Stress In Rodents Research Articles

Environmental enrichment and cafeteria diet attenuate the response to chronic variable stress in rats

Exposure to an enriched environment (EE) or the intake of a highly palatable diet may reduce the response to chronic stress in rodents. To further explore the relationships between EE, dietary intake and stress, male Sprague–Dawley rats were fed one of two diets for 5weeks: high carbohydrate (HC) or “cafeteria” (CAF) (Standard HC plus a choice of highly palatable cafeteria foods: chocolate, biscuits, and peanut butter). In addition, they were either housed in empty cages or cages with EE. After the first two weeks, half of the animals from each group were stressed daily using a chronic variable stress (CVS) paradigm, while the other half were kept undisturbed. Rats were sacrificed at the end of the 5-week period. The effects of stress, enrichment and dietary intake on animal adiposity, serum lipids, and stress hormones were analyzed. Results showed an increase in intra-abdominal fat associated with the CAF diet and an increase in body weight gain associated with both the CAF diet and EE. Furthermore, the increase in ACTH associated with CVS was attenuated in the presence of EE and the CAF diet independently while the stress-induced increase in corticosterone was reduced by the combination of EE and CAF feeding. The present study provides evidence that the availability of a positive environment combined to a highly palatable diet increases resilience to the effects of CVS in rats. These results highlight the important place of palatable food and supportive environments in reducing central stress responses.

Knockdown of ventral tegmental area mu-opioid receptors in rats prevents effects of social defeat stress: Implications for amphetamine cross-sensitization, social avoidance, weight regulation and expression of brain-derived neurotrophic factor

Social defeat stress causes social avoidance and long-lasting cross-sensitization to psychostimulants, both of which are associated with increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA). Moreover, social stress upregulates VTA mu-opioid receptor (MOR) mRNA. In the VTA, MOR activation inhibits GABA neurons to disinhibit VTA dopamine neurons, thus providing a role for VTA MORs in the regulation of psychostimulant sensitization. The present study determined the effect of lentivirus-mediated MOR knockdown in the VTA on the consequences of intermittent social defeat stress, a salient and profound stressor in humans and rodents. Social stress exposure induced social avoidance and attenuated weight gain in animals with non-manipulated VTA MORs, but both these effects were prevented by VTA MOR knockdown. Rats with non-manipulated VTA MOR expression exhibited cross-sensitization to amphetamine challenge (1.0 mg/kg, i.p.), evidenced by a significant augmentation of locomotion. By contrast, knockdown of VTA MORs prevented stress-induced cross-sensitization without blunting the locomotor-activating effects of amphetamine. At the time point corresponding to amphetamine challenge, immunohistochemical analysis was performed to examine the effect of stress on VTA BDNF expression. Prior stress exposure increased VTA BDNF expression in rats with non-manipulated VTA MOR expression, while VTA MOR knockdown prevented stress-induced expression of VTA BDNF. Taken together, these results suggest that upregulation of VTA MOR is necessary for the behavioral and biochemical changes induced by social defeat stress. Elucidating VTA MOR regulation of stress effects on the mesolimbic system may provide new therapeutic targets for treating stress-induced vulnerability to substance abuse.

Prenatal stress and adult drug-seeking behavior: interactions with genes and relation to nondrug-related behavior.

Addiction inflicts large personal, social, and economic burdens, yet its etiology is poorly defined and effective treatments are lacking. As with other neuropsychiatric disorders, addiction is characterized by a core set of symptoms and behaviors that are believed to be influenced by complex gene-environment interactions. Our group focuses on the interaction between early stress and genetic background in determining addiction vulnerability. Prior work by our group and others has indicated that a history of prenatal stress (PNS) in rodents elevates adult drug seeking in a number of behavioral paradigms. The focus of the present chapter is to summarize work in the area of PNS and addiction models as well as our recent studies of PNS on drug seeking in different strains of mice as a strategy to dissect gene-environment interactions underlying cocaine addiction vulnerability. These studies indicate that ability of PNS to elevate adult cocaine seeking is strain dependent. Further, PNS also alters other nondrug behaviors in a fashion that is dependent on different strains and independent from the strain dependence of drug seeking. Thus, it appears that the ability of PNS to alter behavior related to different psychiatric conditions is orthogonal, with similar nonspecific susceptibility to prenatal stress across genetic backgrounds but with the genetic background determining the specific nature of the PNS effects. Finally, the advent of recombinant inbred mouse strains is allowing us to determine the genetic bases of these gene-environment interactions. Understanding these effects will have broad implications to determining the nature of vulnerability to addiction and perhaps other disorders.

