Search

Depression is commonly associated with hypothalamic-pituitary adrenal (HPA) axis dysfunction that primarily manifests as aberrant glucocorticoid secretion. Glucocorticoids act on Type I mineralocorticoid (MR) and Type II glucocorticoid receptors (GR) to modulate mood and endocrine responses. Successful antidepressant treatment normalizes HPA axis function, in part due to modulatory effects on MR and GR in cortico-limbic structures. Although women are twice as likely to suffer from depression, little is known about how antidepressants modulate brain, endocrine, and behavioral stress responses in females. Here, we assessed the impact of CORT118335 (GR modulator/MR antagonist) and imipramine (tricyclic antidepressant) on neuroendocrine and behavioral responses to restraint or forced swim stress (FST) in female rats (n=10-12/group). Increased immobility CORT118335 in the FST is purported to reflect passive coping or depression-like behavior. CORT118335 dampened adrenocorticotropic hormone (ACTH) and corticosterone responses to the FST, but did not affect immobility. Imipramine suppressed ACTH, but had minimal effects on corticosterone responses to FST. Despite these marginal effects, imipramine decreased immobility, suggesting antidepressant efficacy. In an effort to link brain-endocrine responses with behavior, c-Fos was assessed in HPA axis and mood modulatory regions in response to the FST. CORT118335 upregulated c-Fos expression in the paraventricular nucleus of the hypothalamus. Imipramine decreased c-Fos in the basolateral amygdala and hippocampus (CA1 and CA3), but increased c-Fos in the central amygdala. These data suggest the antidepressant-like (e.g., active coping) properties of imipramine may be due to widespread effects on cortico-limbic circuits that regulate emotional and cognitive processes.

Aberrant glucocorticoid secretion is implicated in the pathophysiology of stress-related disorders (i.e., depression, anxiety). Glucocorticoids exert biological effects via mineralocorticoid (MR) and glucocorticoid (GR) receptors. Previous data from our laboratory indicate that GR antagonism/modulation (i.e., mifepristone, CORT 108297) regulate endocrine, behavioral, and central stress responses. Because of the dynamic interplay between MR and GR on HPA axis regulation and emotionality, compounds targeting both receptors are of interest for stress-related pathology. We investigated the effects of CORT 118335 (a dual selective GR modulator/MR antagonist) on endocrine, behavioral, and central (c-Fos) stress responses in male rats. Rats were treated for five days with CORT 118335, imipramine (positive control), or vehicle and exposed to restraint or forced swim stress (FST). CORT 118335 dampened corticosterone responses to both stressors, without a concomitant antidepressant-like effect in the FST. Imipramine decreased corticosterone responses to restraint stress; however, the antidepressant-like effect of imipramine in the FST was independent of circulating glucocorticoids. These findings indicate dissociation between endocrine and behavioral stress responses in the FST. CORT 118335 decreased c-Fos expression only in the CA1 division of the hippocampus. Imipramine decreased c-Fos expression in the basolateral amygdala and CA1 and CA3 divisions of the hippocampus. Overall, the data indicate differential effects of CORT 118335 and imipramine on stress-induced neuronal activity in various brain regions. The data also highlight a complex relationship between neuronal activation in stress and mood regulatory brain regions and the ensuing impact on endocrine and behavioral stress responses.

