Basal Plasma Corticosterone Levels Research Articles

Brief versus long maternal separation in lactating rats: Consequences on maternal behavior, emotionality, and brain oxytocin receptor binding.

Maternal separation is a widely used animal model to study early life adversity in offspring. However, only a few studies have focused on the impact of disrupting the maternal bond from the mother's perspective. Such studies reveal alterations in behavior, whereas the underlying neuroendocrine mechanisms remain largely unknown. In this study, we compared the consequences of daily brief maternal separation (BMS; 15 min) versus long maternal separation (LMS; 180 min) during the first week postpartum with respect to behavioral and neuroendocrine changes in lactating Sprague-Dawley dams. Mothers were tested for their maternal care before and after separation, maternal motivation to retrieve pups, as well as anxiety-related and stress-coping behaviors. In addition, we analyzed their basal plasma corticosterone levels and oxytocin receptor binding in selected brain regions of the limbic system and maternal network. LMS dams showed higher levels of behavioral alterations compared to BMS and non-maternally separated (NMS) dams, including increased licking and grooming of the pups and decreased maternal motivation. Anxiety-related behavior was not affected by either separation paradigm, whereas passive stress-coping behavior tended to increase in the LMS group. Plasma corticosterone concentrations were not different between groups. Oxytocin receptor binding was higher in the medial preoptic area and tended to be higher in the prelimbic cortex of LMS dams, only. Our results demonstrate that especially daily prolonged maternal separation impacts on the mothers' behavior and oxytocin system, which suggests that enhanced oxytocin receptor binding could be a compensatory mechanism for potentially decreased central oxytocin release due to limited pup contact.

Maternal separation induced resilience to depression and spatial memory deficit despite intensifying hippocampal inflammatory responses to chronic social defeat stress in young adult male rats

Early life adversity has been suggested to affect neuroendocrine responses to subsequent stressors and accordingly vulnerability for behavioral disorders. This is the first work to study the effects of maternal separation (MS) stress on the co-occurrence of depression and cognitive impairments along with hippocampal inflammatory response under chronic social defeat stress (CSDS) in young adult male rats. During the first two postnatal weeks, the male pups were either exposed to MS or left undisturbed with their mothers (Std). Subsequently, starting on postnatal day 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent CSDS for three weeks. Totally, there were four groups (n = 10/group), namely Std-Con, Ms-Con, Std-CSDS, and MS-CSDS. Pup retrieval test was performed on daily basis from PND1 to PND14. During the last week of the CSDS exposure, in the light phase, the behavioral tests and the retro-orbital blood sampling were performed to assess basal plasma corticosterone levels. Afterwards, the hippocampus of the animals was removed to measure the interleukin 1β (IL-1β) content. Exposure to CSDS increased the plasma corticosterone levels and induced social avoidance along with memory deficit. Maternal separation intensified hippocampal IL-1β contents as well as the plasma corticosterone levels in response to CSDS. Meanwhile, it facilitated the spatial learning and potentiated resilience to social avoidance and memory deficit. In conclusion, although maternal separation increased the basal plasma corticosterone levels, it could facilitate the learning process and induce resilience to the onset of depression and memory deficit in response to CSDS, probably through the compensatory increase in maternal care and the induction of mild hippocampal inflammatory response.

Microbiota and stress: a loop that impacts memory

Chronic stress and the gut microbiota appear to comprise a feed-forward loop, which contributes to the development of depressive disorders. Evidence suggests that memory can also be impaired by either chronic stress or microbiota imbalance. However, it remains to be established whether these could be a part of an integrated loop model and be responsible for memory impairments. To shed light on this, we used a two-pronged approach in Japanese quail: first stress-induced alterations in gut microbiota were characterized, then we tested whether this altered microbiota could affect brain and memory function when transferred to a germ-free host. The cecal microbiota of chronically stressed quails was found to be significantly different from that of unstressed individuals with lower α and β diversities and increased Bacteroidetes abundance largely represented by the Alistipes genus, a well-known stress target in rodents and humans. The transfer of this altered microbiota into germ-free quails decreased their spatial and cue-based memory abilities as previously demonstrated in the stressed donors. The recipients also displayed increased anxiety-like behavior, reduced basal plasma corticosterone levels and differential gene expression in the brain. Furthermore, cecal microbiota transfer from a chronically stressed individual was sufficient to mimic the adverse impact of chronic stress on memory in recipient hosts and this action may be related to the Alistipes genus. Our results provide evidence of a feed-forward loop system linking the microbiota-gut-brain axis to stress and memory function and suggest that maintaining a healthy microbiota could help alleviate memory impairments linked to chronic stress.