Cardiac autonomic imbalance by social stress in rodents: understanding putative biomarkers.

Exposure to stress or traumatic events can lead to the development of depression and anxiety disorders. In addition to the debilitating consequences on mental health, patients with psychiatric disorders also suffer from autonomic imbalance, making them susceptible to a variety of medical disorders. Emerging evidence utilizing spectral analysis of heart rate variability (HRV), a reliable non-invasive measure of cardiovascular autonomic regulation, indicates that patients with depression and various anxiety disorders (i.e., panic, social, generalized anxiety disorders, and post traumatic stress disorder) are characterized by decreased HRV. Social stressors in rodents are ethologically relevant experimental stressors that recapitulate many of the dysfunctional behavioral and physiological changes that occur in psychological disorders. In this review, evidence from clinical studies and preclinical stress models identify putative biomarkers capable of precipitating the comorbidity between disorders of the mind and autonomic dysfunction. Specifically, the role of corticotropin releasing factor, neuropeptide Y and inflammation are investigated. The impetus for this review is to highlight stress-related biomarkers that may prove critical in the development of autonomic imbalance in stress -related psychiatric disorders.

Regulation of hypoxia-inducible factor-α isoforms and redox state by carotid body neural activity in rats.

Previous studies reported that chronic intermittent hypoxia (CIH) results in an imbalanced expression of hypoxia-inducible factor-α (HIF-α) isoforms and oxidative stress in rodents, which may be due either to the direct effect of CIH or indirectly via hitherto uncharacterized mechanism(s). As neural activity is a potent regulator of gene transcription, we hypothesized that carotid body (CB) neural activity contributes to CIH-induced HIF-α isoform expression and oxidative stress in the chemoreflex pathway. Experiments were performed on adult rats exposed to CIH for 10 days. Rats exposed to CIH exhibited: increased HIF-1α and decreased HIF-2α expression; increased NADPH oxidase 2 and decreased superoxide dismutase 2 expression; and oxidative stress in the nucleus tractus solitarius and rostral ventrolateral medulla as well as in the adrenal medulla (AM), a major end organ of the sympathetic nervous system. Selective ablation of the CB abolished these effects. In the AM, sympathetic activation by the CB chemoreflex mediates CIH-induced HIF-α isoform imbalance via muscarinic acetylcholine receptor-mediated Ca(2+) influx, and the resultant activation of mammalian target of rapamycin pathway and calpain proteases. Rats exposed to CIH presented with hypertension, elevated sympathetic activity and increased circulating catecholamines. Selective ablation of either the CB (afferent pathway) or sympathetic innervation to the AM (efferent pathway) abolished these effects. These observations uncover CB neural activity-dependent regulation of HIF-α isoforms and the redox state by CIH in the central and peripheral nervous systems associated with the chemoreflex.

Chronic social stress does not affect behavioural habituation in male CD1 mice

Various protocols to induce chronic stress in rodents are being used to determine the effects and underlying mechanisms of prolonged stress experience. Recently, a novel chronic social stress (CSS) protocol has been developed for mice where social instability in adolescence and early adulthood is induced. This protocol has been shown to cause an increase in HPA-axis activity and acute avoidance behaviour in the elevated plus maze. The aim of the present study was to investigate the effect of this CSS protocol on habituation to an initially novel environment in CD1 mice, since it has been shown that initially high avoidance behaviour in mice can still be followed by rapid habituation, pointing towards an adaptive response. One group of male mice, the CSS group, was exposed to the CSS protocol for 7 weeks and we compared their behavioural and physiological responses with male mice that were housed in a stable social group, the SH group. The results reveal a decrease in body weight gain and fur condition, changes in adrenal weight and decreased GR mRNA expression in the CA1 and the dentate gyrus of the hippocampus in chronically stressed CD1 animals. Irrespective of such evidence for a significantly stressful effect of the protocol, CD 1 mice, after termination of the stress procedure, revealed habituation profiles that matched those of control animals. We conclude that the physiological and central-nervous effects caused by a CSS procedure as used in this experiment fall within the coping capacities of CD1 mice at the behavioural level.