Preclinical and clinical findings indicate that glucocorticoids (GC) induce lipid accumulation in visceral depots, while inhibiting lipid stores from subcutaneous depots. Whereas some suggest that this is due to adipose depot specific concentration of glucocorticoid receptors (GR) or 11beta-hydroxysteroid dehydrogenase 1 (11β-HSD1), others demonstrate these events emerge from increases in interleukin-1 beta (IL-1β) from macrophages within distinct depots. Regardless of the mechanisms, most of these studies occur in males and thus lack evaluation of sex differences. Here, we examined the impact of 2-week corticosterone (CORT) (3 mg/kg/day) or saline treatment on GR, 11β-HSD1 and IL-1β protein concentration in intra-abdominal (epididymal/parametrial, and visceral) and subcutaneous (inguinal) depots in male and female Sprague Dawley rats. The objective was to examine if factors that regulate GC-induced adipose depot metabolism and distribution, differ between males and females. CORT inhibited, but did not decrease, body weight gain in both sexes. 11β-HSD1 was similar between the sexes in all adipose depots. CORT increased IL-1β in both sexes only in gonadal adipose tissue. Overall, males had greater GR protein concentration in all adipose depots, whereas females had more IL-1β in intra-abdominal adipose depots. Given the male-biased increase in intra-abdominal GR protein concentration, the data suggest that males may be more prone to CORT-induced increases in visceral obesity, which may have implications for increased risk for metabolic diseases. Overall, the data suggest that the effects of GC signaling in adipose tissue are multifaceted, dependent on sex, and the inherent adipocyte characteristics.Lay summaryResearch supports that glucocorticoids (GC) induce visceral adipose tissue accumulation, however few studies have examined if these GC-mediated outcomes are similar between males and females. This study investigates if female rats differentially respond to corticosterone treatment. Results indicate that male rats may have an increased susceptibility to CORT-induced accumulation of visceral adipose tissue compared with females, which may have implication for sex-specific risk for metabolic diseases.

Psychological stress and excess glucocorticoids are associated with metabolic and cardiovascular diseases. Glucocorticoids act primarily through mineralocorticoid (MR) and glucocorticoid receptors (GR), and compounds modulating these receptors show promise in mitigating metabolic and cardiovascular-related phenotypes. CORT118335 (GR/MR modulator) prevents high-fat diet-induced weight gain and adiposity in mice, but the ability of this compound to reverse obesity-related symptoms is unknown. Adult male rats were subcutaneously administered CORT118335 (3, 10, or 30 mg/kg) or vehicle once daily. A 5-day treatment with CORT118335 at 30 mg/kg induced weight loss in rats fed a chow diet by decreasing food intake. However, lower doses of the compound attenuated body weight gain primarily because of decreased calorific efficiency, as there were no significant differences in food intake compared with vehicle. Notably, the body weight effects of CORT118335 persisted during a 2-wk treatment hiatus, suggesting prolonged effects of the compound. To our knowledge, we are the first to demonstrate a sustained effect of combined GR/MR modulation on body weight gain. These findings suggest that CORT118335 may have long-lasting effects, likely due to GR/MR-induced transcriptional changes. Prolonged (18 days) treatment of CORT118335 (10 mg/kg) reversed body weight gain and adiposity in animals fed a high-fat diet for 13 wk. Surprisingly, this occurred despite a worsening of the lipid profile and glucose homeostasis as well as a disrupted diurnal corticosterone rhythm, suggesting GR agonistic effects in the periphery. We conclude that species and tissue-specific targeting may result in promising leads for exploiting the metabolically beneficial aspects of GR/MR modulation.

Stress confers risk for the development and progression of Alzheimer's disease (AD). Relative to men, women are disproportionately more likely to be diagnosed with this neurodegenerative disease. We hypothesized that sex differences in endocrine stress responsiveness may be a factor in this statistic. To test this hypothesis, we assessed basal and stress-induced corticosterone, social recognition, and coat state deterioration (surrogate for depression-like behavior) in male and female 3xTg-AD mice. Prior to reported amyloid plaque deposition, 3xTg females (4 months), but not 3xTg males, had heightened corticosterone responses to restraint exposure. Subsequently, only 3xTg females (6 months) displayed deficits in social memory concomitant with prominent β-amyloid (Aβ) immunostaining. These data suggest that elevated corticosterone stress responses may precede cognitive impairments in genetically vulnerable females. 3xTg mice of both sexes exhibited coat state deterioration relative to same-sex controls. Corticolimbic glucocorticoid receptor (GR) dysfunction is associated with glucocorticoid hypersecretion and cognitive impairment. Our findings indicate sex- and brain-region specific effects of genotype on hippocampal and amygdala GR protein expression. Because olfactory deficits may impede social recognition, in Experiment 2, we assessed olfaction and found no differences between genotypes. Notably, in this cohort, heightened corticosterone stress responses in 3xTg females was not accompanied by social memory deficits or coat state deterioration. However, coat state deterioration was consistent in 3xTg males. We report consistent heightened stress-induced corticosterone levels and Aβ pathology in female 3xTg-AD mice. However, the behavioral findings illuminate unknown inconsistencies in certain phenotypes in this AD mouse model.

