nAChRs in the neuroprotective effect of nicotine in stress-induced impairment of hippocampus-dependent memory,” The International Journal of Neuropsychopharmacology, vol. 16, pp. 1–9, 2013.

K. H. Alzoubi, K. K. Abdul-Razzak, O. F. Khabour, G. M. Al-Tuweiq, M. A. Alzubi, and K. A. Alkadhi, “Adverse effect of combination of chronic psychosocial stress and high fat diet on hippocampus-dependent memory in rats,” Behavioural Brain Research, vol. 204, no. 1, pp. 117–123, 2009.

K. H. Alzoubi, K. K. Abdul-Razzak, O. F. Khabour, G. M. Al-Tuweiq, M. A. Alzubi, and K. A. Alkadhi, “Caffeine prevents cognitive impairment induced by chronic psychosocial stress and/or high fat-high carbohydrate diet,” Behavioural Brain Research, vol. 15, no. 237, pp. 7–14, 2013.

K. A. Alkadhi, K. H. Alzoubi, M. Srivareerat, and T. T. Tran, “Chronic psychosocial stress exacerbates impairment of synaptic plasticity in β-amyloid rat model of alzheimer's disease: prevention by nicotine,” Current Alzheimer Research, vol. 8, no. 7, pp. 718–731, 2011.

D. Manahan-Vaughan, “Long-term depression in freely moving rats is dependent upon strain variation, induction protocol and behavioral state,” Cerebral Cortex, vol. 10, no. 5, pp. 482–487, 2000.

J. Cao, N. Chen, T. Xu, and L. Xu, “Stress-facilitated LTD induces output plasticity through synchronized-spikes and spontaneous unitary discharges in the CA1 region of the hippocampus,” Neuroscience Research, vol. 49, no. 2, pp. 229–239, 2004.

C. Yang, C. Huang, and K. Hsu, “Behavioral stress modifies hippocampal synaptic plasticity through corticosterone-induced sustained extracellular signal-regulated kinase/mitogen-activated protein kinase activation,” Journal of Neuroscience, vol. 24, no. 49, pp. 11029–11034, 2004.

J. Wang and P. T. Kelly, “Postsynaptic calcineurin activity downregulates synaptic transmission by weakening intracellular Ca²⁺ signaling mechanisms in hippocampal CA1 neurons,” Journal of Neuroscience, vol. 17, no. 12, pp. 4600–4611, 1997.

S. M. Rothman, N. Herdener, S. Camandola et al., “3xTgAD mice exhibit altered behavior and elevated Aβ after chronic mild social stress,” Neurobiology of Aging, vol. 33, no. 4, pp. 830.e1–830.e12, 2012.

A. Figurov, L. D. Pozzo-Miller, P. Olafsson, T. Wang, and B. Lu, “Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus,” Nature, vol. 381, no. 6584, pp. 706–709, 1996.

G. Chen, R. Kolbeck, Y. Barde, T. Bonhoeffer, and A. Kossel, “Relative contribution of endogenous neurotrophins in hippocampal long- term potentiation,” Journal of Neuroscience, vol. 19, no. 18, pp. 7983–7990, 1999.

M. Korte, O. Griesbeck, C. Gravel et al., “Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 22, pp. 12547–12552, 1996.

S. L. Patterson, T. Abel, T. A. S. Deuel, K. C. Martin, J. C. Rose, and E. R. Kandel, “Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice,” Neuron, vol. 16, no. 6, pp. 1137–1145, 1996.

J. Alfonso, M. E. Fernández, B. Cooper, G. Flugge, and A. C. Frasch, “The stress-regulated protein M6a is a key modulator for neurite outgrowth and filopodium/spine formation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 47, pp. 17196–17201, 2005.

H. Lakshminarasimhan and S. Chattarji, “Stress leads to contrasting effects on the levels of brain derived neurotrophic factor in the hippocampus and amygdala,” PLoS ONE, vol. 7, no. 1, Article ID e30481, 2012.

A. M. Magariños, C. J. Li, J. Gal Toth et al., “Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons,” Hippocampus, vol. 21, no. 3, pp. 253–264, 2011.

X. Wang, Y. Chen, M. Wolf et al., “Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling,” Neurobiology of Disease, vol. 42, no. 3, pp. 300–310, 2011.

G. Lia, E. Praly, H. Ferreira et al., “Direct observation of DNA distortion by the RSC complex,” Molecular Cell, vol. 21, no. 3, pp. 417–425, 2006.

J. E. Garrett and C. L. Wellman, “Chronic stress effects on dendritic morphology in medial prefrontal cortex: sex differences and estrogen dependence,” Neuroscience, vol. 162, no. 1, pp. 195–207, 2009.

S. C. Cook and C. L. Wellman, “Chronic stress alters dendritic morphology in rat medial prefrontal cortex,” Journal of Neurobiology, vol. 60, no. 2, pp. 236–248, 2004.

J. J. Radley, H. M. Sisti, J. Hao et al., “Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex,” Neuroscience, vol. 125, no. 1, pp. 1–6, 2004.

J. J. Radley, A. B. Rocher, W. G. M. Janssen, P. R. Hof, B. S. McEwen, and J. H. Morrison, “Reversibility of apical dendritic retraction in the rat medial prefrontal cortex following repeated stress,” Experimental Neurology, vol. 196, no. 1, pp. 199–203, 2005.

J. J. Radley, A. B. Rocher, M. Miller et al., “Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex,” Cerebral Cortex, vol. 16, no. 3, pp. 313–320, 2006.

J. J. Radley, A. B. Rocher, A. Rodriguez et al., “Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex,” Journal of Comparative Neurology, vol. 507, no. 1, pp. 1141–1150, 2008.

J. J. Cerqueira, F. Mailliet, O. F. X. Almeida, T. M. Jay, and N. Sousa, “The prefrontal cortex as a key target of the maladaptive response to stress,” Journal of Neuroscience, vol. 27, no. 11, pp. 2781–2787, 2007.

A. Holmes and C. L. Wellman, “Stress-induced prefrontal reorganization and executive dysfunction in rodents,” Neuroscience and Biobehavioral Reviews, vol. 33, no. 6, pp. 773–783, 2009.

R. M. Shansky and J. H. Morrison, “Stress-induced dendritic remodeling in the medial prefrontal cortex: effects of circuit, hormones and rest,” Brain Research, vol. 1293, pp. 108–113, 2009.

D. S. Goldwater, C. Pavlides, R. G. Hunter et al., “Structural and functional alterations to rat medial prefrontal cortex following chronic restraint stress and recovery,” Neuroscience, vol. 164, no. 2, pp. 798–808, 2009.

E. B. Bloss, W. G. Janssen, B. S. McEwen, and J. H. Morrison, “Interactive effects of stress and aging on structural plasticity in the prefrontal cortex,” Journal of Neuroscience, vol. 30, no. 19, pp. 6726–6731, 2010.

N. Li, R. Liu, J. M. Dwyer et al., “Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure,” Biological Psychiatry, vol. 69, no. 8, pp. 754–761, 2011.

E. B. Bloss, W. G. Janssen, D. T. Ohm et al., “Evidence for reduced experience-dependent dendritic spine plasticity in the aging prefrontal cortex,” Journal of Neuroscience, vol. 31, no. 21, pp. 7831–7839, 2011.

