Elevated Plasma Corticosterone Levels Research Articles

BNST CRF receptor type 1 modulates mechanical hypersensitivity induced by adolescent alcohol exposure in adult female mice.

Alcohol exposure during adolescence has been linked to long-lasting behavioral consequences, contributing to the development of alcohol use disorder. Negative affect and chronic pain during alcohol withdrawal are critical factors influencing problematic alcohol use and relapse. Our previous research demonstrated that adolescent intermittent ethanol (AIE) vapor exposure elicits sex-specific negative affect-like behavior in adult mice following stress exposure. Additionally, AIE induces persistent mechanical hypersensitivity, which is accompanied by increased activation of corticotropin-releasing factor receptor type 1 (CRFR1) neurons in the dorsolateral bed nucleus of the stria terminalis (dlBNST). This study extends previous work by investigating plasma corticosterone levels and CRFR1 protein expression in the dlBNST following restraint stress exposure in adult mice with an AIE history. We also aim to explore the role of dlBNST CRFR1 signaling in mediating negative affect-like behavior and mechanical hypersensitivity. Female mice exhibited elevated plasma corticosterone levels compared to males following restraint stress. Moreover, females with AIE history showed higher expression of CRFR1 protein in the dlBNST compared to air controls. Antagonism of CRFR1 in the dlBNST blocked AIE-induced mechanical hypersensitivity in adult females but did not affect stress-induced negative affect-like behavior. In alcohol-naïve females, intra-dlBNST administration of a CRFR1 agonist induced mechanical hypersensitivity. These findings provide new insights into the neurobiological mechanisms underlying stress-induced negative affect and pain-related behavior, both influenced by a history of adolescent alcohol exposure. The results suggest that CRFR1 antagonists warrant further investigation for their potential in addressing alcohol-related chronic pain.

Alterations in food preference and stress reactivity in mice with a knockout of MeCP2 in POMC neurons

Methyl-CpG binding protein 2 (MeCP2) is an epigenetic factor associated with the neurodevelopmental disorders Rett Syndrome and MECP2 duplication syndrome. Previous studies have demonstrated that knocking out MeCP2 globally in the central nervous system leads to an overweight phenotype and hyperphagia, however it is not clear if the hyperphagia is the result of an increased motivation to obtain food reward or enhancements in food preference. Here, we show that mice deficient in MeCP2 specifically in pro-opiomelanocortin (POMC) neurons have an increased preference for high fat diet but do not have a greater motivation to obtain food reward, relative to wildtype (WT) littermate controls. We also demonstrate that POMC-Cre MeCP2 knockout (KO) mice have increased body weight after long-term high fat diet exposure as well as elevated plasma leptin and corticosterone (CORT) levels compared to wildtype mice. Given that our POMC-Cre MeCP2 KO mice have elevated CORT, we wanted to determine if our KO mice also respond differentially to early life stress such as maternal separation stress compared to WT controls. Collectively, our data suggest that POMC-specific loss-of-function Mecp2 mutations leads to dissociable effects on the rewarding/motivational properties of food as well as changes to hormones associated with body weight homeostasis and stress and could underlie differential behavioral responses to early life stress. NIGMS 1SC1GM144190-01 (ESN), Texas Woman's University internal funds. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

POMC-specific knockdown of MeCP2 leads to adverse phenotypes in mice chronically exposed to high fat diet

Methyl-CpG binding protein 2 (MeCP2) is an epigenetic factor associated with the neurodevelopmental disorders Rett Syndrome and MECP2 duplication syndrome. Previous studies have demonstrated that knocking out MeCP2 globally in the central nervous system leads to an obese phenotype and hyperphagia, however it is not clear if the hyperphagia is the result of an increased preference for food reward or due to an increase in motivation to obtain food reward. We show that mice deficient in MeCP2 specifically in pro-opiomelanocortin (POMC) neurons have an increased preference for high fat diet as measured by conditioned place preference but do not have a greater motivation to obtain food reward using a progressive ratio task, relative to wildtype littermate controls. We also demonstrate that POMC-Cre MeCP2 knockout (KO) mice have increased body weight after long-term high fat diet exposure as well as elevated plasma leptin and corticosterone levels compared to wildtype mice. Taken together, these results are the first to show that POMC-specific loss-of-function Mecp2 mutations leads to dissociable effects on the rewarding/motivational properties of food as well as changes to hormones associated with body weight homeostasis and stress.