Chronic stress-associated pathologies frequently associate with alterations in the structure and activity of the medial prefrontal cortex (mPFC). However, the influence of infralimbic cortex (IL) projection neurons on hypothalamic-pituitary-adrenal (HPA) axis activity is unknown, as is the involvement of these cells in chronic stress-induced endocrine alterations. In the current study, a lentiviral-packaged vector coding for a small interfering RNA (siRNA) targeting vesicular glutamate transporter (vGluT) 1 messenger RNA (mRNA) was microinjected into the IL of male rats. vGluT1 is responsible for presynaptic vesicular glutamate packaging in cortical neurons, and knockdown reduces the amount of glutamate available for synaptic release. After injection, rats were either exposed to chronic variable stress (CVS) or remained in the home cage as unstressed controls. Fifteen days after the initiation of CVS, all animals were exposed to a novel acute stressor (30-minute restraint) with blood collection for the analysis of adrenocorticotropic hormone (ACTH) and corticosterone. Additionally, brains were collected for in situ hybridization of corticotrophin-releasing hormone mRNA. In previously unstressed rats, vGluT1 siRNA significantly enhanced ACTH and corticosterone secretion. Compared with CVS animals receiving the green fluorescent protein control vector, the vGluT1 siRNA further increased basal and stress-induced corticosterone release. Further analysis revealed enhanced adrenal responsiveness in CVS rats treated with vGluT1 siRNA. Collectively, our results suggest that IL glutamate output inhibits HPA responses to acute stress and restrains corticosterone secretion during chronic stress, possibly at the level of the adrenal. Together, these findings pinpoint a neurochemical mechanism linking mPFC dysfunction with aberrant neuroendocrine responses to chronic stress.

Eating tasty foods dampens responses to stress – an idea reflected in the colloquial term ‘comfort foods’. To study the neurobiological mechanisms by which palatable foods provide stress relief, we previously characterized a limited sucrose intake (LSI) paradigm in which male rats are given twice-daily access to 4 ml of 30% sucrose solution (vs. water as a control), and subsequently have reduced hypothalamic-pituitary-adrenocortical (HPA) axis responsivity and anxiety-related behaviors. Notably, women may be more prone to ‘comfort feeding’ than men, and this may vary across the menstrual cycle, suggesting the potential for important sex and estrous cycle differences. In support of this idea, LSI reduces HPA axis responses in female rats during the proestrus/estrus (P/E), as opposed to the diestrus 1/diestrus 2 (D1/D2) estrous cycle stage. However, the effect of LSI on anxiety-related behaviors in females remains unknown. Here we show that LSI reduced stress-related behaviors in female rats in the elevated plus-maze and restraint tests, but not in the open field test, though only during P/E. LSI also decreased the HPA axis stress response primarily during P/E, consistent with prior findings. Finally, cFos immunolabeling (a marker of neuronal activation) revealed that LSI increased post-restraint cFos in the central amygdala medial subdivision (CeM) and the bed nucleus of the stria terminalis posterior subnuclei (BSTp) exclusively during P/E. These results suggest that in female rats, palatable food reduces both behavioral and neuroendocrine stress responses in an estrous cycle-dependent manner, and the CeM and BSTp are implicated as potential mediators of these effects.

