Pleasurable behaviors reduce stress via brain reward pathways.

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.

Hydration state controls stress responsiveness and social behavior.

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.

Blood-borne angiotensin II acts in the brain to influence behavioral and endocrine responses to psychogenic stress.

This study elucidates the neural circuits by which circulating angiotensin II (ANGII) acts in the brain to influence humoral and behavioral responses to psychological stressors. To test the hypothesis that systemic ANGII mediates stress responding via the subfornical organ (SFO), we first found that the timing of increased systemic ANGII in response to 60 min restraint coincides with increased c-fos mRNA expression in the SFO. Next, we administered an anterograde neuronal tract tracer into the SFO and found that fibers originating there make appositions onto neurons in the paraventricular nucleus of the hypothalamus that are also c-fos positive following restraint stress. To determine whether circulating ANGII stimulates the release of stress hormones via activation of angiotensin type 1 receptors (AT1R) within the SFO, we delivered lentivirus to knockdown AT1R expression locally in the SFO. Inhibition of AT1R specifically within the SFO blunted the release of adrenocorticotrophin-releasing hormone and corticosterone in response to restraint stress and caused rats to spend more time in the open arms of an elevated-plus maze than controls, indicating that inhibition of AT1R within the SFO is anxiolytic. Collectively, these results suggest that circulating ANGII acts on AT1R in the SFO to influence responding to psychological stressors.

Effect of peripheral administration of cholecystokinin on food intake in apolipoprotein AIV knockout mice.

Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are satiation factors secreted by the small intestine in response to lipid meals. Apo AIV and CCK-8 has an additive effect to suppress food intake relative to apo AIV or CCK-8 alone. In this study, we determined whether CCK-8 (1, 3, or 5 µg/kg ip) reduces food intake in fasted apo AIV knockout (KO) mice as effectively as in fasted wild-type (WT) mice. Food intake was monitored by the DietMax food system. Apo AIV KO mice had significantly reduced 30-min food intake following all doses of CCK-8, whereas WT mice had reduced food intake only at doses of 3 µg/kg and above. Post hoc analysis revealed that the reduction of 10-min and 30-min food intake elicited by each dose of CCK-8 was significantly larger in the apo AIV KO mice than in the WT mice. Peripheral CCK 1 receptor (CCK1R) gene expression (mRNA) in the duodenum and gallbladder of the fasted apo AIV KO mice was comparable to that in WT mice. In contrast, CCK1R mRNA in nodose ganglia of the apo AIV KO mice was upregulated relative to WT animals. Similarly, upregulated CCK1R gene expression was found in the brain stem of apo AIV KO mice by in situ hybridization. Although it is possible that the increased satiating potency of CCK in apo AIV KO mice is mediated by upregulation of CCK 1R in the nodose ganglia and nucleus tractus solitarius, additional experiments are required to confirm such a mechanism.

Differential effects of glucocorticoids on energy homeostasis in Syrian hamsters.

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.

Central angiotensin II has catabolic action at white and brown adipose tissue.

Considerable evidence implicates the renin-angiotensin system (RAS) in the regulation of energy balance. To evaluate the role of the RAS in the central nervous system regulation of energy balance, we used osmotic minipumps to chronically administer angiotensin II (Ang II; icv; 0.7 ng/min for 24 days) to adult male Long-Evans rats, resulting in reduced food intake, body weight gain, and adiposity. The decrease in body weight and adiposity occurred relative to both ad libitum- and pair-fed controls, implying that reduced food intake in and of itself does not underlie all of these effects. Consistent with this, rats administered Ang II had increased whole body heat production and oxygen consumption. Additionally, chronic icv Ang II increased uncoupling protein-1 and ß(3)-adrenergic receptor expression in brown adipose tissue and ß3-adrenergic receptor expression in white adipose tissue, which is suggestive of enhanced sympathetic activation and thermogenesis. Chronic icv Ang II also increased hypothalamic agouti-related peptide and decreased hypothalamic proopiomelanocortin expression, consistent with a state of energy deficit. Moreover, chronic icv Ang II increased the anorectic corticotrophin- and thyroid-releasing hormones within the hypothalamus. These results suggest that Ang II acts in the brain to promote negative energy balance and that contributing mechanisms include an alteration in the hypothalamic circuits regulating energy balance, a decrease in food intake, an increase in energy expenditure, and an increase in sympathetic activation of brown and white adipose tissue.

Cloned mice have an obese phenotype not transmitted to their offspring.