Enhancement of peripheral fatty acyl ethanolamide signaling prevents stress-induced social avoidance and anxiety-like behaviors in male rats

Abstract Rationale Exposure to traumatic events can lead to alterations in social and anxiety-related behaviors. Emerging evidence suggests that peripheral host-defense processes are implicated in the expression of stress-induced behavioral responses and may be targeted to mitigate the negative sequalae of stress exposure. Objectives In this study, we used the peripherally restricted FAAH inhibitor URB937 to investigate the effects of the fatty acyl ethanolamide (FAE) family of lipid mediators – which include the endocannabinoid anandamide and the endogenous PPAR-α agonists, oleoylethanolamide and palmitoylethanolamide – on behavioral and peripheral biochemical responses to two ethologically distinct rat models of stress. Methods Male adult rats were exposed to acute social defeat, a model of psychological stress (Experiment 1), or to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a test of innate predator-evoked fear (Experiment 2), and subsequently treated with URB937 (1 or 3 mg/kg, intraperitoneal) or vehicle. Behavioral analyses were conducted 24 h (Experiment 1) or 7 days (Experiment 2) after exposure. Results URB937 administration prevented the emergence of both social avoidance behavior after social defeat stress and anxiety-related behaviors after TMT exposure. Further, URB937 administration blocked social defeat-induced transient increase in plasma concentrations of pro-inflammatory cytokines and the elevation in plasma corticosterone levels observed 24 h after social defeat Conclusions Enhancement of peripheral FAAH-regulated lipid signaling prevents the emergence of stress-induced social avoidance and anxiety-like behaviors in male rats through mechanisms that may involve an attenuation of peripheral cytokine release induced by stress exposure.

Acute or Chronic Exposure to Corticosterone Promotes Wakefulness in Mice.

Elevated glucocorticoid levels triggered by stress potentially contribute to sleep disturbances in stress-induced depression. However, sleep changes in response to elevated corticosterone (CORT), the major glucocorticoid in rodents, remain unclear. Here, we investigated the effects of acute or chronic CORT administration on sleep using electroencephalogram (EEG) and electromyography (EMG) recordings in freely moving mice. Acute CORT exposure rapidly promoted wakefulness, marked by increased episodes and enhanced EEG delta power, while simultaneously suppressing rapid eye movement (REM) and non-rapid eye movement (NREM) sleep, with the latter marked by decreased mean duration and reduced delta power. Prolonged 28-day CORT exposure led to excessive wakefulness and REM sleep, characterized by higher episodes, and decreased NREM sleep, characterized by higher episodes and reduced mean duration. EEG theta activity during REM sleep and delta activity during NREM sleep were attenuated following 28-day CORT exposure. These effects persisted, except for REM sleep amounts, even 7 days after the drug withdrawal. Elevated plasma CORT levels and depressive phenotypes were identified and correlated with observed sleep changes during and after administration. Fos expression significantly increased in the lateral habenula, lateral hypothalamus, and ventral tegmental area following acute or chronic CORT treatment. Our findings demonstrate that CORT exposure enhanced wakefulness, suppressed and fragmented NREM sleep, and altered EEG activity across all stages. This study illuminates sleep alterations during short or extended periods of heightened CORT levels in mice, providing a neural link connecting insomnia and depression.