R. Liu and G. K. Aghajanian, “Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 1, pp. 359–364, 2008.

M. Zhang, C. Zheng, M. Quan, L. An, Z. Yang, and T. Zhang, “Directional indicator on neural oscillations as a measure of synaptic plasticity in Chronic unpredictable stress rats,” NeuroSignals, vol. 19, no. 4, pp. 189–197, 2011.

L. M. Seib and C. L. Wellman, “Daily injections alter spine density in rat medial prefrontal cortex,” Neuroscience Letters, vol. 337, no. 1, pp. 29–32, 2003.

S. M. Brown, S. Henning, and C. L. Wellman, “Mild, short-term stress alters dendritic morphology in rat medial prefrontal cortex,” Cerebral Cortex, vol. 15, no. 11, pp. 1714–1722, 2005.

A. Izquierdo, C. L. Wellman, and A. Holmes, “Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice,” Journal of Neuroscience, vol. 26, no. 21, pp. 5733–5738, 2006.

A. Vyas, S. Bernal, and S. Chattarji, “Effects of chronic stress on dendritic arborization in the central and extended amygdala,” Brain Research, vol. 965, no. 1-2, pp. 290–294, 2003.

A. Vyas, S. Jadhav, and S. Chattarji, “Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala,” Neuroscience, vol. 143, no. 2, pp. 387–393, 2006.

R. Pawlak, A. M. Magarinos, J. Melchor, B. McEwen, and S. Strickland, “Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior,” Nature Neuroscience, vol. 6, no. 2, pp. 168–174, 2003.

R. Mitra, A. Vyas, G. Chatterjee, and S. Chattarji, “Chronic-stress induced modulation of different states of anxiety-like behavior in female rats,” Neuroscience Letters, vol. 383, no. 3, pp. 278–283, 2005.

M. N. Hill, C. J. Hillard, and B. S. McEwen, “Alterations in corticolimbic dendritic morphology and emotional behavior in cannabinoid CB1 receptor-deficient mice parallel the effects of chronic stress,” Cerebral Cortex, vol. 21, no. 9, pp. 2056–2064, 2011.

M. Qin, Z. Xia, T. Huang, and C. B. Smith, “Effects of chronic immobilization stress on anxiety-like behavior and basolateral amygdala morphology in Fmr1 knockout mice,” Neuroscience, vol. 194, pp. 282–290, 2011.

A. Vyas, A. G. Pillai, and S. Chattarji, “Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior,” Neuroscience, vol. 128, no. 4, pp. 667–673, 2004.

J. A. Rosenkranz, E. R. Venheim, and M. Padival, “Chronic stress causes amygdala hyperexcitability in rodents,” Biological Psychiatry, vol. 67, no. 12, pp. 1128–1136, 2010.

B. Roozendaal, B. S. McEwen, and S. Chattarji, “Stress, memory and the amygdala,” Nature Reviews Neuroscience, vol. 10, no. 6, pp. 423–433, 2009.

R. A. Sarabdjitsingh, D. Kofink, H. Karst, E. R. de Kloet, and M. Joëls, “Stress-induced enhancement of mouse amygdalar synaptic plasticity depends on glucocorticoid and β-adrenergic activity,” PLoS One, vol. 7, no. 8, Article ID e42143, 2012.

D. M. Diamond, N. Ingersoll, M. Fleshner, and G. M. Rose, “Psychological stress impairs spatial working memory: relevance to electrophysiological studies of hippocampal function,” Behavioral Neuroscience, vol. 110, no. 4, pp. 661–672, 1996.

C. Rocher, M. Spedding, C. Munoz, and T. M. Jay, “Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants,” Cerebral Cortex, vol. 14, no. 2, pp. 224–229, 2004.

F. Mailliet, H. Qi, C. Rocher, M. Spedding, P. Svenningsson, and T. M. Jay, “Protection of stress-induced impairment of hippocampal/prefrontal LTP through blockade of glucocorticoid receptors. Implication of MEK signaling,” Experimental Neurology, vol. 211, no. 2, pp. 593–596, 2008.

M. Maroun and G. Richter-Levin, “Exposure to acute stress blocks the induction of long-term potentiation of the amygdala-prefrontal cortex pathway in vivo,” Journal of Neuroscience, vol. 23, no. 11, pp. 4406–4409, 2003.

M. Maroun, “Stress reverses plasticity in the pathway projecting from the ventromedial prefrontal cortex to the basolateral amygdala,” European Journal of Neuroscience, vol. 24, no. 10, pp. 2917–2922, 2006.

P. I. Hanson and H. Schulman, “Neuronal Ca²⁺/calmodulin-dependent protein kinases,” Annual Review of Biochemistry, vol. 61, pp. 559–601, 1992.

A. Barria, V. Derkach, and T. Soderling, “Identification of the Ca²⁺/calmodulin-dependent protein kinase II regulatory phosphorylation site in the α-amino-3-hydroxyl-5-methyl-4- isoxazole-propionate-type glutamate receptor,” The Journal of Biological Chemistry, vol. 272, no. 52, pp. 32727–32730, 1997.

J. Lisman, H. Schulman, and H. Cline, “The molecular basis of CaMKII function in synaptic and behavioural memory,” Nature Reviews Neuroscience, vol. 3, no. 3, pp. 175–190, 2002.

R. C. Malenka, J. A. Kauer, D. J. Perkel et al., “An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation,” Nature, vol. 340, no. 6234, pp. 554–557, 1989.

D. L. Pettit, S. Perlman, and R. Malinow, “Potentiated transmission and prevention of further LTP by increased CaMKII activity in postsynaptic hippocampal slice neurons,” Science, vol. 266, no. 5192, pp. 1881–1885, 1994.

P. Lledo, G. O. Hjelmstad, S. Mukherji, T. R. Soderling, R. C. Malenka, and R. A. Nicoll, “Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 24, pp. 11175–11179, 1995.

K. P. Giese, N. B. Fedorov, R. K. Filipkowski, and A. J. Silva, “Autophosphorylation at Thr286 of the α calcium-calmodulin kinase II in LTP and learning,” Science, vol. 279, no. 5352, pp. 870–873, 1998.

C. Wolfman, C. Fin, M. Dias et al., “Intrahippocampal or intraamygdala infusion of KN62, a specific inhibitor of calcium/calmodulin-dependent protein kinase II, causes retrograde amnesia in the rat,” Behavioral and Neural Biology, vol. 61, no. 3, pp. 203–205, 1994.

R. Malinow, H. Schulman, and R. W. Tsien, “Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP,” Science, vol. 245, no. 4920, pp. 862–866, 1989.

A. J. Silva, C. F. Stevens, S. Tonegawa, and Y. Wang, “Deficient hippocampal long-term potentiation in α-calcium-calmodulin kinase II mutant mice,” Science, vol. 257, no. 5067, pp. 201–206, 1992.

A. J. Silva, R. Paylor, J. M. Wehner, and S. Tonegawa, “Impaired spatial learning in α-calcium-calmodulin kinase II mutant mice,” Science, vol. 257, no. 5067, pp. 206–211, 1992.

T. Miyazaki, K. Takase, W. Nakajima et al., “Disrupted cortical function underlies behavior dysfunction due to social isolation,” The Journal of Clinical Investigation, vol. 122, no. 7, pp. 2690–2701, 2012.