Dysfunction in central glucocorticoid signaling is implicated in hypothalamic-pituitary-adrenocortical (HPA) axis dysregulation and major depression. In comparison with men, women are twice as likely to suffer from depression and have heightened HPA axis responses to stress. We hypothesized that this striking increase in stress vulnerability in females may be because of sex differences in central glucocorticoid signaling. The current study tests the role of the forebrain type II glucocorticoid receptor (GR) on HPA axis function in female mice and depression-like behavior in both female and male mice. This was accomplished by using mice with selective deletion of GR in forebrain cortico-limbic sites including the prefrontal cortex, hippocampus, and basolateral amygdala (forebrain glucocorticoid receptor knockout mouse (FBGRKO)). In order to examine HPA axis function in female FBGRKO, we measured nadir, peak circadian and restraint-induced corticosterone concentrations in female FBGRKO. The data indicate that unlike male FBGRKO, basal and stress-induced corticosterone concentrations are not increased in female FBGRKO. Given the pronounced effect of central glucocorticoid signaling on mood, we also examined the necessity of corticolimbic GR on depression-like behavior with the sucrose preference and forced swim tests (FST) in male and female FBGRKO mice. Consistent with previous studies, male FBGRKO displayed increased depression-like behavior as indicated by greater immobility in the FST and decreased sucrose preference compared with littermate controls, effects that were not observed in females. Overall the findings indicate a marked sex difference in the function of forebrain GR on HPA axis regulation and depression-like behaviors, and may have implications for therapeutic approaches using GR-modulating drugs.

Syrian hamsters, like many humans, increase food intake and body adiposity in response to stress. We hypothesized that glucocorticoids (cortisol and corticosterone) mediate these stress-induced effects on energy homeostasis. Because Syrian hamsters are dual secretors of cortisol and corticosterone, differential effects of each glucocorticoid on energy homeostasis were investigated. First, adrenal intact hamsters were injected with varying physiological concentrations of cortisol, corticosterone, or vehicle to emulate our previously published defeat regimens (i.e., 1 injection/day for 5 days). Neither food intake nor body weight was altered following glucocorticoid injections. Therefore, we investigated the effect of sustained glucocorticoid exposure on energy homeostasis. This was accomplished by implanting hamsters with supraphysiological steady-state pellets of cortisol, corticosterone, or cholesterol as a control. Cortisol, but not corticosterone, significantly decreased food intake, body mass, and lean and fat tissue compared with controls. Despite decreases in body mass and adiposity, cortisol significantly increased circulating free fatty acids, triglyceride, cholesterol, and hepatic triglyceride concentrations. Although corticosterone did not induce alterations in any of the aforementioned metabolic end points, Syrian hamsters were responsive to the effects of corticosterone since glucocorticoids both induced thymic involution and decreased adrenal mass. These findings indicate that cortisol is the more potent glucocorticoid in energy homeostasis in Syrian hamsters. However, the data suggest that cortisol alone does not mediate stress-induced increases in food intake or body mass in this species.

Adolescent development is proposed to represent a time of increased susceptibility to stress. During adolescence, the brain demonstrates a high level of plasticity and can be positively or negatively affected by the environment. This study tests the hypothesis that adolescent development is a stage of enhanced vulnerability to chronic stress. Male Sprague-Dawley rats were exposed to our 14-d chronic variable stress (CVS) paradigm at three developmental stages: 1) early adolescence (35 d; age at initiation of CVS); 2) late adolescence (50 d); or 3) adulthood (80 d). We examined the effects of CVS on the following: 1) depression-like behavior; 2) somatic indices; 3) hypothalamic-pituitary-adrenal (HPA) axis activity; and 4) neuropeptide expression in the hypothalamus. Results show, regardless of age, CVS exposure: 1) decreased body weight; 2) increased adrenal size; 3) decreased fat weight; and 4) increased HPA response to stress. The somatic effects of CVS were exaggerated in late adolescent animals, and late adolescent animals were the only group where CVS decreased oxytocin expression and increased basal corticosterone. In response to CVS, adult animals increased immobility during the forced-swim test while early and late adolescent animals were resistant to the effects of chronic stress on depression-like behavior. Results show that adolescent animals were protected from the effect of chronic stress on depression-like behavior while late adolescent animals were more susceptible to the somatic, HPA axis, and neuropeptide effects of chronic stress. Thus, adolescent development is a unique window of vulnerabilities and protections to the effects of chronic stress.