Repeated witness social stress causes cardiomyocyte contractile impairment and intracellular Ca2+ derangement in female rats

The impact of psychosocial stressors on cardiovascular health in women is of growing interest in both the popular and scientific literature. Rodent models are useful for providing direct experimental evidence of the adverse cardiovascular consequences of psychosocial stressors, yet studies in females are scarce. Here, we investigated the effects of repeated exposure to witness social defeat stress (WS) on cardiomyocyte contractile function and intracellular Ca2+ homeostasis in young adult wild-type Groningen female rats. Female rats bore witness to an aggressive social defeat episode between two males for nine consecutive days or were exposed to a control procedure. Stress-related behaviors were assessed during the first and last WS/control exposure. Twenty-four hours after the last exposure, plasma corticosterone levels were measured, and cardiomyocytes were isolated for analyses of contractile properties and Ca2+ transients, and expression levels of proteins involved in intracellular Ca2+dynamics. The results show an impairment of the intrinsic cardiac mechanical properties and prolonged intracellular Ca2+decay in WS female rats showing social stress-related behavioral (larger amounts of burying behavior) and neuroendocrine (elevated plasma corticosterone levels) phenotypes. Further, the results implicate alterations in the sarcoplasmic reticulum Ca2+-ATPase/phospholamban complex in the contractile defects described in cardiomyocytes of WS female rats. In conclusion, this study highlights the utility of the WS model as an ethologically relevant social stressor for investigating pathophysiological processes that occur in the heart of female subjects and may increase vulnerability to social stress-related cardiovascular risk.

367-OR: E-cigarette Vaping Exposure Increases Adipose 11ß-HSD1 Expression and Disturbs Glucose Homeostasis in Mice

Electronic cigarette (E-cigs) use may increase the prediabetic risk, but the underlying mechanisms remain underexplored. Pre-receptor activation of glucocorticoids (GCs) via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in adipose tissues has been identified as an important mediator of insulin resistance and type 2 diabetes. However, little is known about the effects of E-cig vaping on 11β-HSD1 and glucose homeostasis. To address this issue, we conducted animal model studies with mice exposed to aerosolized PBS, nicotine-free or nicotine-containing E-cigs, with concurrent exposure to either vehicle or the GC receptor (GR) antagonist RU486. We observed that exposure of E-cig vaping nicotine for 4 weeks increased 11β-HSD1 expression and induced lipase HSL and ATGL abundance within the adipose tissues with induction of hypercortisolemia in response to elevated plasma nicotine levels in mice compared with those of aerosolized E-cig vaping vehicle or PBS controls. Induction of adipose 11β-HSD1 was correlated with elevated the expression of hepatic gluconeogenic enzymes PEPCK and G6Pase and corresponded to the elevated fasting glucose levels. Moreover, E-cig vaping nicotine also increased glucose intolerance, but decreased the glucose-lowing effects of insulin and elevated plasma FFA levels in mice compared with PBS controls. However, E-cig vapor without nicotine did not affect these metabolic parameters. Furthermore, RU486 treatment attenuated E-cig vaping nicotine-induced adipose 11β-HSD1 and lipase expression. In addition, RU486 also attenuated the E-cig-mediated activation of hepatic PEPCK and G6Pase and decreased plasma FFA levels, but did not change the elevated plasma corticosterone levels in mice on E-cig vaping nicotine. These data indicate that E-cig vapor exposure harmfully affects glucose homeostasis and these effects may arise, in part, from aerosol nicotine-induced adipose 11β-HSD1 and GR expression. Disclosure J.Wang: None. T.Friedman: None. M.Jiang: None. Y.Liu: None. J.Liu: None. Y.Wang: None. S.C.J.Kim: None. E.Espinal: None. R.Yang: None. H.Zhong: None. X.M.Shao: None. K.Lutfy: None. Funding Tobacco-Related Disease Research Program (T31IR1603)

Adipocytes control hematopoiesis and inflammation through CD40 signaling.