V. A. Derkach, M. C. Oh, E. S. Guire, and T. R. Soderling, “Regulatory mechanisms of AMPA receptors in synaptic plasticity,” Nature Reviews Neuroscience, vol. 8, no. 2, pp. 101–113, 2007.

G. Novak, T. Fan, O. 'Dowd BF, and S. R. George, “Postnatal maternal deprivation and pubertal stress have additive effects on dopamine D2 receptor and CaMKII beta expression in the striatum,” International Journal of Developmental Neuroscience, vol. 31, no. 3, pp. 189–195, 2013.

I. M. Mansuy, D. G. Winder, T. M. Moallem et al., “Inducible and reversible gene expression with the rtTA system for the study of memory,” Neuron, vol. 21, no. 2, pp. 257–265, 1998.

R. M. Mulkey, C. E. Herron, and R. C. Malenka, “An essential role for protein phosphatases in hippocampal long-term depression,” Science, vol. 261, no. 5124, pp. 1051–1055, 1993.

R. M. Mulkey, S. Endo, S. Shenolikar, and R. C. Malenka, “Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression,” Nature, vol. 369, no. 6480, pp. 486–487, 1994.

R. D. Groth, R. L. Dunbar, and P. G. Mermelstein, “Calcineurin regulation of neuronal plasticity,” Biochemical and Biophysical Research Communications, vol. 311, no. 4, pp. 1159–1171, 2003.

K. A. Alkadhi, K. H. Alzoubi, M. Srivareerat, and T. T. Tran, “Chronic psychosocial stress exacerbates impairment of synaptic plasticity in β-amyloid rat model of alzheimer's disease: prevention by nicotine,” Current Alzheimer Research, vol. 8, no. 7, pp. 718–731, 2011.

K. Takase, Y. Yamamoto, and T. Yagami, “Maternal deprivation in the middle of a stress hyporesponsive period decreases hippocampal calcineurin expression and causes abnormal social and cognitive behaviours in adult male Wistar rats: relevance to negative symptoms of schizophrenia,” Behavioural Brain Research, vol. 232, no. 1, pp. 306–315, 2012.

V. B. Matthews, M.-B. Åström, M. H. S. Chan et al., “Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase,” Diabetologia, vol. 52, no. 7, pp. 1409–1418, 2009.

C. R. Bramham and E. Messaoudi, “BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis,” Progress in Neurobiology, vol. 76, no. 2, pp. 99–125, 2005.

J. Soulé, E. Messaoudi, and C. R. Bramham, “Brain-derived neurotrophic factor and control of synaptic consolidation in the adult brain,” Biochemical Society Transactions, vol. 34, no. 4, pp. 600–604, 2006.

K. Yamada and T. Nabeshima, “Brain-derived neurotrophic factor/TrkB signaling in memory processes,” Journal Pharmacological Sciences, vol. 91, no. 4, pp. 267–270, 2003.

S. Cohen and M. E. Greenberg, “Communication between the synapse and the nucleus in neuronal development, plasticity, and disease,” Annual Review of Cell and Developmental Biology, vol. 24, pp. 183–209, 2008.

S. D. Skaper, “The biology of neurotrophins, signalling pathways, and functional peptide mimetics of neurotrophins and their receptors,” CNS and Neurological Disorders, vol. 7, no. 1, pp. 46–62, 2008.

M. C. Pardon, “Role of neurotrophic factors in behavioral processes: implications for the treatment of psychiatric and neurodegenerative disorders,” in Vitamins and Hormones, vol. 82, chapter 10, pp. 185–200, Elsevier, 2010.

E. J. Huang and L. F. Reichardt, “Trk receptors: roles in neuronal signal transduction,” Annual Review of Biochemistry, vol. 72, pp. 609–642, 2003.

L. F. Reichardt, “Neurotrophin-regulated signalling pathways,” Philosophical Transactions of the Royal Society B, vol. 361, no. 1473, pp. 1545–1564, 2006.

R. S. Duman, G. R. Heninger, and E. J. Nestler, “A molecular and cellular theory of depression,” Archives of General Psychiatry, vol. 54, no. 7, pp. 597–606, 1997.

E. J. Nestler, M. Barrot, R. J. DiLeone, A. J. Eisch, S. J. Gold, and L. M. Monteggia, “Neurobiology of depression,” Neuron, vol. 34, no. 1, pp. 13–25, 2002.

M. A. Smith, S. Makino, R. Kvetnansky, and R. M. Post, “Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus,” Journal of Neuroscience, vol. 15, no. 3, part 1, pp. 1768–1777, 1995.

K. Cieśelik, M. Sowa-Kućma, G. Ossowska et al., “Chronic unpredictable stress-induced reduction in the hippocampal brain-derived neurotrophic factor (BDNF) gene expression is antagonized by zinc treatment,” Pharmacological Reports, vol. 63, no. 2, pp. 537–543, 2011.

Y. Dwivedi, H. S. Rizavi, and G. N. Pandey, “Antidepressants reverse corticosterone-mediated decrease in brain-derived neurotrophic factor expression: differential regulation of specific exons by antidepressants and corticosterone,” Neuroscience, vol. 139, no. 3, pp. 1017–1029, 2006.

F. Karege, G. Vaudan, M. Schwald, N. Perroud, and R. La Harpe, “Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs,” Molecular Brain Research, vol. 136, no. 1-2, pp. 29–37, 2005.

J. S. Dunham, J. F. W. Deakin, F. Miyajima, A. Payton, and C. T. Toro, “Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains,” Journal of Psychiatric Research, vol. 43, no. 14, pp. 1175–1184, 2009.

F. Jeanneteau, M. J. Garabedian, and M. V. Chao, “Activation of Trk neurotrophin receptors by glucocorticoids provides a neuroprotective effect,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 12, pp. 4862–4867, 2008.

F. D. Jeanneteau, W. M. Lambert, N. Ismaili et al., “BDNF and glucocorticoids regulate corticotrophin-releasing hormone (CRH) homeostasis in the hypothalamus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 4, pp. 1305–1310, 2012.

E. Gould, C. S. Woolley, and B. S. McEwen, “Short-term glucocorticoid manipulations affect neuronal morphology and survival in the adult dentate gyrus,” Neuroscience, vol. 37, no. 2, pp. 367–375, 1990.

E. Y. Yuen, W. Liu, I. N. Karatsoreos, J. Feng, B. S. McEwen, and Z. Yan, “Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 33, pp. 14075–14079, 2009.

E. Y. Yuen, W. Liu, I. N. Karatsoreos et al., “Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory,” Molecular Psychiatry, vol. 16, no. 2, pp. 156–170, 2011.

C. Liston and W. Gan, “Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 38, pp. 16074–16079, 2011.

M. A. Smith, S. Makino, S. Kim, and R. Kvetnansky, “Stress increases brain-derived neurotropic factor messenger ribonucleic acid in the hypothalamus and pituitary,” Endocrinology, vol. 136, no. 9, pp. 3743–3750, 1995.

T. Ueyama, Y. Kawai, K. Nemoto, M. Sekimoto, S. Toné, and E. Senba, “Immobilization stress reduced the expression of neurotrophins and their receptors in the rat brain,” Neuroscience Research, vol. 28, no. 2, pp. 103–110, 1997.