The influence of vitamin-rich diet on the extent of lipoperoxidation in brain of mice during an acute post-insulin hypoglycaemia

Antioxidatives are widely used and recommended in common clinical praxis, even though they may have negative impact on our health under some circumstances (i.e. N-acetylcysteine, vitamin E, risk of lung cancer etc.). Our aim was to evaluate the role of exogenous scavengers in prevention of induced oxidative stress in rodents. Male ICR mice were used and acute hypoglycaemia was induced with insulin. The mice were randomized into eight experimental groups, either pretreated by vitamin C or vitamin E or combinations with respective vehicles. Total malondialdehyde (MDA), superoxide dismutase (SOD), and selenium-dependent glutathione peroxidase (GSHPx) activity were measured in brain tissue samples. ANOVA with a post-hoc Duncan or Turkey׳s tests were used for statistical evaluation. A statistically significant increase in brain MDA was observed after insulin-induced severe hypoglycaemia relative to normoglycaemia. Animals pretreated with vitamins, both in monotherapy and in combination (both P<0.05), had significantly lower MDA values compared with animals without pretreatment. Importantly, significant differences were also observed after combination of vitamin C and E in GSHPx and SOD (both P<0.05).

Delayed Effects of Corticosterone on Slow After-Hyperpolarization Potentials in Mouse Hippocampal versus Prefrontal Cortical Pyramidal Neurons

The rodent stress hormone corticosterone changes neuronal activity in a slow and persistent manner through transcriptional regulation. In the rat dorsal hippocampus, corticosterone enhances the amplitude of calcium-dependent potassium currents that cause a lingering slow after-hyperpolarization (sAHP) at the end of depolarizing events. In this study we compared the putative region-dependency of the delayed effects of corticosterone (approximately 5 hrs after treatment) on sAHP as well as other active and passive properties of layer 2/3 pyramidal neurons from three prefrontal areas, i.e. the lateral orbitofrontal, prelimbic and infralimbic cortex, with the hippocampus of adult mice. In agreement with previous studies, corticosterone increased sAHP amplitude in the dorsal hippocampus with depolarizing steps of increasing amplitude. However, in the lateral orbitofrontal, prelimbic and infralimbic cortices we did not observe any modifications of sAHP amplitude after corticosterone treatment. Properties of single action potentials or % ratio of the last spike interval with respect to the first spike interval, an indicator of accommodation in an action potential train, were not significantly affected by corticosterone in all brain regions examined. Lastly, corticosterone treatment did not induce any lasting changes in passive membrane properties of hippocampal or cortical neurons. Overall, the data indicate that corticosterone slowly and very persistently increases the sAHP amplitude in hippocampal pyramidal neurons, while this is not the case in the cortical regions examined. This implies that changes in excitability across brain regions reached by corticosterone may vary over a prolonged period of time after stress.

Chronic variable stress improves glucose tolerance in rats with sucrose-induced prediabetes.