The co-stimulatory CD40-CD40L dyad plays an important role in chronic inflammatory diseases associated with aging. Although CD40 is mainly expressed by immune cells, CD40 is also present on adipocytes. We aimed to delineate the role of adipocyte CD40 in the aging hematopoietic system and evaluated the effects of adipocyte CD40 deficiency on cardiometabolic diseases. Adult adipocyte CD40-deficient mice (AdiCD40KO) mice had a decrease in bone marrow hematopoietic stem cells (Lin-Sca+cKit+, LSK) and common lymphoid progenitors, which was associated with increased bone marrow adiposity and T-cell activation, along with elevated plasma corticosterone levels, a phenotype that became more pronounced with age. Atherosclerotic AdiCD40koApoE-/- (CD40AKO) mice also displayed changes in the LSK population, showing increased myeloid and lymphoid multipotent progenitors, and augmented corticosterone levels. Increased T-cell activation could be observed in bone marrow, spleen, and adipose tissue, while the numbers of B cells were decreased. Although atherosclerosis was reduced in CD40AKO mice, plaques contained more activated T cells and larger necrotic cores. Analysis of peripheral adipose tissue in a diet-induced model of obesity revealed that obese AdiCD40KO mice had increased T-cell activation in adipose tissue and lymphoid organs, but decreased weight gain and improved insulin sensitivity, along with increased fat oxidation. In conclusion, adipocyte CD40 plays an important role in maintaining immune cell homeostasis in bone marrow during aging and chronic inflammatory diseases, particularly of the lymphoid populations. Although adipocyte CD40 deficiency reduces atherosclerosis burden and ameliorates diet-induced obesity, the accompanying T-cell activation may eventually aggravate cardiometabolic diseases.

Effect of artificial light at night on sleep and metabolism in weaver birds.

Artificial light at night is constantly minimizing the span of dark nights from the natural light-dark cycle of earth. Over the past century, the "lightscape" of earth has completely changed owing to technological advancements which subsequently changed the lifestyle of human as well as the nearby animal species. This motivated the present study, wherein we investigated the impact of light at night (LAN) on behavior and physiology of a diurnal passerine finch, baya weaver (Ploceus philippinus). A group of bird (N=10) exposed to 12L:12D photoperiod was initially subjected to dark nights (0 lux) for a period of 1.5 weeks followed by 5 lux, night light for a span of 4 weeks. The first week in LAN served as acute treatment with respect to the fourth week (chronic). The results reveal significant increase in nighttime activity and sleep loss with respect to acute LAN, while significant inclusion of drowsiness behavior during the day in response to chronic LAN. Besides these behavioral alterations, changes in physiological parameters such as reduction in body mass, loss of gradient between pre- and post- prandial blood glucose levels, and elevation in plasma corticosterone levels were more prominent during acute exposure of LAN. Plasma metabolites such as triglycerides, total protein, serum glutamic-oxaloacetic transaminase (SGOT), and creatinine concentrations also hiked in response to acute LAN treatment. Thus, acute exposure of LAN seems to serve as a novel environment for the bird leading to more pronounced impacts on behavioral and physiological observations during the experiment. In chronic exposure, the birds sort of adapted themselves to the prevailing circumstances as evident by decreased nighttime activity, rebound of sleep and corticosterone levels, etc. Thus, the study clearly demonstrates the differential impact of acute and chronic exposure of LAN on behavior and physiology of birds.