Mammalian cloning using somatic cells has been accomplished successfully in several species, and its potential basic, clinical and therapeutic applications are being pursued on many fronts. Determining the long-term effects of cloning on offspring is crucial for consideration of future application of the technique. Although full-term development of animals cloned from adult somatic cells has been reported, problems in the resulting progeny indicate that the cloning procedure may not produce animals that are phenotypically identical to their cell donor. We used a mouse model to take advantage of its short generation time and lifespan. Here we report that the increased body weight of cloned B6C3F1 female mice reflects an increase of body fat in addition to a larger body size, and that these mice share many characteristics consistent with obesity. We also show that the obese phenotype is not transmitted to offspring generated by mating male and female cloned mice.

Glucose parameters are altered in mouse offspring produced by assisted reproductive technologies and somatic cell nuclear transfer.

Fortunately, the majority of children conceived through assisted reproductive technologies (ARTs) appear healthy; however, metabolic abnormalities, including elevated glucose and increased and altered adipose tissue deposition, have been reported in adolescents. To parse out factors that may be responsible, we investigated the effects of two different ARTs--in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI)--as well as somatic cell nuclear transfer (SCNT) on glucose clearance, body weight, and body composition of young adult mice. Female and male mice generated through ART weighed more than control (naturally conceived [STOCK]) mice at birth. No differences in body weight were observed in males up to 8 wk of age. ART females took longer than control mice to clear a glucose bolus, with glucose clearance most impaired in SCNT females. IVF females secreted more insulin and had a higher insulin peak 15 min after glucose injection compared with all other groups. Male mice exhibited no differences in glucose clearance, but IVF males required more insulin to do so. SCNT females weighed more than IVF, ICSI, and STOCK females, and they had higher fat content than ICSI females and higher leptin levels than all other groups. These results show that glucose parameters are altered in young adult mice conceived through techniques associated with ART before onset of obesity and may be responsible for its development later in life. The present study suggests that more investigation regarding the long-term effects of manipulations associated with ART is warranted.

Meal patterns and hypothalamic NPY expression during chronic social stress and recovery.

In the present study, we examined meal patterns during and after exposure to the visible burrow system (VBS), a rodent model of chronic social stress, to determine how the microstructure of food intake relates to the metabolic consequences of social subordination. Male Long-Evans rats were housed in mixed-sex VBS colonies (4 male, 2 female) for 2 wk, during which time a dominance hierarchy formed [1 dominant male (DOM) and 3 subordinate males (SUB)], and then male rats were individually housed for a 3-wk recovery period. Controls were individually housed with females during the 2-wk VBS period and had no changes in ingestive behavior compared with a habituation period. During the hierarchy-formation phase of VBS housing, DOM and SUB had a reduced meal frequency, whereas SUB also had a reduced meal size. However, during the hierarchy-maintenance phase of VBS housing, DOM meal patterns did not differ from controls, whereas SUB continued to display a reduced food intake via less frequent meals. During recovery, DOM had comparable meal patterns to controls, whereas SUB had an increased meal size. Hypothalamic neuropeptide Y (NPY) mRNA levels were not different between these groups during the experimental period. Together, the results suggest that exposure to chronic social stress alters ingestive behavior both acutely and in the long term, which may influence the metabolic changes that accompany bouts of stress and recovery; however, these differences in meal patterns do not appear to be mediated by hypothalamic NPY.

Angiotensin type 1 receptors in the subfornical organ mediate the drinking and hypothalamic-pituitary-adrenal response to systemic isoproterenol.

Circulating angiotensin II (ANGII) elicits water intake and activates the hypothalamic-pituitary-adrenal (HPA) axis by stimulating angiotensin type 1 receptors (AT1Rs) within circumventricular organs. The subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) are circumventricular organs that express AT1Rs that bind blood-borne ANGII and stimulate integrative and effector regions of the brain. The goal of these studies was to determine the contribution of AT1Rs within the SFO and OVLT to the water intake and HPA response to increased circulating ANGII. Antisense oligonucleotides directed against the AT1R [AT1R antisense (AT1R AS)] were administered into the OVLT or SFO. Quantitative receptor autoradiography confirmed that AT1R AS decreased ANGII binding in the SFO and OVLT compared with the scrambled sequence control but did not affect AT1R binding in other nuclei. Subsequently, water intake, ACTH, and corticosterone (CORT) were assessed after administration of isoproterenol, a beta-adrenergic agonist that decreases blood pressure and elevates circulating ANGII. Delivery of AT1R AS into the SFO attenuated water intake, ACTH, and CORT after isoproterenol, whereas similar treatment in the OVLT had no effect. To determine the specificity of this blunted drinking and HPA response, the same parameters were measured after treatment with hypertonic saline, a stimulus that induces drinking independently of ANGII. Delivery of AT1R AS into the SFO or OVLT had no effect on water intake, ACTH, or CORT after hypertonic saline. The results imply that AT1R within the SFO mediate drinking and HPA responses to stimuli that increase circulating ANGII.