Postpartum maternal exposure to predator odor alters offspring antipredator behavior, basal HPA axis activity and immunoglobulin levels in adult Brandt’s voles

Predation risk can program offspring behavior, physiology, and fitness through maternal effect, but most studies have mainly focused on this effect during pregnancy; little is known about the effect of postpartum predation risk on offspring’s phenotype. Here, we compared the antipredator behaviors of adult offspring (approximately 90 days old) produced by female Brandt’s voles (Lasiopodomys brandtii) exposed to one of three treatments: cat odor (CO), rabbit odor (RO), and distilled water (DW) for 60 min daily from postpartum day 1–18. Basal levels of plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT), hypothalamic corticotrophin releasing hormone (CRH), as well as spleen immunoglobulins (IgA, IgM, and IgG) were also measured. Our data showed that the offspring of CO-exposed mothers displayed less head-out behavior to acute 15-min CO exposure, and female offspring showed more freezing behavior. CO offspring showed significantly lower basal ACTH and CORT levels than the RO and DW offspring. Additionally, female but not male CO offspring had higher hypothalamic CRH expression and spleen IgG levels than controls, showing a sex-specific effect. These findings demonstrate that postpartum maternal predator risk exposure promotes a passive-avoidant response to these cues in adult offspring, showing a cross-generational maternal effect of postpartum predation risk. Further, these changes may be associated with alterations in the hypothalamic-pituitary-adrenal axis and immune function.

Modulatory action of environmental enrichment on hormonal and behavioral responses induced by chronic stress in rats: Hypothalamic renin-angiotensin system components

Environmental enrichment (EE) has been studied as a protocol that can improve brain plasticity and may protect against negative insults such as chronic stress. The aim of this study was to evaluate the effects of EE on the hormonal and behavioral responses induced by chronic mild unpredictable stress (CMS) in rats, considering the involvement of the renin-angiotensin system. Male adult rats were divided into 4 groups: control, CMS, EE, and CMS + EE, and the experimental protocol lasted for 7 weeks. EE was performed during 7 weeks, 5 days per week, 2 h per day. CMS was applied during weeks 3, 4, and 5. After the CMS (week 6), depression-like behavior was evaluated by forced swimming and sucrose consumption tests, anxiety level was evaluated using the elevated plus-maze test, and memory was evaluated using the Y-maze test. On week 7, the animals were euthanized and basal plasma levels of corticosterone and catecholamines were determined. The hypothalamus was isolated and tissue levels of angiotensin peptides were evaluated. CMS increased plasma corticosterone, norepinephrine, and epinephrine basal concentrations, induced depression-like behaviors, impaired memory, and increased hypothalamic angiotensin I, II, and IV concentrations. EE decreased stress hormones secretion, depression-like behaviors, memory impairment, and hypothalamic angiotensin II induced by stress. Reductions of anxiety-like behavior and norepinephrine secretion were observed in both stressed and unstressed groups. The results indicated that EE seemed to protect adult rats against hormonal and behavioral CMS effects, and that the reduction of angiotensin II could contribute to these effects.