The nucleus of the solitary tract (NTS) is a critical integrative site for coordination of autonomic and endocrine stress responses. Stress-excitatory signals from the NTS are communicated by both catecholaminergic [norepinephrine (NE), epinephrine (E)] and noncatecholaminergic [e.g., glucagon-like peptide-1 (GLP-1)] neurons. Recent studies suggest that outputs of the NE/E and GLP-1 neurons of the NTS are selectively engaged during acute stress. This study was designed to test mechanisms of chronic stress integration in the paraventricular nucleus, focusing on the role of glucocorticoids. Our data indicate that chronic variable stress (CVS) causes downregulation of preproglucagon (GLP-1 precursor) mRNA in the NTS and reduction of GLP-1 innervation to the paraventricular nucleus of the hypothalamus. Glucocorticoids were necessary for preproglucagon (PPG) reduction in CVS animals and were sufficient to lower PPG mRNA in otherwise unstressed animals. The data are consistent with a glucocorticoid-mediated withdrawal of GLP-1 in key stress circuits. In contrast, expression of tyrosine hydroxylase mRNA, the rate-limiting enzyme in catecholamine synthesis, was increased by stress in a glucocorticoid-independent manner. These suggest differential roles of ascending catecholamine and GLP-1 systems in chronic stress, with withdrawal of GLP-1 involved in stress adaptation and enhanced NE/E capacity responsible for facilitation of responses to novel stress experiences.

Glucocorticoid dyshomeostasis is observed in a proportion of depressed individuals. As a result, glucocorticoid receptor (GR) antagonists are currently being tested as potential anti-depressants. The current study was designed to test the efficacy of mifepristone, a GR antagonist, in mitigating behavioral, neuroendocrine and central nervous system (CNS) responses to an acute stressor. Adult male rats were treated for five days with mifepristone (10 mg/kg) and then exposed to the forced swim test (FST). Treatment with mifepristone decreased immobility and increased swimming (but not climbing) behavior in the FST, consistent with antidepressant action. In addition, mifepristone dampened the ACTH response to FST exposure. In the CNS, mifepristone increased c-Fos expression in all subdivisions of the medial prefrontal cortex (mPFC) and decreased neuronal activity in some subdivisions of the hippocampus including the CA2, CA3, and hilus region of the dentate gyrus in animals exposed to FST. In contrast, mifepristone increased neuronal activity in the ventral subiculum (output region of the hippocampus) and decreased c-Fos expression in the central amygdala (CeA) in animals exposed to FST. These data suggest that antidepressant efficacy and perhaps HPA dampening properties of RU486 are related to alterations in key limbic circuits mediating CNS stress responses, resulting in enhanced stress inhibition (via the mPFC and ventral subiculum) as well as decreased stress excitation (central amygdala). Overall the data suggest that drugs targeting the glucocorticoid receptor may ameliorate stress dysfunction associated with depressive illness.

Glucocorticoids act rapidly at the paraventricular nucleus (PVN) to inhibit stress-excitatory neurons and limit excessive glucocorticoid secretion. The signaling mechanism underlying rapid feedback inhibition remains to be determined. The present study was designed to test the hypothesis that the canonical glucocorticoid receptors (GRs) is required for appropriate hypothalamic-pituitary-adrenal (HPA) axis regulation. Local PVN GR knockdown (KD) was achieved by breeding homozygous floxed GR mice with Sim1-cre recombinase transgenic mice. This genetic approach created mice with a KD of GR primarily confined to hypothalamic cell groups, including the PVN, sparing GR expression in other HPA axis limbic regulatory regions, and the pituitary. There were no differences in circadian nadir and peak corticosterone concentrations between male PVN GR KD mice and male littermate controls. However, reduction of PVN GR increased ACTH and corticosterone responses to acute, but not chronic stress, indicating that PVN GR is critical for limiting neuroendocrine responses to acute stress in males. Loss of PVN GR induced an opposite neuroendocrine phenotype in females, characterized by increased circadian nadir corticosterone levels and suppressed ACTH responses to acute restraint stress, without a concomitant change in corticosterone responses under acute or chronic stress conditions. PVN GR deletion had no effect on depression-like behavior in either sex in the forced swim test. Overall, these findings reveal pronounced sex differences in the PVN GR dependence of acute stress feedback regulation of HPA axis function. In addition, these data further indicate that glucocorticoid control of HPA axis responses after chronic stress operates via a PVN-independent mechanism.