The incidence of type-2 diabetes (T2D) and the burden it places on individuals, as well as society as a whole, compels research into the causes, factors and progression of this disease. Epidemiological studies suggest that chronic stress exposure may contribute to the development and progression of T2D in human patients. To address the interaction between chronic stress and the progression of T2D, we developed a dietary model of the prediabetic state in rats utilizing unlimited access to 30% sucrose solution (in addition to unlimited access to normal chow and water), which led to impaired glucose tolerance despite elevated insulin levels. We then investigated the effects of a chronic variable stress paradigm (CVS; twice daily exposure to an unpredictable stressor for 2 weeks) on metabolic outcomes in this prediabetic model. Chronic stress improved glucose tolerance in prediabetic rats following a glucose challenge. Importantly, pair-fed control groups revealed that the beneficial effect of chronic stress did not result from the decreased food intake or body weight gain that occurred during chronic stress. The present work suggests that chronic stress in rodents can ameliorate the progression of diet-induced prediabetic disease independent of chronic stress-induced decreases in food intake and body weight.

Olfactory exposure to males, including men, causes stress and related analgesia in rodents.

We found that exposure of mice and rats to male but not female experimenters produces pain inhibition. Male-related stimuli induced a robust physiological stress response that results in stress-induced analgesia. This effect could be replicated with T-shirts worn by men, bedding material from gonadally intact and unfamiliar male mammals, and presentation of compounds secreted from the human axilla. Experimenter sex can thus affect apparent baseline responses in behavioral testing.

Interferon Regulatory Factor 8 Expressed in Microglia Contributes to Tactile Allodynia Induced by Repeated Cold Stress in Rodents

We investigated the role of interferon regulatory factor 8 (IRF8) in a model of chronic pain in which repeated cold stress (RCS) exposure produces tactile allodynia. RCS exposure produced a decrease in paw withdrawal threshold (PWT) to mechanical stimulation. Spinal microglia of RCS-exposed mice were morphologically activated. Expression of IRF8 was significantly increased in the spinal cord of RCS-exposed mice and was localized in microglia. IRF8-knockout mice failed to show the RCS-induced decrease in PWT. Thus, RCS exposure activates spinal microglia and upregulation of IRF8 in these cells is involved in the development of tactile allodynia after RCS exposure.

Age- and Sex-Dependent Effects of Early Life Stress on Hippocampal Neurogenesis

Early life stress is a well-documented risk factor for the development of psychopathology in genetically predisposed individuals. As it is hard to study how early life stress impacts human brain structure and function, various animal models have been developed to address this issue. The models discussed here reveal that perinatal stress in rodents exerts lasting effects on the stress system as well as on the structure and function of the brain. One of the structural parameters strongly affected by perinatal stress is adult hippocampal neurogenesis. Based on compiled literature data, we report that postnatal stress slightly enhances neurogenesis until the onset of puberty in male rats; when animals reach adulthood, neurogenesis is reduced as a consequence of perinatal stress. By contrast, female rats show a prominent reduction in neurogenesis prior to the onset of puberty, but this effect subsides when animals reach young adulthood. We further present preliminary data that transient treatment with a glucocorticoid receptor antagonist can normalize cell proliferation in maternally deprived female rats, while the compound had no effect in non-deprived rats. Taken together, the data show that neurogenesis is affected by early life stress in an age- and sex-dependent manner and that normalization may be possible during critical stages of brain development.

Sex-dependent effects of an early life treatment in rats that increases maternal care: vulnerability or resilience?

Early life stress (ELS) in rodents has profound long-term effects that are partially mediated by changes in maternal care. ELS not only induces “detrimental” effects in adulthood, increasing psychopathology, but also promotes resilience to further stressors. In Long-Evans rats, we evaluated a combination of two procedures as a model of ELS: restriction of bedding during the first post-natal days and exposure to a “substitute” mother. The maternal care of biological and “substitute” mothers was measured. The male and female offspring were evaluated during adulthood in several contexts. Anxiety was measured by the elevated plus-maze (EPM), acoustic startle response (ASR) and forced swim test (FST). In other group of animals, novelty-seeking was measured (activity in an inescapable novel environment, preference for novel environments and exploration of novel objects). Plasmatic ACTH and corticosterone in basal conditions and in response to stress were also measured. Cognitive impulsivity was assessed by a delay-discounting paradigm, and impulsive action, attention and compulsive-like behavior by a five choice serial reaction time task (5CSRTT). ELS decreased pup body weight and increased the care of the biological mother; however, the “substitute” mother did not exhibit overt maltreatment. A mixture of “detrimental” and “beneficial” effects was shown. In the 5CSRTT, attention was impaired in both genders, and in females, ELS increased compulsive-like behavior. Novel object exploration was only increased by ELS in males, but the preference for novel spaces decreased in both genders. Baseline anxiety (EPM and ASR) and recognition memory were not affected. Unexpectedly, ELS decreased the ACTH response to novelty and swim stress and increased active coping in the FST in both genders. Cognitive impulsivity was decreased only in females, but impulsive action was not affected. The enhancement in maternal care may “buffer” the effects of ELS in a context-dependent manner.