Hypothalamic apolipoprotein A-IV is regulated by leptin.

Apolipoprotein A-IV (apo A-IV) is a satiety factor involved in the control of food intake and body weight. Our previous studies demonstrated that apo A-IV is present in areas of the hypothalamus where leptin acts to influence energy homeostasis. In the present studies, we found that leptin-deficient obese (ob/ob) mice have significantly reduced hypothalamic apo A-IV mRNA levels. Intragastric infusion of a lipid emulsion significantly stimulated hypothalamic apo A-IV gene expression in lean controls but not in ob/ob mice. Daily ip administration of leptin (3 microg/g) for 5 d significantly increased hypothalamic apo A-IV mRNA levels of ob/ob mice relative to pair-fed controls. In addition, centrally administered leptin raised the reduced apo A-IV gene expression induced by fasting. Using immunohistochemistry, we demonstrated that apo A-IV is present in leptin-sensitive phosphorylated signal transducer and activator of transcription 3 (pSTAT3)-positive cells of the arcuate nucleus of the hypothalamus. Knockdown of STAT3 expression by small interfering RNA significantly attenuated the stimulatory effect of leptin on apo A-IV protein expression in cultured primary hypothalamic neurons, implying that the hypothalamic apo A-IV is regulated by leptin, at least partially, via the STAT3 signaling pathway. Third-ventricular (intracerebroventricular) administration of a subthreshold dose of leptin (1 microg) potentiated apo A-IV-induced (subthreshold dose, 0.5 microg) reduction of feeding, indicating the existence of a functional synergistic interaction between leptin and apo A-IV, leading to suppression of food intake.

Androgenic influences on behavior, body weight, and body composition in a model of chronic social stress.

The visible burrow system (VBS) is a model used to study chronic social stress in colony-housed rats. A hierarchy develops among the males resulting in dominant (DOM) and subordinate (SUB) animals. Hierarchy-associated changes in body weight, body composition, behavior, and neuroendocrine measures have been observed. After 14 d of VBS housing, SUB animals have decreased body weight, elevated corticosterone, and decreased testosterone (T), compared with DOM animals and controls, placing SUB animals in an ideal endocrine state to regain lost body weight as adipose tissue. It is hypothesized that maintaining constant androgen concentrations in SUB males during stress will prevent body weight loss by maintaining more lean body mass. To test this, animals were gonadectomized and implanted with SILASTIC implants containing T, 5alpha-dihydrotestosterone (DHT), or cholesterol. Implants maintained constant physiological levels of T. Standard intact, T, and DHT implant colonies formed hierarchies, whereas cholesterol colonies did not. Androgen manipulations significantly altered offensive and defensive behaviors only on the first day of VBS housing. After VBS stress, intact, T, and DHT SUB animals weighed less and lost more adipose and lean tissue than DOM and control males, whereas DOM animals primarily lost adipose tissue. However, on recovery, DHT SUB animals maintained more lean tissue than intact SUB animals. Oral glucose tolerance tests revealed that glucose clears faster in stressed T-implanted males that have increased adipose tissue. Overall, these data suggest that constant androgen concentrations in SUB animals do not prevent weight loss and changes in body composition during stress but do so during recovery.

Dynamic body weight and body composition changes in response to subordination stress.

Social stress is prevalent in many facets of modern society. Epidemiological data suggest that stress is linked to the development of overweight, obesity and metabolic disease. Although there are strong associations between the incidence of obesity with stress and elevated levels of hormones such as cortisol, there are limited animal models to allow investigation of the etiology of increased adiposity resulting from exposure to stress. Perhaps more importantly, an animal model that mirrors the consequences of stress in humans will provide a vehicle to develop rational clinical therapy to treat or prevent adverse outcomes from exposure to chronic social stress. In the visible burrow system (VBS) model of chronic social stress mixed gender colonies are housed for 2 week periods during which male rats of the colony quickly develop a dominance hierarchy. We found that social stress has significant effects on body weight and body composition such that subordinate rats progressively develop characteristics of obesity that occurs, in part, through neuroendocrine alterations and changes in food intake amount. Although subordinate rats are hyperphagic following social stress they do not increase their intake of sucrose solution as control and dominants do suggesting that they are anhedonic. Consumption of a high fat diet does not appear to affect development of a social hierarchy and appears to enhance the effect that chronic stress has on body composition. The visible burrow system (VBS) model of social stress may be a potential laboratory model for studying stress-associated metabolic disease, including the metabolic syndrome.