Chronic variable stress (CVS) exposure modifies the paraventricular nucleus of the hypothalamus (PVN) in a manner consistent with enhanced central drive of the hypothalamo-pituitary-adrenocortical axis. Since previous reports suggest that post-stress enhancement of norepinephrine (NE) action contributes to chronic stress regulation at the level of the PVN, we hypothesized that PVN- projecting NE neurons were necessary for the stress facilitatory effects of CVS. Following intra-PVN injection of saporin toxin conjugated to a dopamine- beta- hydroxylase (DBH) antibody (DSAP), PVN DBH immunoreactivity was almost completely eliminated, while sparing immunoreactive afferents to other key regions involved in stress integration (e.g. DBH fiber densities were unaffected in the central nucleus of the amygdala). Reductions in DBH- positive fiber density were associated with reduced numbers of DBH-immunoreactive neurons in the nucleus of the solitary tract (NTS) and locus coeruleus (LC). Following two weeks of CVS, DSAP injection did not alter stress-induced adrenal hypertrophy or attenuation of body weight gain, indicating that PVN-projecting NE (and epinephrine (E)) neurons are not essential for these physiological effects of chronic stress. In response to acute restraint stress, PVN-targeted DSAP injection attenuated peak adrenocorticotrophic hormone (ACTH) and corticosterone in controls, but only attenuated peak ACTH in CVS animals, suggesting that enhanced adrenal sensitivity compensated for reduced excitatory drive of the PVN. Our data suggest that PVN-projecting NE/E neurons contribute to the generation of acute stress responses, and are required for HPA axis drive (ACTH release) during chronic stress. However, loss of NE/E drive at the PVN appears to be buffered by compensation at the level of the adrenal.

Pre-clinical and clinical studies have employed treatment with glucocorticoid receptor (GR) antagonists in an attempt to limit the deleterious behavioral and physiological effects of excess glucocorticoids. Here, we examined the effects of GR antagonists on neuroendocrine and behavioral stress responses, using two compounds: mifepristone, a GR antagonist that is also a progesterone receptor antagonist, and CORT 108297, a specific GR antagonist lacking anti-progestin activity. Given its well-documented impact on neuroendocrine and behavioral stress responses, imipramine (tricyclic antidepressant) served as a positive control. Male rats were treated for five days with mifepristone (10mg/kg), CORT 108297 (30mg/kg and 60mg/kg), imipramine (10mg/kg) or vehicle and exposed to forced swim test (FST) or restraint stress. Relative to vehicle, imipramine potently suppressed adrenocorticotropin hormone (ACTH) responses to FST and restraint exposure. Imipramine also decreased immobility in the FST, consistent with antidepressant actions. Both doses of CORT 108297 potently suppressed peak corticosterone responses to FST and restraint stress. However, only the higher dose of CORT 108297 (60mg/kg) significantly decreased immobility in the FST. In contrast, mifepristone induced protracted secretion of corticosterone in response to both stressors, and modestly decreased immobility in the FST. Taken together, the data indicate distinct effects of each compound on neuroendocrine stress responses and also highlight dissociation between corticosterone responses and immobility in the FST. Within the context of the present study, our data suggest that CORT 108297 may be an attractive alternative for mitigating neuroendocrine and behavioral states associated with excess glucocorticoid secretion.