Rapid corticosteroid actions on synaptic plasticity in the mouse basolateral amygdala: Relevance of recent stress history and β-adrenergic signaling

The rodent stress hormone corticosterone rapidly enhances long-term potentiation in the CA1 hippocampal area, but leads to a suppression when acting in a more delayed fashion. Both actions are thought to contribute to stress effects on emotional memory. Emotional memory formation also involves the basolateral amygdala, an important target area for corticosteroid actions. We here (1) investigated the rapid effects of corticosterone on amygdalar synaptic potentiation, (2) determined to what extent these effects depend on the mouse’s recent stress history or (3) on prior β-adrenoceptor activation; earlier studies at the single cell level showed that especially a recent history of stress changes the responsiveness of basolateral amygdala neurons to corticosterone. We report that, unlike the hippocampus, stress enhances amygdalar synaptic potentiation in a slow manner. In vitro exposure to 100nM corticosterone quickly decreases synaptic potentiation, and causes only transient potentiation in tissue from stressed mice. This transient type of potentiation is also seen when β-adrenoceptors are blocked during stress and this is further exacerbated by subsequent in vitro administered corticosterone. We conclude that stress and corticosterone change synaptic potentiation in the basolateral amygdala in a manner opposite to that seen in the hippocampus and that renewed exposure to corticosterone only allows induction of non-persistent forms of synaptic potentiation.

Effects of acupuncture and electroacupuncture on estradiol-induced inflammation and oxidative stress in health rodents

To investigate the effects of classical acupuncture (Ac) and electroacupuncture (EAc) on estradiol-induced inflammation and oxidative stress in health rodents. Twenty-four eight-week old female rats were treated with estradiol valerate (EV) 4.0 mg i.m. single dose and randomly assigned to four groups (n=6): G1(control), G2 (Ac), G3 (EAc 2 Hz) and G4 (EAc 100 Hz). After 60 days all rats were anesthetized with chloral hydrate 10% (0.1 ml/30 g weight of the animal) and submitted to Ac/EAc for twenty minutes. The procedures were repeated on days three, five, seven and nine of the study. The equivalent of the human right ST-36 (Zusanli) and SP-6 (Sanyinjiao) acupoints were chosen for needling and electrical stimulation. On the 10th day of the experiment, all rats were anesthetized for collection of blood and tissues (ovaries) samples for biochemical analysis and histological examination. Glutathione (GSH) and malonaldehyde (MDA) concentrations increased significantly in all groups (plasma and ovary) while myeloperoxidase (MPO) activity decreased significantly in all groups compared with control group (G1). Both classical acupuncture and electroacupuncture decrease systemic and local oxidative stress and ovary inflammation in healthy rats exposed to estrogenic stimulation. EAc enhances lipid peroxidation at systemic and local levels in female rats exposed to estrogenic stimulation.

Distribution of the glucocorticoid receptor in the human amygdala; changes in mood disorder patients