Developmental, behavioral, and physiological phenotype of cloned mice.

Cloning from adult somatic cells has been successful in at least ten species. Although generating viable cloned mammals from adult cells is technically feasible, prenatal and perinatal mortality is high and live cloned offspring have had health problems. This chapter summarizes the health consequences of cloning in mice and discusses possible mechanisms through which these conditions may arise. These studies have further significance as other assisted reproductive techniques (ART) also involve some of the same procedures used in cloning, and there are some reports that offspring generated by ART display aberrant phenotypes as well. At the moment, the long-term consequences of mammalian cloning remain poorly characterized. Data available thus far suggest that we should use this technology with great caution until numerous questions are addressed and answered.

A closer look at the subordinate population within the visible burrow system.

The visible burrow system (VBS) utilizes the natural social behavior of rodents to model chronic social stress. Classically, when male and female rats are housed together in the VBS a dominance hierarchy rapidly forms with one dominant (DOM) and three subordinate (SUB) males. SUB animals show signs of chronic social stress, including loss of body weight and elevated basal corticosterone. This study furthered examined differences among the SUB population. Quantitative observations across numerous VBS colonies within the Sakai Lab suggest that there is variability in the effects of stress on the SUB population, specifically that some animals may experience more severe effects of chronic social stress than others. To further examine this observation, SUB animals were classified as OMEGA if they received a disproportionate amount of their colonies' wounds. OMEGA animals received more wounds to their body compared to SUB (P<0.0001) and lost significantly more weight throughout the stress period compared to all other VBS-housed animals (group×time interaction P<0.0001). Following VBS housing it was determined the OMGEA also lost lean body mass (P<0.01 vs. controls and DOM), are hyporesponsive to an acute restraint challenge (P<0.01 vs all other groups) and show depressive-like behavior during a forced swim test. Furthermore, expression of neuropeptide Y within the amygdala, known for anxiolytic properties following chronic stress, was elevated among OMEGA (group×region interaction P<0.001). Together these observations suggest that an additional phenotype exists among the SUB animals within a VBS colony and represents the variability of the effects of chronic social stress.

Stress coping style does not determine social status, but influences the consequences of social subordination stress.

Chronic stress exposure may have negative consequences for health. One of the most common sources of chronic stress is stress associated with social interaction. In rodents, the effects of social stress can be studied in a naturalistic way using the visual burrow system (VBS). The way an individual copes with stress, their "stress coping style", may influence the consequences of social stress. In the current study we tested the hypothesis that stress coping style may modulate social status and influence the consequences of having a lower social status. We formed 7 VBS colonies, with 1 proactive coping male, 1 passive coping male, and 4 female rats per colony to assess whether a rat's coping style prior to colony formation could predict whether that individual is more likely to become socially dominant. The rats remained in their respective colonies for 14days and the physiological and behavioral consequences of social stress were assessed. Our study shows that stress coping style does not predict social status. However, stress coping style may influence the consequences of having a lower social status. Subordinate passive and proactive rats had distinctly different wound patterns; proactive rats had more wounds on the front of their bodies. Behavioral analysis confirmed that proactive subordinate rats engaged in more offensive interactions. Furthermore, subordinate rats with a proactive stress coping style had larger adrenals, and increased stress responsivity to a novel acute stressor (restraint stress) compared to passive subordinate rats or dominant rats, suggesting that the allostatic load may have been larger in this group.

Susceptibility or resilience? Prenatal stress predisposes male rats to social subordination, but facilitates adaptation to subordinate status.