Early life stress-induced alterations in the activity and morphology of ventral tegmental area neurons in female rats

Childhood maltreatment, which can take the form of physical or psychological abuse, is experienced by more than a quarter of all children. Early life stress has substantial and long-term consequences, including an increased risk of drug abuse and psychiatric disorders in adolescence and adulthood, and this risk is higher in women than in men. The neuronal mechanisms underlying the influence of early life adversities on brain functioning remain poorly understood; therefore, in the current study, we used maternal separation (MS), a rodent model of early-life neglect, to verify its influence on the properties of neurons in the ventral tegmental area (VTA), a brain area critically involved in reward and motivation processing. Using whole-cell patch-clamp recordings in brain slices from adolescent female Sprague-Dawley rats, we found an MS-induced increase in the excitability of putative dopaminergic (DAergic) neurons selectively in the medial part of the VTA. We also showed an enhancement of excitatory synaptic transmission in VTA putative DAergic neurons. MS-induced alterations in electrophysiology were accompanied by an increase in the diameter of dendritic spine heads on lateral VTA DAergic neurons, although the overall dendritic spine density remained unchanged. Finally, we reported MS-related increases in basal plasma ACTH and corticosterone levels. These results show the long-term consequences of early life stress and indicate the possible neuronal mechanisms of behavioral disturbances in individuals who experience early life neglect.

Colonization by Enterobacteriaceae is crucial for acute inflammatory responses in murine small intestine via regulation of corticosterone production

ABSTRACT Although dysbiosis in the gut microbiota is known to be involved in several inflammatory diseases, whether any specific bacterial taxa control host response to inflammatory stimuli is still elusive. Here, we hypothesized that dysbiotic indigenous taxa could be involved in modulating host response to inflammatory triggers. To test this hypothesis, we conducted experiments in germ-free (GF) mice and in mice colonized with dysbiotic taxa identified in conventional (CV) mice subjected to chemotherapy-induced mucositis. First, we report that the absence of microbiota decreased inflammation and damage in the small intestine after administration of the chemotherapeutic agent 5-fluorouracil (5-FU). Also, 5-FU induced a shift in CV microbiota resulting in higher amounts of Enterobacteriaceae, including E. coli, in feces and small intestine and tissue damage. Prevention of Enterobacteriaceae outgrowth by treating mice with ciprofloxacin resulted in diminished 5-FU-induced tissue damage, indicating that this bacterial group is necessary for 5-FU-induced inflammatory response. In addition, monocolonization of germ-free (GF) mice with E. coli led to reversal of the protective phenotype during 5-FU chemotherapy. E. coli monocolonization decreased the basal plasma corticosterone levels and blockade of glucocorticoid receptor in GF mice restored inflammation upon 5-FU treatment. In contrast, treatment of CV mice with ciprofloxacin, that presented reduction of Enterobacteriaceae and E. coli content, induced an increase in corticosterone levels. Altogether, these findings demonstrate that Enterobacteriaceae outgrowth during dysbiosis impacts inflammation and tissue injury in the small intestine. Importantly, indigenous Enterobacteriaceae modulates host production of the anti-inflammatory steroid corticosterone and, consequently, controls inflammatory responsiveness in mice.

VLDL/LDL serves as the primary source of cholesterol in the adrenal glucocorticoid response to food deprivation

The contribution of individual lipoprotein species to the generation of the adrenal cholesterol pool used for the synthesis of anti-inflammatory glucocorticoid species remains unknown. Here we examined the impact of specific lowering of very low-density lipoprotein (VLDL) and low-density (LDL) levels on adrenal cholesterol and glucocorticoid homeostasis. Hereto, lethally-irradiated hypercholesterolemic apolipoprotein E (APOE) knockout mice received APOE-containing bone marrow from wild-type mice (n = 6) or APOE knockout control bone marrow (n = 10) and were subsequently fed a regular chow diet. Transplantation with wild-type bone marrow was associated with a 10-fold decrease in VLDL/LDL-cholesterol levels. No changes were observed in adrenal weights, adrenal cholesterol content, or basal plasma corticosterone levels. However, food deprivation-induced corticosterone secretion was 64% lower (P < 0.05) in wild-type bone marrow recipients as compared to APOE knockout bone marrow recipients, in the context of similar plasma adrenocorticotropic hormone (ACTH) levels. A parallel 19–29% decrease in adrenal relative mRNA expression levels of ACTH-responsive genes SR-BI (P < 0.01), STAR (P < 0.05), and CYP11A1 (P < 0.05) was detected. In support of relative glucocorticoid insufficiency, blood lymphocyte and eosinophil concentrations were respectively 2.4-fold (P < 0.01) and 8-fold (P < 0.001) higher in wild-type bone marrow recipients under food deprivation stress conditions.In conclusion, we have shown that a selective lowering of VLDL/LDL levels in APOE knockout mice through a transplantation with APOE-containing wild-type bone marrow is associated with a decreased maximal adrenal glucocorticoid output. Our studies provide experimental support for the hypothesis that, in vivo, VLDL/LDL serves as the primary source of cholesterol used for glucocorticoid synthesis during food deprivation stress.