Exposure to stress activates the hypothalamic-pituitary-adrenal (HPA) axis that stimulates glucocorticoid (GC) release from the adrenal. These hormones exert numerous effects in the body and brain and bind to a.o. glucocorticoid receptors (GR) expressed in the limbic system, including the hippocampus and amygdala. Hyperactivity of the HPA axis and disturbed stress feedback are common features in major depression. GR protein is present in the human hypothalamus and hippocampus, but little is known-neither in healthy subjects nor in depressed patients-about GR expression in the amygdala, a brain structure involved in fear and anxiety. Since chronic stress in rodents affects GR expression in the amygdala, altered GR protein level in depressed versus healthy controls can be expected. To test this, we investigated GR-α protein expression in the post-mortem human amygdala and assessed changes in ten major or bipolar depressed patients and eight non-depressed controls. Abundant GR immunoreactivity was observed in the human amygdala, both in neurons and astrocytes, with a similar pattern in its different anatomical subnuclei. In major depression, GR protein level as well as the percentage of GR-containing astrocytes was significantly higher than in bipolar depressed patients or in control subjects. Taken together, the prominent expression of GR protein in the human amygdala indicates that this region can form an important target for corticosteroids and stress, while the increased GR expression in major, but not bipolar, depression suggests possible involvement in the etiology of major depression.

N-acetylcysteine reverses cardiac myocyte dysfunction in a rodent model of behavioral stress

Compelling clinical reports reveal that behavioral stress alone is sufficient to cause reversible myocardial dysfunction in selected individuals. We developed a rodent stress cardiomyopathy model by a combination of prenatal and postnatal behavioral stresses (Stress). We previously reported a decrease in percent fractional shortening by echo, both systolic and diastolic dysfunction by catheter-based hemodynamics, as well as attenuated hemodynamic and inotropic responses to the β-adrenergic agonist, isoproterenol (ISO) in Stress rats compared with matched controls (Kan H, Birkle D, Jain AC, Failinger C, Xie S, Finkel MS. J Appl Physiol 98: 77-82, 2005). We now report enhanced catecholamine responses to behavioral stress, as evidenced by increased circulating plasma levels of norepinephrine (P < 0.01) and epinephrine (P < 0.01) in Stress rats vs. controls. Cardiac myocytes isolated from Stress rats also reveal evidence of oxidative stress, as indicated by decreased ATP, increased GSSG, and decreased GSH-to-GSSG ratio in the presence of increased GSH peroxidase and catalase activities (P < 0.01, for each). We also report blunted inotropic and intracellular Ca(2+) concentration responses to extracellular Ca(2+) (P < 0.05), as well as altered inotropic responses to the intracellular calcium regulator, caffeine (20 mM; P < 0.01). Treatment of cardiac myocytes with N-acetylcysteine (NAC) (10(-3) M) normalized calcium handling in response to ISO and extracellular Ca(2+) concentration and inotropic response to caffeine (P < 0.01, for each). NAC also attenuated the blunted inotropic response to ISO and Ca(2+) (P < 0.01, for each). Surprisingly, NAC did not reverse the changes in GSH, GSSG, or GSH-to-GSSG ratio. These data support a GSH-independent salutary effect of NAC on intracellular calcium signaling in this rodent model of stress-induced cardiomyopathy.

Induced erythropoiesis during acute anemia in Atlantic salmon: A transcriptomic survey

Anemia is a common pathophysiological response to stressors, malnutrition and infections in salmonid fish. In order to improve our understanding of the molecular mechanisms and markers associated with induced erythropoiesis (EP) during acute anemia in Atlantic salmon (Salmo salar L.), we performed transcriptome analysis of fish injected with the hemolytic compound phenylhydrazine (PHZ). Treatment with a low dose of PHZ resulted in moderate but significant reduction of hematocrit (Hct) and increased transcription of cardiac erythropoietin (epo) at 2days post challenge (dpc), and epo receptor (epor) in spleen from 2 to 4dpc. Oligonucleotide microarrays were used to characterize the events of EP in the spleen, an important organ for expansive EP during acute erythropoietic stress in rodents, and these were compared to gene expression profiles of untreated mature red blood cells (RBC) in order to search for erythroid-specific genes. Splenic responses suggested a prevalence of protective mechanisms at the first stage, characterized by induced xenobiotic metabolism and responses to oxidative and protein stress. Erythroid-specific regulation was evident at 2dpc and enhanced by 4dpc, and gene expression profiles witnessed a rapid establishment of RBC phenotype although Hct levels remained low. A large group of genes showed a strong correlation to globins by expression profiles. In addition to epor this included genes of heme and iron metabolism, scavengers of free radicals and chaperones, channels and transporters, markers of erythrocytes, regulators of proliferation and cell cycle arrest and many genes with unidentified roles in RBC differentiation. Induced EP in spleen was characterized by specific features, such as upregulation of innate antiviral immune genes and sustained high expression of proapoptotic genes including caspases. Transcriptome changes suggested an association between EP and suppression of several developmental programs including adaptive immune responses. In conclusion, acute hemolysis and resulting anemia rapidly induced EP in the spleen of Atlantic salmon, which showed both common characteristics for all vertebrates as well as fish-specific properties.