Repeated Treadmill Running Attenuates Indomethacin‐caused Gastric Injury in Rats with Streptozotocin‐induced Diabetes

Diabetes is one of the most common chronic diseases leading to disability and death. Physical activity has a beneficial effect on all vital functions of the body under the norm as well as pathology including diabetes. Previously we have shown that treadmill running attenuates the vulnerability of gastric mucosa to ulcerogenic action of indomethacin (IM). The aim of the study was to investigate the effect of treadmill running on the vulnerability of the gastric mucosa to ulcerogenic action of IM in rats with streptozotocin‐induced diabetes. Diabetes was induced by a single injection of streptozotocin (STZ, 70 mg/kg, ip). Two regimens of treadmill running, repeated (Experiment 1) and single (Experiment 2), were used. There were four groups of rats in each experiment: two groups (running and sedentary) treated with STZ and two groups (running and sedentary) treated with vehicle of STZ (control). In Experiment 1 daily repeated treadmill running was initiated 7 days before STZ (or its vehicle) administration and continued daily 7 days after STZ administration. The intensity and duration of treadmill running gradually increased from 10 to 15 cm/s and from 10 to 20 min/day, respectively. In Experiment 2 only single treadmill session (15 cm/s, 15 min) was initiated 7 days after STZ (or its vehicle) administration. In both experiments, IM (35 mg/kg, sc) was administered immediately after completion of treadmill session in preliminary (24 h) fasted rats 7 days after STZ injection. Gastric erosion was examined 4 h after IM administration. Glucose level, body weight, water consumption and plasma corticosterone levels were also measured. Signs of diabetes (an increase of glucose level, loss of body weight, an increase of water consumption and elevation of plasma corticosterone levels) were developed 1 week after STZ administration. IM administration caused the gastric erosion 4 h after the injection. STZ‐induced diabetes aggravated ulcerogenic action of IM: the mean area of gastric erosion was significantly greater in rats with STZ injection compared to that in control animals. Repeated as well as single treadmill running did not significantly affect the signs of diabetes. However, repeated daily treadmill running resulted in a significant decrease of the area of gastric erosion in rats with STZ‐induced diabetes as well as control (non‐diabetic) rats compared to corresponding sedentary groups. A single running, before IM administration, reduced the area of gastric erosion in non‐diabetic rats, but it did not affect the gastric injury in rats with STZ‐induced diabetes. The data suggest that regular physical activity started before STZ‐induced diabetes can protect the gastric mucosa against the ulcerogenic action of IM.

Pharmacological Preconditioning by Corticotropin Releasing Factor (CRF) or ACTH Protects the Gastric Mucosa against Ulcerogenic Action of Indomethacin through Involvement of Glucocorticoids

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are widely used as analgesic and anti‐inflammatory drugs. However, adverse effects, including gastrointestinal, renal, cardiovascular side effects, seriously complicate NSAIDs use. Their gastrointestinal side effects are the most known serious complications in patients taking these drugs. Previously we have shown that preconditioning stress attenuates the ulcerogenic action of indomethacin (IM) on the gastric mucosa. According our findings glucocorticoids, released in response to stressor, are gastroprotective hormones and involved in stress preconditioning protective effects. Corticotropin releasing factor (CRF), a major mediator of stress response, stimulates ACTH release through CRF receptors of subtype 1 and ACTH, in turn, stimulates glucocorticoid production. Here we verify the hypothesis that pharmacological preconditioning by CRF or ACTH can protect the gastric mucosa against ulcerogenic action of IM in rats through mechanism associated with glucocorticoids. For this, preliminary fasted (24 h) rats were administered by CRF (2.5 or 5 µg/ kg, ip) or ACTH (1U/kg, ip) 30 min before IM injection (35 mg/kg, sc). Gastric lesions were examined 4 h after IM administration. Plasma corticosterone levels were measured before and 4 h after IM injection. Since the gastrointestinal injury is accompanied by changes in somatic pain sensitivity, we also measured tail flick latencies (tail flick test) before and 4 h after IM. Both CRF and ACTH by itself caused an elevation of plasma corticosterone levels, which was accompanied by an increase of tail flick latencies (analgesic effect). IM administration resulted in the gastric erosion 4 h later. Pretreatment with CRF or ACTH reduced an area of gastric lesions caused by IM (gastroprotective effect). IM‐induced gastric injury was accompanied by an increase of tail flick latencies, which was prevented by CRF (normalization of somatic pain sensitivity). To estimate the role of glucocorticoids in CRF‐induced gastroprotection an inhibitor of corticosterone synthesis metyrapone (30 mg/kg) or CRF receptor type 1 antagonist NBI 27914 (10 mg/kg) or glucocorticoid receptor antagonist RU‐38486 (20 mg/kg) was administered before CRF. Both metyrapone and NBI 27914 injected before CRF administration caused an inhibition of CRF‐induced corticosterone response and prevented protective effect of CRF on the gastric mucosa against the IM‐induced injury. The gastroprotective effect of CRF was also eliminated by the pretreatment with RU‐38486. Thus, CRF as well as ACTH can protect the gastric mucosa against ulcerogenic action of IM. Gastroprotective action of CRF accompanied by normalization of somatic pain sensitivity is provided by mechanism associated with glucocorticoids.