T. Lee, J. Saruta, K. Sasaguri, S. Sato, and K. Tsukinoki, “Allowing animals to bite reverses the effects of immobilization stress on hippocampal neurotrophin expression,” Brain Research, vol. 1195, pp. 43–49, 2008.

S. Murakami, H. Imbe, Y. Morikawa, C. Kubo, and E. Senba, “Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly,” Neuroscience Research, vol. 53, no. 2, pp. 129–139, 2005.

N. M. Tsankova, O. Berton, W. Renthal, A. Kumar, R. L. Neve, and E. J. Nestler, “Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action,” Nature Neuroscience, vol. 9, no. 4, pp. 519–525, 2006.

A. Nair, K. C. Vadodaria, S. B. Banerjee et al., “Stressor-specific regulation of distinct brain-derived neurotrophic factor transcripts and cyclic AMP response element-binding protein expression in the postnatal and adult rat hippocampus,” Neuropsychopharmacology, vol. 32, no. 7, pp. 1504–1519, 2007.

F. Marmigère, L. Givalois, F. Rage, S. Arancibia, and L. Tapia-Arancibia, “Rapid induction of BDNF expression in the hippocampus during immobilization stress challenge in adult rats,” Hippocampus, vol. 13, no. 5, pp. 646–655, 2003.

R. Molteni, F. Calabrese, A. Cattaneo et al., “Acute stress responsiveness of the neurotrophin bdnf in the rat hippocampus is modulated by chronic treatment with the antidepressant duloxetine,” Neuropsychopharmacology, vol. 34, no. 6, pp. 1523–1532, 2009.

E. W. Neeley, R. Berger, J. I. Koenig, and S. Leonard, “Strain dependent effects of prenatal stress on gene expression in the rat hippocampus,” Physiology and Behavior, vol. 104, no. 2, pp. 334–339, 2011.

S. T. Bland, M. J. Schmid, A. Der-Avakian, L. R. Watkins, R. L. Spencer, and S. F. Maier, “Expression of c-fos and BDNF mRNA in subregions of the prefrontal cortex of male and female rats after acute uncontrollable stress,” Brain Research, vol. 1051, no. 1-2, pp. 90–99, 2005.

Y. Lee, R. S. Duman, and G. J. Marek, “The mGlu2/3 receptor agonist LY354740 suppresses immobilization stress-induced increase in rat prefrontal cortical BDNF mRNA expression,” Neuroscience Letters, vol. 398, no. 3, pp. 328–332, 2006.

S. Fanous, R. P. Hammer, and E. M. Nikulina, “Short- and long-term effects of intermittent social defeat stress on brain-derived neurotrophic factor expression in mesocorticolimbic brain regions,” Neuroscience, vol. 167, no. 3, pp. 598–607, 2010.

S. L. Gourley, A. T. Kedves, P. Olausson, and J. R. Taylor, “A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF,” Neuropsychopharmacology, vol. 34, no. 3, pp. 707–716, 2009.

J. C. P. Yin, J. S. Wallach, M. Del Vecchio et al., “Induction of a dominant negative CREB transgene specifically blocks long- term memory in Drosophila,” Cell, vol. 79, no. 1, pp. 49–58, 1994.

T. Tully, “Regulation of gene expression and its role in long-term memory and synaptic plasticity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4239–4241, 1997.

T. Abel and E. Kandel, “Positive and negative regulatory mechanisms that mediate long-term memory storage,” Brain Research Reviews, vol. 26, no. 2-3, pp. 360–378, 1998.

L. E. Ecke, J. N. Cleck, P. White, J. Schug, L. Mifflin, and J. A. Blendy, “CREB-mediated alterations in the amygdala transcriptome: coordinated regulation of immune response genes following cocaine,” International Journal of Neuropsychopharmacology, vol. 14, no. 8, pp. 1111–1126, 2011.

N. A. Datson, N. Speksnijder, J. L. Mayer et al., “The transcriptional response to chronic stress and glucocorticoid receptor blockade in the hippocampal dentate gyrus,” Hippocampus, vol. 22, no. 2, pp. 359–371, 2012.

M. R. Montminy and L. M. Bilezikjian, “Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene,” Nature, vol. 328, no. 6126, pp. 175–178, 1987.

K. K. Yamamoto, G. A. Gonzalez, W. H. Biggs III, and M. R. Montminy, “Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB,” Nature, vol. 334, no. 6182, pp. 494–498, 1988.

P. B. Shieh, S. Hu, K. Bobb, T. Timmusk, and A. Ghosh, “Identification of a signaling pathway involved in calcium regulation of BDNF expression,” Neuron, vol. 20, no. 4, pp. 727–740, 1998.

P. K. Dash, B. Hochner, and E. R. Kandel, “Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation,” Nature, vol. 345, no. 6277, pp. 718–721, 1990.

B.-K. Kaang, E. R. Kandel, and S. G. N. Grant, “Activation of cAMP-responsive genes by stimuli that produce long-term facilitation in Aplysia sensory neurons,” Neuron, vol. 10, no. 3, pp. 427–435, 1993.

R. Bourtchuladze, B. Frenguelli, J. Blendy, D. Cioffi, G. Schutz, and A. J. Silva, “Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein,” Cell, vol. 79, no. 1, pp. 59–68, 1994.

M. Qi, M. Zhuo, B. S. Skålhegg et al., “Impaired hippocampal plasticity in mice lacking the Cβ1 catalytic subunit of cAMP-dependent protein kinase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 4, pp. 1571–1576, 1996.

S. T. Wong, J. Athos, X. A. Figueroa et al., “Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP,” Neuron, vol. 23, no. 4, pp. 787–798, 1999.

A. Trentani, S. D. Kuipers, G. J. Ter Horst, and J. A. Den Boer, “Selective chronic stress-induced in vivo ERK1/2 hyperphosphorylation in medial prefrontocortical dendrites: implications for stress-related cortical pathology?” European Journal of Neuroscience, vol. 15, no. 10, pp. 1681–1691, 2002.

S. D. Kuipers, A. Trentani, J. A. Den Boer, and G. J. Ter Horst, “Molecular correlates of impaired prefrontal plasticity in response to chronic stress,” Journal of Neurochemistry, vol. 85, no. 5, pp. 1312–1323, 2003.

K. A. Alkadhi, “Chronic stress and Alzheimer's disease-like pathogenesis in a rat model: prevention by nicotine,” Current Neuropharmacology, vol. 9, no. 4, pp. 587–597, 2011.

K. F. Jensen, C. A. Ohmstede, R. S. Fisher, J. K. Olin, and N. Sahyoun, “Acquisition and loss of a neuronal Ca²⁺/calmodulin-dependent protein kinase during neuronal differentiation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 9, pp. 4050–4053, 1991.

K. F. Jensen, C.-A. Ohmstede, R. S. Fisher, and N. Sahyoun, “Nuclear and axonal localization of Ca²⁺/calmodulin-dependent protein kinase type Gr in rat cerebellar cortex,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 7, pp. 2850–2853, 1991.

A. R. Means, F. Cruzalegui, B. LeMagueresse, D. S. Needleman, G. R. Slaughter, and T. Ono, “A novel Ca²⁺/calmodulin-dependent protein kinase and a male germ cell-specific calmodulin-binding protein are derived from the same gene,” Molecular and Cellular Biology, vol. 11, no. 8, pp. 3960–3971, 1991.