Short photoperiod restores ventral subicular lesion-induced deficits in affective and socio-cognitive behavior in male Wistar rats.

Photoperiod (day-length) has enduring effects on an organism's physiological functions like metabolism and behavioral phenotypes including cognition and affect. Circadian rhythm manipulations are potentially effective non-pharmacological strategies in the management of central nervous system insults. In our previous study, we demonstrated the efficacy of short photoperiod regime (SPR; 06/18hr light-dark cycle) in establishing functional recovery in ventral subicular lesion (VSL) rats. The present study further demonstrates the efficacy of SPR in mitigating anxiety and depression as well as facilitating socio-cognitive behavior in VSL rats. VSL elevated the basal plasma corticosterone levels, increased anxiety, anhedonia, and behavioral despair with decreased self-care. The VSL rats also exhibited a considerable degree of impaired social cognition, in terms of altered social preference and social novelty. Exposure to SPR for 21days mitigated the anxiety- and depressive-like phenotypes as well as improved social cognition significantly. Thus, the study demonstrated the effectiveness of SPR strategy in reversing most of the behavioral deficits caused by VSL. SPR, perhaps, would have regulated the hypothalamo-pituitary-adrenal axis responsiveness as we observed a decrease in plasma corticosterone levels following SPR in VSL rats. The study implies the need for developing a task-dependent SPR strategy to achieve complete behavioral recovery as the functional demands of each behavior is distinct. In summary, the study highlights the efficacy of photoperiod manipulation as a novel, non-pharmacological approach in mitigating the affective and cognitive deficits associated with neuropsychiatric disorders such as bipolar disorder and Alzheimer's disease wherein circadian rhythm alterations are implicated.

Developmental nicotine exposure elicits multigenerational disequilibria in proBDNF proteolysis and glucocorticoid signaling in the frontal cortices, striata, and hippocampi of adolescent mice

Maternal smoking of conventional or vapor cigarettes during pregnancy, a form of developmental nicotine exposure (DNE), enhances the risk of neurodevelopmental disorders such as ADHD, autism, and schizophrenia in children. Modeling the multigenerational effects of smoking during pregnancy and nursing in the first- (F1) and second- (F2) generation adolescent offspring of oral nicotine-treated female C57BL/6J mice, we have previously reported that DNE precipitates intergenerational transmission of nicotine preference, hyperactivity and impulsivity-like behaviors, altered rhythmicity of home cage activity, corticostriatal nicotinic acetylcholine receptor and dopamine transporter dysfunction, and corticostriatal global DNA methylome deficits. In aggregate, these DNE-evoked behavioral, neuropharmacological, and epigenomic anomalies mirror fundamental etiological aspects of neurodevelopmental disorders including ADHD, autism, and schizophrenia. Expanding this line of research, the current study profiled the multigenerational neurotrophic and neuroendocrine consequences of DNE. Results reveal impaired proBDNF proteolysis as indicated by proBDNF-BDNF imbalance, downregulation of the proBDNF processing enzyme furin, atypical glucocorticoid receptor (GR) activity as implied by decreased relative nuclear GR localization, and deficient basal plasma corticosterone (CORT) levels in adolescent DNE offspring and grandoffspring. Collectively, these data recapitulate the BDNF deficits and HPA axis dysregulation characteristic of neurodevelopmental disorders such as ADHD, autism, and schizophrenia as well as the children of maternal smokers. Notably, as BDNF is a quintessential mediator of neurodevelopment, our prior findings of multigenerational DNE-induced behavioral and neuropharmacological abnormalities may stem from neurodevelopmental insults conferred by the proBDNF-BDNF imbalance detected in DNE mice. Similarly, our findings of multigenerational GR hypoactivity may contribute to the increased risk-taking behaviors and aberrant circadian rhythmicity of home cage activity that we previously documented in first- and second-generation DNE mice.