Mood disorders such as major depressive disorder (MDD) affect a significant proportion of the population. Although progress has been made in the development of therapeutics, a large number of individuals do not attain full remission of symptoms and adverse side effects affect treatment compliance for some. In order to develop new therapies, there is a push for new models that better reflect the multiple risk factors that likely contribute to the development of depressive illness. We hypothesized that early life stress would exacerbate the depressive-like phenotype that we have previously observed in socially subordinate (SUB) adult male rats in the visible burrow system (VBS), a semi-natural, ethologically relevant environment in which males in a colony form a dominance hierarchy. Dams were exposed to chronic variable stress (CVS) during the last week of gestation, resulting in a robust and non-habituating glucocorticoid response that did not alter maternal food intake, body weight or litter size and weight. As adults, one prenatal CVS (PCVS) and one non-stressed (NS) male were housed in the VBS with adult females. Although there were no overt differences between PCVS and NS male offspring prior to VBS housing, a greater percentage of PCVS males became SUB. However, the depressive-like phenotype of SUB males was not exacerbated in PCVS males; rather, they appeared to better cope with SUB status than NS SUB males. They had lower basal plasma corticosterone than NS SUB males at the end of VBS housing. In situ hybridization for CRH in the PVN and CeA did not reveal any prenatal treatment or status effects, while NPY expression was higher within the MeA of dominant and subordinate males exposed to the VBS in comparison with controls, but with no effect of prenatal treatment. These data suggest that prenatal chronic variable stress may confer resilience to offspring when exposed to social stress in adulthood.

The impact of moderate daily alcohol consumption on aggression and the formation of dominance hierarchies in rats.

RATIONALE AND OBJECTIVE: Group-housed male rats form social hierarchies, and under these conditions, it has been reported that subordinate (SUB) rats consume more alcohol than dominant (DOM) rats. We tested the hypothesis that a history of drinking alcohol would cause SUB rats to consume even greater amounts of alcohol. METHODS: Male Long-Evans rats were trained to drink 10% alcohol or a sucrose/quinine solution equal in calories for 1 h/day using a sucrose-fading procedure. Subsequently, rats were housed in colonies (four males, two females) in a visible burrow system (VBS) for 14 days. Individual control male rats were housed in a tub cage with one female. Rats were removed from the VBS (or control environment) daily and given 1 h to drink alcohol or sucrose/quinine. RESULTS: Colonies given daily access to sucrose/quinine formed clear DOM/SUB relationships in all measured parameters. Alcohol-drinking colonies failed to establish a dominance hierarchy and displayed little aggression, with an average of 14.6 +/- 6.1 offensive attacks compared with 58.5 +/- 12.3 attacks carried out by DOM sucrose/quinine rats. During VBS housing, alcohol and sucrose/quinine intake decreased independent of housing environment or social status. CONCLUSIONS: Contrary to prior reports of the effect of alcohol on aggressive behavior, moderate daily alcohol intake before and during VBS housing reduced aggression and precluded the formation of a dominance hierarchy in rats.

Deficient hippocampal c-fos expression results in reduced anxiety and altered response to chronic stress in female mice.

Stress response is an important neuroendocrine function. Overt or prolonged stress hormone secretion can lead to various disease states. The hippocampus plays an important role in the negative feedback onto the major player in the stress response, the hypothalamo-pituitary-adrenal axis. The transcription factor c-Fos is activated in the hippocampus following a number of stressors, including restraint stress. To determine whether c-fos modulates stress response, we previously generated mutant mice carrying a hippocampal mutation of the c-fos gene. In the current study, we found that female mutant mice display lower anxiety-like behavior than female wild-type mice in the elevated plus maze, whereas male mice are apparently normal. While both male and female mutant mice exhibit normal diurnal glucocorticoid (CORT) production and normal responses to acute restraint stress, female mutant mice habituated faster than female wild-type mice in response to chronic restraint stress. These findings suggest that hippocampal c-fos plays a role in gender-dependent response to stress.

Chronic social stress in a changing dietary environment.

The human population has slowly transformed from the "hunter-gatherer" period to the current environment of high energy consumption, minimal physical activity and a lifestyle that includes stress and anxiety. Modeling the current environment in the laboratory can help to elucidate mechanisms responsible for the development of obesity, diabetes and, ultimately, the metabolic syndrome. Using the visible burrow system (VBS) model of social stress we have begun to examine the short- and long-term consequences of chronic social stress on energy homeostasis. We demonstrated that social stress has significant effects on body weight and body composition such that subordinate rats progressively develop characteristics of obesity and have additionally determined that this occurs, in part, through changes in food intake amount and behavior. Changes in body weight and body composition are similar or greater when animals are maintained on a high fat diet. These data suggest that consumption of a high-fat diet during social stress in the VBS, while it does not appear to affect development of a social hierarchy, enhances the effect that chronic stress has on body composition and may be more representative of what happens in humans in modern society where the typical diet has progressively moved toward higher calorie, high-fat foods.