C. A. Ohmstede, M. M. Bland, B. M. Merrill, and N. Sahyoun, “Relationship of genes encoding Ca²⁺/calmodulin-dependent protein kinase Gr and calspermin: a gene within a gene,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, pp. 5784–5788, 1991.

B. E. Lonze and D. D. Ginty, “Function and regulation of CREB family transcription factors in the nervous system,” Neuron, vol. 35, no. 4, pp. 605–623, 2002.

C.-A. Ohmstede, K. F. Jensen, and N. E. Sahyoun, “Ca²⁺/Calmodulin-dependent protein kinase enriched in cerebellar granule cells. Identification of a novel neuronal calmodulin-dependent protein kinase,” The Journal of Biological Chemistry, vol. 264, no. 10, pp. 5866–5875, 1989.

H. Bito, K. Deisseroth, and R. W. Tsien, “CREB phosphorylation and dephosphorylation: a Ca²⁺- and stimulus duration-dependent switch for hippocampal gene expression,” Cell, vol. 87, no. 7, pp. 1203–1214, 1996.

M. Tokuda, B. Y. Ahmed, Y. Lu et al., “Involvement of calmodulin-dependent protein kinases-I and -IV in long-term potentiation,” Brain Research, vol. 755, no. 1, pp. 162–166, 1997.

N. Ho, J. A. Liauw, F. Blaeser et al., “Impaired synaptic plasticity and cAMP response element-binding protein activation in Ca²⁺/calmodulin-dependent protein kinase type IV/Gr-Deficient mice,” Journal of Neuroscience, vol. 20, no. 17, pp. 6459–6472, 2000.

H. Kang, L. D. Sun, C. M. Atkins, T. R. Soderling, M. A. Wilson, and S. Tonegawa, “An important role of neural activity-dependent CaMKIV signaling in the consolidation of long-term memory,” Cell, vol. 106, no. 6, pp. 771–783, 2001.

F. W. F. Shum, S. W. Ko, Y. Lee, B. Kaang, and M. Zhuo, “Genetic alteration of anxiety and stress-like behavior in mice lacking CaMKIV,” Molecular Pain, vol. 1, article 22, 2005.

K. A. Alkadhi, M. Srivareerat, and T. T. Tran, “Intensification of long-term memory deficit by chronic stress and prevention by nicotine in a rat model of Alzheimer's disease,” Molecular and Cellular Neuroscience, vol. 45, no. 3, pp. 289–296, 2010.

B. A. Schindler, “Stress, affective disorders, and immune function,” Medical Clinics of North America, vol. 69, no. 3, pp. 585–597, 1985.

E. Walker, V. Mittal, and K. Tessner, “Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia,” Annual Review of Clinical Psychology, vol. 4, pp. 189–216, 2008.

J. A. Whitworth, G. J. Mangos, and J. J. Kelly, “Cushing, cortisol, and cardiovascular disease,” Hypertension, vol. 36, no. 5, pp. 912–916, 2000.

K. Alkadhi and K. Alzoubi, “Role of long-term potentiation of sympathetic ganglia (gLTP) in hypertension,” Clinical and Experimental Hypertension, vol. 29, no. 5, pp. 267–286, 2007.

K. A. Muscatell and N. I. Eisenberger, “A social neuroscience perspective on stress and health,” Social and Personality Psychology Compass, vol. 6, no. 12, pp. 890–904, 2012.

A. Kibel and I. Drenjančević-Perić, “Impact of glucocorticoids and chronic stress on progression of Parkinson's disease,” Medical Hypotheses, vol. 71, no. 6, pp. 952–956, 2008.

B. S. McEwen, “Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators,” European Journal of Pharmacology, vol. 583, no. 2-3, pp. 174–185, 2008.

G. A. Metz, N. M. Jadavji, and L. K. Smith, “Modulation of motor function by stress: A novel concept of the effects of stress and corticosterone on behavior,” European Journal of Neuroscience, vol. 22, no. 5, pp. 1190–1200, 2005.

D. Hering, T. Kara, W. Kucharska, V. K. Somers, and K. Narkiewicz, “High-normal blood pressure is associated with increased resting sympathetic activity but normal responses to stress tests,” Blood Press, vol. 22, no. 3, pp. 183–187, 2013.

A. E. van Dijk, M. van Eijsden, K. Stronks, R. J. B. J. Gemke, and T. G. M. Vrijkotte, “Prenatal stress and balance of the child's cardiac autonomic nervous system at age 5-6 years,” PLoS ONE, vol. 7, no. 1, Article ID e30413, 2012.

M. Esler, S. Julius, and A. Zweifler, “Mild high renin essential hypertension. Neurogenic human hypertension?” New England Journal of Medicine, vol. 296, no. 8, pp. 405–411, 1977.

J. L. Boone, “Stress and hypertension,” Primary Care - Clinics in Office Practice, vol. 18, no. 3, pp. 623–649, 1991.

W. B. Kannel, W. F. Peter, and M. D. Wilson, “Cardiovascular risk factors and hypertension,” in Hypertension Primer: The Essentials of High Blood Pressure, J. L. Izzo and H. R. Black, Eds., pp. 199–200, Lippincott Williams and Wilkens, Baltimore, Md, USA, 1999.

A. L. Mark, “The sympathetic nervous system in hypertension: A potential long-term regulator of arterial pressure,” Journal of Hypertension, Supplement, vol. 14, no. 5, pp. S159–S165, 1996.

K. A. Alkadhi, K. H. Alzoubi, A. M. Aleisa, F. L. Tanner, and A. S. Nimer, “Psychosocial stress-induced hypertension results from in vivo expression of long-term potentiation in rat sympathetic ganglia,” Neurobiology of Disease, vol. 20, no. 3, pp. 849–857, 2005.

J. P. Naftel and S. G. Hardy, “Visceral motor pathways,” in Fundemental Neuroscience, D. E. Haines, Ed., pp. 417–429, Churchill-Livingstone, Philadelphia, Pa, USA, 1997.

W. J. T. Nauta, “Comparative anatomy,” in The Frontal Granular Cortex and Behavior, J. W. Warren and K. Akert, Eds., pp. 372–396, McGraw-Hill, New York, NY, USA, 1964.

J. E. Skinner and J. C. Reed, “Blockade of frontocortical-brain stem pathway prevents ventricular fibrillation of ischemic heart,” American Journal of Physiology - Heart and Circulatory Physiology, vol. 9, no. 2, pp. H156–H163, 1981.

K. H. Alzoubi, A. M. Aleisa, and K. A. Alkadhi, “Expression of gLTP in sympathetic ganglia of obese Zucker rats in vivo: Molecular evidence,” Journal of Molecular Neuroscience, vol. 35, no. 3, pp. 297–306, 2008.

K. H. Alzoubi, A. M. Aleisa, and K. A. Alkadhi, “Expression of gLTP in sympathetic ganglia from stress-hypertensive rats: Molecular evidence,” Journal of Molecular Neuroscience, vol. 35, no. 2, pp. 201–209, 2008.

K. A. Alkadhi, K. H. Alzoubi, and A. M. Aleisa, “Synaptic plasticity of autonomic ganglia: role of chronic stress and implication in cardiovascular diseases and sudden death,” in Sudden Death in Epilepsy: Forensic and Clinical Issue, C. M. Lathers, P. L. Schraeder, M. W. Bungo, and J. E. Leestma, Eds., chapter 26, pp. 395–424, 2011.