104-OR: Glucoregulatory Effects of Hypothalamic Glucocorticoid Action In Vivo

Diabetes is characterized by dysregulated glucose homeostasis that leads to hyperglycemia, due in part to increased hepatic glucose production (GP) and insulin resistance. Excessive levels and/or action of glucocorticoids (GCs) are associated with obesity, insulin resistance, and hyperglycemia. We aim to delineate a mechanism of GC action in the mediobasal hypothalamus (MBH) that modulates GP in normal and pre-obese rodents. Male SD rats underwent stereotaxic MBH bilateral cannulation and intravenous (iv) and intraarterial catheterization to enable simultaneous direct infusions into the MBH, iv infusions, and blood sampling, respectively. Mildly hyperinsulinemic-euglycemic clamps with tracer dilution methodology combined with MBH GC infusion ± GC receptor (GR) inhibition enables measurement of GP and utilization while assessing MBH GC interaction with its MBH receptors independent of changes in plasma insulin, glucagon, and glucose levels. MBH GC infusion potently stimulates GP and lowers the requirement for exogenous glucose infusion without altering glucose utilization. This effect is mediated via GRs since co-infusion of GR antagonist mifepristone, or a HSP90 inhibitor, negates the ability of MBH GCs to increase GP. MBH GCs similarly increased glucose excursions during iv glucose tolerance tests, which was reversed with concomitant MBH mifepristone infusion. Rats fed with high fat diet (HFD) for 3 days had altered glucose kinetics and increased basal plasma corticosterone, insulin, and blood glucose levels without changes in body weight. Chronic MBH GR inhibition with MBH GR shRNA lowered GP compared to MBH mismatch control HFD rats with MBH vehicle infusions, suggesting that blocking excessive MBH GC action resulting from HFD-feeding attenuates GP to improve glucose homeostasis. We provide novel evidence that MBH GC action modulates GP in healthy and pre-obese rats. Importantly, targeted inhibition of MBH GC action may help improve glucose regulation in obesity-related metabolic disease. Disclosure E. Beaulieu-Bayne: None. M. Cardoso: None. H. Kim: None. S. Yang: None. J.T. Yue: None. Funding Diabetes Canada; Natural Sciences and Engineering Research Council of Canada; Alberta Diabetes Institute; Canadian Institutes of Health Research

Maternal separation induces anhedonia in female heterozygous serotonin transporter knockout rats

The serotonin transporter (SERT) gene has been linked to depression, especially the short allele of the serotonin transporter linked polymorphic region (5-HTTLPR). When short allele carriers are exposed to stressful life events, their risk for developing depression is increased. The neurochemical properties of the short allele of the 5-HTTLPR in humans can be mimicked in heterozygous serotonin transporter knockout (SERT+/−) rats. These animals have a similar reduction in SERT expression as humans with a 5-HTTLPR short allele. Several stress protocols have been used in SERT+/− animals but behavioural outcomes were mixed. Many studies used males to examine the behavioural effects of stress in SERT+/− rats, ignoring possible effects in females. However, women are depressed twice as often compared to men, therefore it is of great importance to study the effects of stress in females as well. Because early postnatal adversity can contribute to the psychopathology of depression, especially in vulnerable individuals, our aim was to investigate the effects of early-life stress in female SERT+/- rats and determine whether female SERT+/− rats could model the human short allele 5HTTLPR carriers.To this end, SERT+/− rats were maternally separated for six hours a day from postnatal day 2-15. Control rats were handled for 15 min from PND2-15 to control for litter disturbances. In adulthood, female rats were assessed for affective, social and coping behaviour. In addition, nerve growth factor (NGF) gene expression in the basolateral amygdala (BLA) and paraventricular nucleus of the hypothalamus (PVN) and basal plasma corticosterone levels were measured.Results show that maternal separation lowered sucrose preference in female SERT+/− rats compared to control SERT+/− rats, reflecting anhedonic behaviour. In addition, compared to control SERT+/− rats, maternal separation significantly lowered NGF gene expression in SERT+/− rats in both BLA and PVN, but did not affect plasma corticosterone levels. Together, these results show that early-life stress in female SERT+/− rats leads to depression-like behaviour and related plasticity impairments in the BLA and PVN.