The location of glucocorticoid receptors (GR) implicated in depression symptoms and antidepressant action remains unclear. Forebrain glucocorticoid receptor deletion on a C57B/6×129×CBA background (FBGRKO-T50) reportedly produces increased depression-like behavior and elevated glucocorticoids. We further hypothesized that forebrain GR deletion would reduce behavioral sensitivity to glucocorticoids and to antidepressants. We have tested this hypothesis in mice with calcium calmodulin kinase IIα-Cre-mediated forebrain GR deletion derived from a new founder on a pure C57BL/6 background (FBGRKO-T29-1). We measured immobility in forced swim or tail suspension tests after manipulating glucocorticoids or after dose response experiments with tricyclic or monoamine oxidase inhibitor antidepressants. Despite forebrain GR deletion that was at least as rapid and more extensive than reported in the mixed-strain FBGRKO-T50 mice (Boyle et al. 2005), and possibly because of their different founder, our FBGRKO-T29-1 mice did not exhibit increases in depression-like behavior or adrenocortical axis hormones. Nevertheless, FBGRKO-T29-1 mice were at least as sensitive as floxed GR controls to the depressive effects of glucocorticoids and the effects of two different classes of antidepressants. FBGRKO-T29-1 mice also unexpectedly exhibited increased mineralocorticoid receptor (MR) gene expression. Our results reinforce prior evidence that antidepressant action does not require forebrain GR, and suggest a correlation between the absence of depression-like phenotype and combined MR up-regulation and central amygdala GR deficiency. Our findings demonstrate that GR outside the areas targeted in FBGRKO-T29-1 mice are involved in the depressive effects of glucocorticoids, and leave open the possibility that these GR populations also contribute to antidepressant action.

Background Stress-related disorders (e.g., depression) are associated with hypothalamic-pituitary-adrenocortical axis dysregulation and prefrontal cortex (PFC) dysfunction, suggesting a functional link between aberrant prefrontal corticosteroid signaling and mood regulation. Methods We used a virally mediated knockdown strategy (short hairpin RNA targeting the glucocorticoid receptor [GR]) to attenuate PFC GR signaling in the rat PFC. Adult male rats received bilateral microinjections of vector control or short hairpin RNA targeting the GR into the prelimbic ( n = 44) or infralimbic ( n = 52) cortices. Half of the animals from each injection group underwent chronic variable stress, and all were subjected to novel restraint. The first 2 days of chronic variable stress were used to assess depression- and anxiety-like behavior in the forced swim test and open field. Results The GR knockdown confined to the infralimbic PFC caused acute stress hyper-responsiveness, sensitization of stress responses after chronic variable stress, and induced depression-like behavior (increased immobility in the forced swim test). Knockdown of GR in the neighboring prelimbic PFC increased hypothalamic-pituitary-adrenocortical axis responses to acute stress and caused hyperlocomotion in the open field, but did not affect stress sensitization or helplessness behavior. Conclusions The data indicate a marked functional heterogeneity of glucocorticoid action in the PFC and highlight a prominent role for the infralimbic GR in appropriate stress adaptation, emotional control, and mood regulation.

Life stress frequently occurs within the context of homeostatic challenge, requiring integration of physiological and psychological need into appropriate hormonal, cardiovascular, and behavioral responses. To test neural mechanisms underlying stress integration within the context of homeostatic adversity, we evaluated the impact of a pronounced physiological (hypernatremia) challenge on hypothalamic-pituitary-adrenal (HPA), cardiovascular, and behavioral responses to an acute psychogenic stress. Relative to normonatremic controls, rats rendered mildly hypernatremic had decreased HPA activation in response to physical restraint, a commonly used rodent model of psychogenic stress. In addition, acute hypernatremia attenuated the cardiovascular response to restraint and promoted faster recovery to prestress levels. Subsequent to restraint, hypernatremic rats had significantly more c-Fos expression in oxytocin- and vasopressin-containing neurons within the supraoptic and paraventricular nuclei of the hypothalamus. Hypernatremia also completely eliminated the increased plasma renin activity that accompanied restraint in controls, but greatly elevated circulating levels of oxytocin. The endocrine and cardiovascular profile of hypernatremic rats was predictive of decreased anxiety-like behavior in the social interaction test. Collectively, the results indicate that acute hypernatremia is a potent inhibitor of the HPA, cardiovascular, and behavioral limbs of the stress response. The implications are that the compensatory responses that promote renal-sodium excretion when faced with hypernatremia also act on the nervous system to decrease reactivity to psychogenic stressors and facilitate social behavior, which may suppress the anxiety associated with approaching a communal water source and support the social interactions that may be encountered when engaging in drinking behavior.