H. Ito, I. Kanno, J. Hatazawa, and S. Miura, “Changes in human cerebral blood flow and myocardial blood flow during mental stress measured by dual positron emission tomography,” Annals of Nuclear Medicine, vol. 17, no. 5, pp. 381–386, 2003.

P. A. Shapiro, R. P. Sloan, E. Bagiella, J. P. Kuhl, S. Anjilvel, and J. J. Mann, “Cerebral activation, hostility, and cardiovascular control during mental stress,” Journal of Psychosomatic Research, vol. 48, no. 4-5, pp. 485–491, 2000.

A. Alzheimer, “UbereineeigenartigeErkrankung der Hirnrinde,” Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medizin, vol. 64, pp. 146–148, 1907.

A. Alzheimer, “UbereigenartigeKrankheitsfalle des sparteren Alters,” Zeitschrift für die Gesamte Neurologie und Psychiatrie, vol. 4, pp. 356–385, 1911.

M. Goedert and M. G. Spillantini, “A century of Alzheimer's disease,” Science, vol. 314, no. 5800, pp. 777–781, 2006.

J. Hardy, “A Hundred Years of Alzheimer's Disease Research,” Neuron, vol. 52, no. 1, pp. 3–13, 2006.

K. Blennow, M. J. de Leon, and H. Zetterberg, “Alzheimer's disease,” The Lancet, vol. 368, no. 9533, pp. 387–403, 2006.

Alzheimers-Association, “Alzheimers disease facts and figures,” Alzheimers Dement, vol. 6, pp. 158–194, 2010.

R. S. Wilson, D. A. Evans, J. L. Bienias, C. F. Mendes De Leon, J. A. Schneider, and D. A. Bennett, “Proneness to psychological distress is associated with risk of Alzheimer's disease,” Neurology, vol. 61, no. 11, pp. 1479–1485, 2003.

R. S. Wilson, L. L. Barnes, D. A. Bennett et al., “Proneness to psychological distress and risk of Alzheimer disease in a biracial community,” Neurology, vol. 64, no. 2, pp. 380–382, 2005.

P. S. Aisen, K. L. Davis, J. D. Berg et al., “A randomized controlled trial of prednisone in Alzheimer's disease,” Neurology, vol. 54, no. 3, pp. 588–593, 2000.

W. A. Pedersen, P. J. McMillan, J. J. Kulstad, J. B. Leverenz, S. Craft, and G. R. Haynatzki, “Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice,” Experimental Neurology, vol. 199, no. 2, pp. 265–273, 2006.

J. J. Kulstad, P. J. McMillan, J. B. Leverenz et al., “Effects of chronic glucocorticoid administration on insulin-degrading enzyme and amyloid-beta peptide in the aged macaque,” Journal of Neuropathology and Experimental Neurology, vol. 64, no. 2, pp. 139–146, 2005.

P. W. Landfield, E. M. Blalock, K. Chen, and N. M. Porter, “A new glucocorticoid hypothesis of brain aging: Implications for Alzheimer's disease,” Current Alzheimer Research, vol. 4, no. 2, pp. 205–212, 2007.

L. Jacobson and R. Sapolsky, “The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis,” Endocrine Reviews, vol. 12, no. 2, pp. 118–134, 1991.

A. Hartmann, J. D. Veldhuis, M. Deuschle, H. Standhardt, and I. Heuser, “Twenty-four hour cortisol release profiles in patients with Alzheimer's and Parkinson's disease compared to normal controls: Ultradian secretory pulsatility and diurnal variation,” Neurobiology of Aging, vol. 18, no. 3, pp. 285–289, 1997.

D.-J. de Quervain, R. Poirier, M. A. Wollmer et al., “Glucocorticoid-related genetic susceptibility for Alzheimer's disease,” Human Molecular Genetics, vol. 13, no. 1, pp. 47–52, 2004.

C. Catania, I. Sotiropoulos, R. Silva et al., “The amyloidogenic potential and behavioral correlates of stress,” Molecular Psychiatry, vol. 14, no. 1, pp. 95–105, 2009.

K. A. Alkadhi, K. H. Alzoubi, M. Srivareerat, and T. T. Tran, “Elevation of BACE in an Aβ rat model of Alzheimer's disease: Exacerbation by chronic stress and prevention by nicotine,” International Journal of Neuropsychopharmacology, vol. 15, no. 2, pp. 223–233, 2012.

U. Böer, C. Noll, I. Cierny, D. Krause, C. Hiemke, and W. Knepel, “A common mechanism of action of the selective serotonin reuptake inhibitors citalopram and fluoxetine: reversal of chronic psychosocial stress-induced increase in CRE/CREB-directed gene transcription in transgenic reporter gene mice,” European Journal of Pharmacology, vol. 633, no. 1–3, pp. 33–38, 2010.

L. K. Smith, N. M. Jadavji, K. L. Colwell, S. Katrina Perehudoff, and G. A. Metz, “Stress accelerates neural degeneration and exaggerates motor symptoms in a rat model of Parkinson's disease,” European Journal of Neuroscience, vol. 27, no. 8, pp. 2133–2146, 2008.

K. H. Alzoubi, A. M. Aleisa, and K. A. Alkadhi, “Effect of chronic stress or nicotine on hypothyroidism-induced enhancement of LTD: Electrophysiological and molecular studies,” Neurobiology of Disease, vol. 32, no. 1, pp. 81–87, 2008.

J. E. Spar and R. Gerner, “Does the dexamethasone suppression test distinguish dementia from depression?” American Journal of Psychiatry, vol. 139, no. 2, pp. 238–240, 1982.

J. Balldin, C. G. Gottfries, and I. Karlsson, “Dexamethasone suppression test and serum prolactin in dementia disorders,” British Journal of Psychiatry, vol. 143, no. 3, pp. 277–281, 1983.

M. A. Jenike and M. S. Albert, “The dexamethasone suppression test in patients with presenile and senile dementia of the Alzheimer's type,” Journal of the American Geriatrics Society, vol. 32, no. 6, pp. 441–444, 1984.

I. G. McKeith, “Clinical use of the DST in a psychogeriatric population,” British Journal of Psychiatry, vol. 145, pp. 389–393, 1984.

K. L. Davis, B. M. Davis, and B. S. Greenwald, “Cortisol and Alzheimer's disease. I: Basal studies,” American Journal of Psychiatry, vol. 143, no. 3, pp. 300–305, 1986.

D. S. Kerr, L. W. Campbell, O. Thibault, and P. W. Landfield, “Hippocampal glucocorticoid receptor activation enhances voltage-dependent Ca²⁺ conductances: Relevance to brain aging,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 18, pp. 8527–8531, 1992.

P. W. Landfield and J. C. Eldridge, “Evolving aspects of the glucocorticoid hypothesis of brain aging: Hormonal modulation of neuronal calcium homeostasis,” Neurobiology of Aging, vol. 15, no. 4, pp. 579–588, 1994.

W. A. Pedersen, R. Wan, and M. P. Mattson, “Impact of aging on stress-responsive neuroendocrine systems,” Mechanisms of Ageing and Development, vol. 122, no. 9, pp. 963–983, 2001.

T. J. Shors, M. R. Foy, S. Levine, and R. F. Thompson, “Unpredictable and uncontrollable stress impairs neuronal plasticity in the rat hippocampus,” Brain Research Bulletin, vol. 24, no. 5, pp. 663–667, 1990.