Adrenocortical and bioenergetic responses to cold in laboratory-born northern red-backed voles (Myodes rutilus) from two populations in south Siberia, Russia

In animal populations inhabiting ecologically suboptimal environmental conditions, phenotypical shifts in physiological traits responsible for coping with environmental challenges can be expected. If such variations are of heritable origin, then they will manifest themselves even in individuals bred in captivity. In laboratory-born red-backed voles (Myodes rutilus (Pallas, 1779)) originating from a population with constantly low density, maximum cold-induced metabolic rates were higher than in voles from a high-density population, similar to the data obtained on wild-caught individuals from the same populations. However, unlike wild-caught voles, in laboratory-born individuals maintained under comfortable conditions, we revealed no interpopulation differences either in basal plasma corticosterone level or in corticosterone response to acute cooling. These data confirm the suggestion about the heritable origin of increased maximum cold-induced metabolic rate in a red-backed vole population with relatively low density.

Chronic-Stress-Induced Behavioral Changes Associated with Subregion-Selective Serotonin Cell Death in the Dorsal Raphe.

The current study examined the neurochemical mechanisms and neuroanatomical changes underlying coexisting behavioral effects associated with chronic-stress-induced alterations in serotonin (5HT) neurons. Chronic unpredictable stress (CUS) to adult male rats produced depression-like changes with cognitive dysfunction and selective cell death in the interfascicular nucleus of the dorsal raphe (DRif), resulting in decreased 5HTergic innervation of medial prefrontal cortex (mPFC). Twenty-one days of CUS decreased basal plasma levels of corticosterone and produced a shorter latency to immobility and longer durations of immobility in the force-swim test that persisted for 1 month after CUS. Deficits in acquisition, recall, perseveration, and reversal learning were evident 1 month after CUS. MK801 treatment during CUS blocked the changes in the forced-swim test and deficits in memory recall. These behavioral changes were associated with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive soma and the eventual loss of 5HT neurons in the DRif and its projections to the mPFC as evidenced by fewer labeled cells in the DRif after retrograde tracer injections into the mPFC of stressed rats. Similar to the effects of MK801 on behavior, MK801 pretreatment during stress blocked the CUS-induced decreases in 5HT soma within the DRif and its projections to the mPFC. Finally, the depression-like behaviors were blocked by acute injection of the 5HT2A/C agonist (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride into the mPFC before forced-swim testing. These results identify a cause and mechanism of 5HTergic dysfunction of the mPFC and associated mood and cognitive behaviors.SIGNIFICANCE STATEMENT Chronic stress causes persistent mood and cognitive changes typically associated with dysregulated serotonin (5HT) transmission in the medial prefrontal cortex (mPFC), but the cause of this dysregulation is unknown. Prior studies have focused on 5HTergic terminals in this region, but this study shows that chronic stress causes NMDA-receptor-dependent and subregion-specific cell death of 5HT neurons in the dorsal raphe. The consequent decreased 5HT innervation of the mPFC was associated with mood and cognitive changes that persisted long after the termination of stress. These findings identify a mechanism of subregion-selective death of 5HT neurons in the dorsal raphe, a defined neuroanatomical pathway, and a behavioral phenotype that mirror stress-associated diseases such as major depressive disorder.

The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans.

FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity. The purpose of this study is to characterize alcohol preference and related phenotypes in Fkbp5 knockout (KO) mice and to examine the role of FKBP5 in human alcohol consumption. The following experiments were performed to characterize Fkpb5 KO mice. (1) Fkbp5 KO and wild-type (WT) EtOH consumption was tested using a two-bottle choice paradigm; (2) The EtOH elimination rate was measured after intraperitoneal (IP) injection of 2.0 g/kg EtOH; (3) Blood alcohol concentration (BAC) was measured after 3 h limited access of alcohol; (4) Brain region expression of Fkbp5 was identified using LacZ staining; (5) Baseline corticosterone (CORT) was assessed. Additionally, two SNPs, rs1360780 (C/T) and rs3800373 (T/G), were selected to study the association of FKBP5 with alcohol consumption in humans. Participants were college students (n = 1162) from 21–26 years of age with Chinese, Korean or Caucasian ethnicity. The results, compared to WT mice, for KO mice exhibited an increase in alcohol consumption that was not due to differences in taste sensitivity or alcohol metabolism. Higher BAC was found in KO mice after 3 h of EtOH access. Fkbp5 was highly expressed in brain regions involved in the regulation of the stress response, such as the hippocampus, amygdala, dorsal raphe and locus coeruleus. Both genotypes exhibited similar basal levels of plasma corticosterone (CORT). Finally, single nucleotide polymorphisms (SNPs) in FKBP5 were found to be associated with alcohol drinking in humans. These results suggest that the association between FKBP5 and alcohol consumption is conserved in both mice and humans.

Sex differences in sleep, anhedonia, and HPA axis activity in a rat model of chronic social defeat

Repeated bouts of a major stressor such as social defeat are well known to induce a depression phenotype in male rats. Despite strong evidence and acknowledgement that women have a two-fold lifetime greater risk of developing major depression compared to men, the inclusion of female rats in studies employing social defeat are very rare; their absence is attributed to less aggressive interactions. This study sought to compare in male and female rats the impact of repeated social defeat, three times per week for four weeks, on the development of changes in sleep architecture and continuity, sucrose preference as a measure of anhedonia, changes in body weight, and basal plasma corticosterone levels. We found significant reductions in rapid eye movement sleep (REMS) during the light phase in both females and males, and significant increases in numbers of vigilance state transitions during the early dark phase in females but not in males. Additionally, females exhibited significantly greater reductions in sucrose intake than males. On the other hand, no sex differences in significantly elevated basal corticosterone levels were evident, and only the males exhibited changes in body weight. Taken together these findings suggest that the inclusion of female rats in studies of social defeat may offer greater insights in studies of stress and depression.

Involvement of Endogenous Brain-Derived Neurotrophic Factor in Hypothalamic-Pituitary-Adrenal Axis Activity.

Brain-derived neurotrophic factor (BDNF) appears to be highly involved in hypothalamic-pituitary-adrenal (HPA) axis regulation during adulthood, playing an important role in homeostasis maintenance. The present study aimed to determine the involvement of BDNF in HPA axis activity under basal and stress conditions via partial inhibition of this endogenous neurotrophin. Experiments were conducted in rats and mice with two complementary approaches: (i) BDNF knockdown with stereotaxic delivery of BDNF-specific small interfering RNA (siRNA) into the lateral ventricle of adult male rats and (ii) genetically induced knockdown (KD) of BDNF expression specifically in the central nervous system during the first ontogenesis in mice (KD mice). Delivery of siRNA in the rat brain decreased BDNF levels in the hippocampus (-31%) and hypothalamus (-35%) but not in the amygdala, frontal cortex and pituitary. In addition, siRNA induced no change of the basal HPA axis activity. BDNF siRNA rats exhibited decreased BDNF levels and concomitant altered adrenocortoctrophic hormone (ACTH) and corticosterone responses to restraint stress, suggesting the involvement of BDNF in the HPA axis adaptive response to stress. In KD mice, BDNF levels in the hippocampus and hypothalamus were decreased by 20% in heterozygous and by 60% in homozygous animals compared to wild-type littermates. Although, in heterozygous KD mice, no significant change was observed in the basal levels of plasma ACTH and corticosterone, both hormones were significantly increased in homozygous KD mice, demonstrating that robust cerebral BDNF inhibition (60%) is necessary to affect basal HPA axis activity. All of these results in both rats and mice demonstrate the involvement and importance of a robust endogenous pool of BDNF in basal HPA axis regulation and the pivotal function of de novo BDNF synthesis in the establishment of an adapted response to stress.