Stress induced obesity: lessons from rodent models of stress

Stress was once defined as the non-specific result of the body to any demand or challenge to homeostasis. A more current view of stress is the behavioral and physiological responses generated in the face of, or in anticipation of, a perceived threat. The stress response involves activation of the sympathetic nervous system and recruitment of the hypothalamic-pituitary-adrenal (HPA) axis. When an organism encounters a stressor (social, physical, etc.), these endogenous stress systems are stimulated in order to generate a fight-or-flight response, and manage the stressful situation. As such, an organism is forced to liberate energy resources in attempt to meet the energetic demands posed by the stressor. A change in the energy homeostatic balance is thus required to exploit an appropriate resource and deliver useable energy to the target muscles and tissues involved in the stress response. Acutely, this change in energy homeostasis and the liberation of energy is considered advantageous, as it is required for the survival of the organism. However, when an organism is subjected to a prolonged stressor, as is the case during chronic stress, a continuous irregularity in energy homeostasis is considered detrimental and may lead to the development of metabolic disturbances such as cardiovascular disease, type II diabetes mellitus and obesity. This concept has been studied extensively using animal models, and the neurobiological underpinnings of stress induced metabolic disorders are beginning to surface. However, different animal models of stress continue to produce divergent metabolic phenotypes wherein some animals become anorexic and lose body mass while others increase food intake and body mass and become vulnerable to the development of metabolic disturbances. It remains unclear exactly what factors associated with stress models can be used to predict the metabolic outcome of the organism. This review will explore a variety of rodent stress models and discuss the elements that influence the metabolic outcome in order to further extend our understanding of stress-induced obesity.

Differential response of hippocampal subregions to stress and learning.

The hippocampus has two functionally distinct subregions–the dorsal portion, primarily associated with spatial navigation, and the ventral portion, primarily associated with anxiety. In a prior study of chronic unpredictable stress (CUS) in rodents, we found that it selectively enhanced cellular plasticity in the dorsal hippocampal subregion while negatively impacting it in the ventral. In the present study, we determined whether this adaptive plasticity in the dorsal subregion would confer CUS rats an advantage in a spatial task–the radial arm water maze (RAWM). RAWM exposure is both stressful and requires spatial navigation, and therefore places demands simultaneously upon both hippocampal subregions. Therefore, we used Western blotting to investigate differential expression of plasticity-associated proteins (brain derived neurotrophic factor [BDNF], proBDNF and postsynaptic density-95 [PSD-95]) in the dorsal and ventral subregions following RAWM exposure. Lastly, we used unbiased stereology to compare the effects of CUS on proliferation, survival and neuronal differentiation of cells in the dorsal and ventral hippocampal subregions. We found that CUS and exposure to the RAWM both increased corticosterone, indicating that both are stressful; nevertheless, CUS animals had significantly better long-term spatial memory. We also observed a subregion-specific pattern of protein expression following RAWM, with proBDNF increased in the dorsal and decreased in the ventral subregion, while PSD-95 was selectively upregulated in the ventral. Finally, consistent with our previous study, we found that CUS most negatively affected neurogenesis in the ventral (compared to the dorsal) subregion. Taken together, our data support a dual role for the hippocampus in stressful experiences, with the more resilient dorsal portion undergoing adaptive plasticity (perhaps to facilitate escape from or neutralization of the stressor), and the ventral portion involved in affective responses.