T. J. Shors and R. F. Thompson, “Acute stress impairs (or induces) synaptic long-term potentiation (LTP) but does not affect paired-pulse facilitation in the stratum radiatum of rat hippocampus,” Synapse, vol. 11, no. 3, pp. 262–265, 1992.

I. J. E. Heuser, T. N. Chase, and M. Maral Mouradian, “The limbic-hypothalamic-pituitary-adrenal axis in Huntington's disease,” Biological Psychiatry, vol. 30, no. 9, pp. 943–952, 1991.

F. R. Patacchioli, P. Monnazzi, A. Scontrini et al., “Adrenal dysregulation in amyotrophic lateral sclerosis,” Journal of Endocrinological Investigation, vol. 26, no. 12, pp. RC23–RC25, 2003.

A. M. Snyder, E. M. Stricker, and M. J. Zigmond, “Self-induced neurological impairments in an animal model of parkinsonism,” Annals of Neurology, vol. 18, no. 5, pp. 544–551, 1985.

D. F. Swaab, A. Bao, and P. J. Lucassen, “The stress system in the human brain in depression and neurodegeneration,” Ageing Research Reviews, vol. 4, no. 2, pp. 141–194, 2005.

D. Weintraub, C. L. Comella, and S. Horn, “Parkinson's disease—part 1: pathophysiology, symptoms, burden, diagnosis, and assessment,” American Journal of Managed Care, vol. 14, no. 2, pp. S40–S48, 2008.

A. M. Hemmerle, J. P. Herman, and K. B. Seroogy, “Stress, depression and Parkinson's disease,” Experimental Neurology, vol. 233, no. 1, pp. 79–86, 2012.

A. Lieberman, “Depression in Parkinsons disease—a review,” Acta Neurologica Scandinavica, vol. 113, pp. 1–8, 2006.

D. Weintraub, C. L. Comella, and S. Horn, “Parkinson's disease—part 3: neuropsychiatric symptoms,” American Journal of Managed Care, vol. 14, no. 2, pp. S59–S69, 2008.

K. S. P. McNaught, D. P. Perl, A. Brownell, and C. W. Olanow, “Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease,” Annals of Neurology, vol. 56, no. 1, pp. 149–162, 2004.

D. R. Ziegler, W. A. Cass, and J. P. Herman, “Excitatory influence of the locus coeruleus in hypothalamic-pituitary-adrenocortical axis responses to stress,” Journal of Neuroendocrinology, vol. 11, no. 5, pp. 361–369, 1999.

N. Rasheed, A. Ahmad, C. P. Pandey, R. K. Chaturvedi, M. Lohani, and G. Palit, “Differential response of central dopaminergic system in acute and chronic unpredictable stress models in rats,” Neurochemical Research, vol. 35, no. 1, pp. 22–32, 2010.

E. Gould and P. Tanapat, “Stress and hippocampal neurogenesis,” Biological Psychiatry, vol. 46, no. 11, pp. 1472–1479, 1999.

A. Charlett, R. J. Dobbs, A. G. Purkiss et al., “Cortisol is higher in parkinsonism and associated with gait deficit,” Acta Neurologica Scandinavica, vol. 97, no. 2, pp. 77–85, 1998.

T. Müller, J. Welnic, and S. Muhlack, “Acute levodopa administration reduces cortisol release in patients with Parkinson's disease,” Journal of Neural Transmission, vol. 114, no. 3, pp. 347–350, 2007.

F. B. Gibberd and J. P. Simmonds, “Neurological disease in ex-Far-East prisoners of war,” The Lancet, vol. 2, no. 8186, pp. 135–137, 1980.

R. M. Sapolsky, “Why stress is bad for your brain,” Science, vol. 273, no. 5276, pp. 749–750, 1996.

M. Macht, S. Brandstetter, and H. Ellgring, “Stress affects hedonic responses but not reaching-grasping in Parkinson's disease,” Behavioural Brain Research, vol. 177, no. 1, pp. 171–174, 2007.

F. Ros-Bernal, S. Hunot, M. T. Herrero et al., “Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 16, pp. 6632–6637, 2011.

P. da Silva Sousa, K. Lin, E. Garzon, A. C. Sakamoto, and E. M. T. Yacubian, “Self-perception of factors that precipitate or inhibit seizures in juvenile myoclonic epilepsy,” Seizure, vol. 14, no. 5, pp. 340–346, 2005.

M. M. Frucht, M. Quigg, C. Schwaner, and N. B. Fountain, “Distribution of seizure precipitants among epilepsy syndromes,” Epilepsia, vol. 41, no. 12, pp. 1534–1539, 2000.

S. R. Haut, M. Vouyiouklis, and S. Shinnar, “Stress and epilepsy: a patient perception survey,” Epilepsy and Behavior, vol. 4, no. 5, pp. 511–514, 2003.

R. H. Mattson, “Emotional effects on seizure occurrence,” Advances in neurology, vol. 55, pp. 453–460, 1991.

K. O. Nakken, M. H. Solaas, M. J. Kjeldsen, M. L. Friis, J. M. Pellock, and L. A. Corey, “Which seizure-precipitating factors do patients with epilepsy most frequently report?” Epilepsy and Behavior, vol. 6, no. 1, pp. 85–89, 2005.

M. R. Sperling, C. A. Schilling, D. Glosser, J. I. Tracy, and A. A. Asadi-Pooya, “Self-perception of seizure precipitants and their relation to anxiety level, depression, and health locus of control in epilepsy,” Seizure, vol. 17, no. 4, pp. 302–307, 2008.

N. T. Sawyer and A. Escayg, “Stress and epilepsy: multiple models, multiple outcomes,” Journal of Clinical Neurophysiology, vol. 27, no. 6, pp. 445–452, 2010.

S. D. Shorvon, “The causes of epilepsy: changing concepts of etiology of epilepsy over the past 150 years,” Epilepsia, vol. 52, no. 6, pp. 1033–1044, 2011.

M. P. Jacobs, G. G. Leblanc, A. Brooks-Kayal et al., “Curing epilepsy: progress and future directions,” Epilepsy and Behavior, vol. 14, no. 3, pp. 438–445, 2009.

W. A. M. Swinkels, M. Engelsman, D. G. A. Kasteleijn-Nolst Trenité, M. G. Baal, G. J. De Haan, and J. Oosting, “Influence of an evacuation in February 1995 in The Netherlands on the seizure frequency in patients with epilepsy: a controlled study,” Epilepsia, vol. 39, no. 11, pp. 1203–1207, 1998.

J. Bosnjak, M. Vukovic-Bobic, and V. Mejaski-Bosnjak, “Effect of war on the occurrence of epileptic seizures in children,” Epilepsy and Behavior, vol. 3, no. 6, pp. 502–509, 2002.

R. M. Arida, F. A. Scorza, V. C. Terra, C. A. Scorza, A. de Almeida, and E. A. Cavalheiro, “Physical exercise in epilepsy: what kind of stressor is it?” Epilepsy and Behavior, vol. 16, no. 3, pp. 381–387, 2009.

M. Lai, G. L. Holmes, K. Lee et al., “Effect of neonatal isolation on outcome following neonatal seizures in rats—the role of corticosterone,” Epilepsy Research, vol. 68, no. 2, pp. 123–136, 2006.