Infralimbic cortex controls the activity of the hypothalamus–pituitary–adrenal axis and the formation of aversive memory: Effects of environmental enrichment

The aim of the present study was to investigate the effects of the stimulation and inhibition of the ventral part of the medial prefrontal cortex (infralimbic cortex) on basal and stress-induced plasma levels of corticosterone and on the acquisition of aversive memory in animals maintained in control and environmental enrichment (EE) conditions. Intracortical microinjections of the GABAA antagonist picrotoxin and agonist muscimol were performed in male Wistar rats to stimulate and inhibit, respectively, the activity of the infralimbic cortex. Injections were performed 60min before foot shock stress and training in the inhibitory avoidance task. Picrotoxin injections into the infralimbic cortex increased basal plasma levels of corticosterone. These increases were higher in EE rats which suggest that EE enhances the control exerted by infralimbic cortex over the hypothalamus–pituitary–adrenal (HPA) axis and corticosterone release. Muscimol injections into the infralimbic cortex reduced the stress-induced plasma levels of corticosterone and the retention latency 24h after training in the inhibitory avoidance performance in control and EE animals, respectively. These results further suggest that the infralimbic cortex is required for the activation of the HPA axis during stress and for the acquisition of contextual aversive memories.

Cocaine self-administration in Wistar-Kyoto rats: a behavioral and biochemical analysis

Depression and cocaine abuse disorders are common concurrent diagnoses. In the present study, we employed Wistar-Kyoto (WKY) rats that showed a depressive-like phenotype to study intravenous cocaine self-administration and extinction/reinstatement procedures. We also investigated the basal tissue level of neurotransmitters, their metabolites and plasma corticosterone (CORT) concentrations in WKY rats, bulbectomized (OBX) rats, and control rats. The WKY rats exhibited an attenuation of the cocaine-associated lever presses and cocaine intake during the acquisition/maintenance of cocaine self-administration only under specific conditions. Active lever presses exhibited by the WKY rats and control animals did not differ during the extinction training and cocaine-seeking behaviors. The WKY rats demonstrated alterations in the basal levels of dopamine, norepinephrine, and serotonin in selected brain structures involved in depression and drug addiction. The changes in the level of neurotransmitters in these animals refer not only to the control (Wistar) rats but also to bulbectomized animals, which represent another depression model. Furthermore, we identified unchanged levels of CORT in the WKY and OBX rats during the light phase and free-stress conditions. This finding suggests that WKY rats should not be used to investigate the co-occurrence of depression and cocaine addiction, as this rat strain does not show an enhanced risk of relapse.

Adrenocortical LDL receptor function negatively influences glucocorticoid output.

Over 50% of the cholesterol needed by adrenocortical cells for the production of glucocorticoids is derived from lipoproteins. However, the overall contribution of the different lipoproteins and associated uptake pathways to steroidogenesis remains to be determined. Here we aimed to show the importance of LDL receptor (LDLR)-mediated cholesterol acquisition for adrenal steroidogenesis in vivo. Female total body LDLR knockout mice with a human-like lipoprotein profile were bilaterally adrenalectomized and subsequently provided with one adrenal either expressing or genetically lacking the LDLR under their renal capsule to solely modulate adrenocortical LDLR function. Plasma total cholesterol levels and basal plasma corticosterone levels were identical in the two types of adrenal transplanted mice. Strikingly, restoration of adrenal LDLR function significantly reduced the ACTH-mediated stimulation of adrenal steroidogenesis (P<0.001), with plasma corticosterone levels that were respectively 44-59% lower (P<0.01) as compared to adrenal LDLR negative controls. In addition, LDLR positive adrenal transplanted mice exhibited a significant decrease (-39%; P<0.001) in their plasma corticosterone level under fasting stress conditions. Biochemical analysis did not show changes in the expression of genes involved in cholesterol mobilization. However, LDLR expressing adrenal transplants displayed a marked 62% reduction (P<0.05) in the transcript level of the key steroidogenic enzyme HSD3B2. In conclusion, our studies in a mouse model with a human-like lipoprotein profile provide the first in vivo evidence for a novel inhibitory role of the LDLR in the control of adrenal glucocorticoid production.