Individuals often eat calorically dense, highly palatable “comfort” foods during stress for stress relief. This article demonstrates that palatable food intake (limited intake of sucrose drink) reduces neuroendocrine, cardiovascular, and behavioral responses to stress in rats. Artificially sweetened (saccharin) drink reproduces the stress dampening, whereas oral intragastric gavage of sucrose is without effect. Together, these results suggest that the palatable/rewarding properties of sucrose are necessary and sufficient for stress dampening. In support of this finding, another type of natural reward (sexual activity) similarly reduces stress responses. Ibotenate lesions of the basolateral amygdala (BLA) prevent stress dampening by sucrose, suggesting that neural activity in the BLA is necessary for the effect. Moreover, sucrose intake increases mRNA and protein expression in the BLA for numerous genes linked with functional and/or structural plasticity. Lastly, stress dampening by sucrose is persistent, which is consistent with long-term changes in neural activity after synaptic remodeling. Thus, natural rewards, such as palatable foods, provide a general means of stress reduction, likely via structural and/or functional plasticity in the BLA. These findings provide a clearer understanding of the motivation for consuming palatable foods during times of stress and influence therapeutic strategies for the prevention and/or treatment of obesity and other stress-related disorders.

Stress pathologies such as depression and eating disorders (i.e. anorexia nervosa) are associated with amygdalar dysfunction, which are linked with hypothalamic-pituitary-adrenal axis (HPA) axis hyperactivity. The medial amygdaloid nucleus (MeA), a key output nucleus of the amygdaloid complex, promotes HPA axis activation to acute psychogenic stress and is in a prime position to mediate the deleterious effects of chronic stress on physiology and behaviour. The present study tests the hypothesis that the MeA is necessary for the development of maladaptive physiological changes caused by prolonged stress exposure. Male rats received bilateral ibotenate or sham lesions targeting the MeA and one half underwent 2 weeks of chronic variable stress (CVS) or served as home cage controls. Sixteen hours post CVS, all animals were exposed to an acute restraint challenge. CVS induced thymic involution, adrenal hypertrophy, and attenuated body weight gain and up-regulation of hypothalamic corticotrophin-releasing hormone mRNA expression. Consistent with previous literature, lesions of the MeA dampened stress-induced increases in corticosterone after 30 min of exposure to acute restraint stress. However, this effect was independent of CVS exposure, suggesting that the MeA may not be critical for modulating neuroendocrine responses after chronic HPA axis drive. Interestingly, lesion of the MeA modestly exaggerated the stress-induced attenuation of weight gain. Overall, the data obtained suggest that the MeA modulates the neuroendocrine responses to acute but not chronic stress. In addition, the data suggest that the MeA may be an important neural component for the control of body weight in the face of chronic stress.

Overeating and increases in body and fat mass are the most common responses to day-to-day stress in humans, whereas stressed laboratory rats and mice respond oppositely. Group housing of Syrian hamsters increases body mass, adiposity, and food intake, perhaps due to social confrontation-induced stress. In experiment 1 we asked, Does repeated social defeat increase food intake, body mass, and white adipose tissue (WAT) mass in Syrian hamsters? Male hamsters subjected to the resident-intruder social interaction model and defeated intermittently 15 times over 34 days for 7-min sessions significantly increased their food intake, body mass, and most WAT masses compared with nondefeated controls. Defeat significantly increased terminal adrenal norepinephrine, but not epinephrine, content. In experiment 2 we asked, Are 15 intermittent resident-intruder interactions necessary to increase body mass and food intake? Body mass and food intake of subordinate hamsters defeated only once were similar to those of nondefeated controls, but four or eight defeats similarly and significantly increased these responses. In experiment 3 we asked, Do intermittent defeats increase adiposity and food intake more than consecutive defeats? Four intermittent or consecutive defeats similarly and significantly increased food intake and body mass compared with nondefeated controls, but only intermittent defeats significantly increased all WAT masses. Consecutive defeats significantly increased mesenteric and inguinal WAT masses. Plasma leptin, but not insulin, concentrations were similarly and significantly increased compared with nondefeated controls. Collectively, social defeat, a natural stressor, significantly increased food intake, body mass, and adiposity in Syrian hamsters and may prove useful in determining mechanisms underlying human stress-induced obesity.