M. Salzberg, G. Kumar, L. Supit et al., “Early postnatal stress confers enduring vulnerability to limbic epileptogenesisy,” Epilepsia, vol. 48, no. 11, pp. 2079–2085, 2007.

H. E. Edwards, D. Dortok, J. Tam, D. Won, and W. M. Burnham, “Prenatal stress alters seizure thresholds and the development of kindled seizures in infant and adult rats,” Hormones and Behavior, vol. 42, no. 4, pp. 437–447, 2002.

A. S. Koe, N. C. Jones, and M. R. Salzberg, “Early life stress as an influence on limbic epilepsy: an hypothesis whose time has come?” Frontiers in Behavioral Neuroscience, vol. 3, article 24, 2009.

I. Ali, M. R. Salzberg, C. French, and N. C. Jones, “Electrophysiological insights into the enduring effects of early life stress on the brain,” Psychopharmacology, vol. 214, no. 1, pp. 155–173, 2011.

G. Kumar, N. C. Jones, M. J. Morris, S. Rees, T. J. O'Brien, and M. R. Salzberg, “Early life stress enhancement of limbic epileptogenesis in adult rats: mechanistic insights,” PLoS ONE, vol. 6, no. 9, Article ID e24033, 2011.

J. Engel, P. Williamson, and H. Wieser, “Mesial temporal lobe epilepsy with hippocampal sclerosis,” in Epilepsy: A Comprehensive Textbook, J. Engel and T. Pedley, Eds., pp. 2479–2486, Wolters Kluwer, Philadelphia, 2 edition, 2007.

A. M. Kanner, “Depression in epilepsy: a complex relation with unexpected consequences,” Current Opinion in Neurology, vol. 21, no. 2, pp. 190–194, 2008.

H. Karst, “Episodic corticosterone treatment accelerates kindling epileptogenesis and triggers long-term changes in hippocampal CA1 cells, in the fully kindled state,” European Journal of Neuroscience, vol. 11, no. 3, pp. 889–898, 1999.

G. Kumar, A. Couper, T. J. O'Brien et al., “The acceleration of amygdala kindling epileptogenesis by chronic low-dose corticosterone involves both mineralocorticoid and glucocorticoid receptors,” Psychoneuroendocrinology, vol. 32, no. 7, pp. 834–842, 2007.

T. R. Taher, M. Salzberg, M. J. Morris, S. Rees, and T. J. O'Brien, “Chronic low-dose corticosterone supplementation enhances acquired epileptogenesis in the rat amygdala kindling model of TLE,” Neuropsychopharmacology, vol. 30, no. 9, pp. 1610–1616, 2005.

F. G. Freeman, “Development of kindled seizures and circadian rhythms,” Behavioral and Neural Biology, vol. 30, no. 2, pp. 231–235, 1980.

R. P. Rose, F. Morell, and T. J. Hoeppner, “Influences of pituitary-adrenal hormones on kindling,” Brain Research, vol. 169, no. 2, pp. 303–315, 1979.

G. K. Weiss, K. Lucero, M. Fernandez, D. Karnaze, and N. Castillo, “The effect of adrenalectomy on the circadian variation in the rate of kindled seizure development,” Brain Research, vol. 612, no. 1-2, pp. 354–356, 1993.

G. K. Weiss, N. Castillo, and M. Fernandez, “Amygdala kindling rate is altered in rats with a deficit in the responsiveness of the hypothalamo-pituitary-adrenal axis,” Neuroscience Letters, vol. 157, no. 1, pp. 91–94, 1993.

T. Z. Baram and L. Schultz, “Corticotropin-releasing hormone is a rapid and potent convulsant in the infant rat,” Developmental Brain Research, vol. 61, no. 1, pp. 97–101, 1991.

T. Z. Baram, E. Hirsch, O. C. Snead III, and L. Schultz, “Corticotropin-releasing hormone-induced seizures in infant rats originate in the amygdala,” Annals of Neurology, vol. 31, no. 5, pp. 488–494, 1992.

C. L. Ehlers, S. J. Henriksen, and M. Wang, “Corticotropin releasing factor produces increases in brain excitability and convulsive seizures in rats,” Brain Research, vol. 278, no. 1-2, pp. 332–336, 1983.

F. Marrosu, W. Fratta, P. Carcangiu, M. Giagheddu, and G. L. Gessa, “Localized epileptiform activity induced by murine CRF in rats,” Epilepsia, vol. 29, no. 4, pp. 369–373, 1988.

S. R. B. Weiss, R. M. Post, and P. W. Gold, “CRF-induced seizures and behavior: interaction with amygdala kindling,” Brain Research, vol. 372, no. 2, pp. 345–351, 1986.

W. Deng, J. B. Aimone, and F. H. Gage, “New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?” Nature Reviews Neuroscience, vol. 11, no. 5, pp. 339–350, 2010.

B. L. Murphy, R. Y. K. Pun, H. Yin, C. R. Faulkner, A. W. Loepke, and S. C. Danzer, “Heterogeneous integration of adult-generated granule cells into the epileptic brain,” Journal of Neuroscience, vol. 31, no. 1, pp. 105–117, 2011.

J. M. Parent and G. G. Murphy, “Mechanisms and functional significance of aberrant seizure-induced hippocampal neurogenesis,” Epilepsia, vol. 49, no. 5, pp. 19–25, 2008.

S. C. Danzer, “Depression, stress, epilepsy and adult neurogenesis,” Experimental Neurology, vol. 233, no. 1, pp. 22–32, 2012.

E. Walker, V. Mittal, and K. Tessner, “Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia,” Annual Review of Clinical Psychology, vol. 4, pp. 189–216, 2008.

J. A. Whitworth, G. J. Mangos, and J. J. Kelly, “Cushing, cortisol, and cardiovascular disease,” Hypertension, vol. 36, no. 5, pp. 912–916, 2000.

A. Willemsen-Dunlap, P. A. Leonard, and J. L. Cutkomp, “Thyroid storm precipitated by stress in an undiagnosed hyperthyroid patient: a simulated medical crisis,” Simulation in Healthcare, vol. 7, no. 1, pp. 48–53, 2012.

G. Effraimidis, J. G. Tijssen, J. F. Brosschot, and W. M. Wiersinga, “Involvement of stress in the pathogenesis of autoimmune thyroid disease: a prospective study,” Psychoneuroendocrinology, vol. 37, no. 8, pp. 1191–1198, 2012.

S. Sofianopoulos, B. Williams, and F. Archer, “Paramedics and the effects of shift work on sleep: a literature review,” Emergency Medicine Journal, vol. 29, no. 2, pp. 152–155, 2012.

C. J. Brackenridge, “Relation of occupational stress to the age at onset of Huntington's disease,” Acta Neurologica Scandinavica, vol. 60, no. 5, pp. 272–276, 1979.

E. Maiera, “Bipolar disorder and stress,” Psychiatria Danubina, vol. 24, 1, pp. S59–S60, 2012.

E. Brietzke, R. B. Mansur, J. Soczynska, A. M. Powell, and R. S. McIntyre, “A theoretical framework informing research about the role of stress in the pathophysiology of bipolar disorder,” Progress in Neuro-Psychopharmacology & Biological Psychiatry, vol. 39, no. 1, pp. 1–8, 2012.