IDF21-0029 Maternal separation aggravated pancreatic oxidative and inflammatory damage in chronic socially defeated adult male rats

Background: It is believed that psychosocial stress as one of the main sources of stress in humans may play an essential role in developing chronic degenerative metabolic diseases. Early life adverse experiences were supposed to affect the response to stress in later life. Aim: This research was done to test the effect of maternal separation on the metabolic response to chronic social defeat stress (CSDS) at young adulthood. In this respect, the possible contribution of oxidative stress and inflammatory damage to the pancreas along with insulin resistance in response to CSDS exposure in young adult male rats who experienced early life maternal separation was explored. Method: During the first 2 weeks of life, male Wistar rats were exposed to either maternal separation (MS) or left undisturbed with their mothers (Std). Starting on postnatal date 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent chronic social defeat stress (CSDS) for 3 weeks. Thus, totally there were 4 groups (n=6/group). Then, fasting plasma corticosterone, insulin, and glucose levels were measured and insulin resistance was calculated. Pancreatic Catalase (CAT) activity, reduced Glutathione (GSH), Malondialdehyde (MDA) and interleukin-1 beta contents were measured. Results: In this study, MS-CSDS animals showed an elevated fasting plasma corticosterone and insulin levels along with insulin resistance in comparison with standard-reared controls (Std-Con); however, neither early nor adult life adversity affected fasting glucose levels. Likewise, CAT activity, MDA, and Il-1β contents of pancreatic tissue were increased only in MS-CSDS rats compared to Std-Cons. Discussion: The finding of this study shows that maternal separation intensifies vulnerability to develop HPA axis over-activation, insulin resistance, pancreatic oxidative and inflammatory damage associated with chronic exposure to social defeat stress in young adult male rats, which could play an important role in mediating the effects of chronic stress‐related risk of diabetes mellitus. Abnormal responses to stress in adults, who were exposed to stress in early life, almost occurred because of increasing basal tone of central CRFergic activity and coincident intensified HPA axis responsiveness. It may be secondary to facilitation of noradrenergic neurocircuits, central glucocorticoid resistance, and/or dampened regional GABAergic tone that have been observed to happen in response to maternal separation stress. Elevated levels of circulating glucocorticoid have been reported to influence the insulin signaling cascade at the level of insulin receptor and insulin-sensitive glucose transporter 4 (GLUT4) functionality, which may contribute to insulin resistance. In the face of insulin resistance, the β cells adapt by increasing insulin secretion, leading to peripheral compensatory hyperinsulinemia as a protective measure to maintain normal glucose concentrations without hypoglycemia. Augmented pancreatic oxidative stress in MS-CSDS animals may exceeded the increased compensatory antioxidant mechanisms, as evidenced by excessive peroxidation of cell membrane lipids. Based on the central role of IL-1β in the destruction of pancreatic β cells, raised pancreatic IL-1β content could be related to oxidative stress-mediated β cell damage and development of diabetes in response to CSDS exposure in young adult rats who underwent early life maternal separation.

Effects of nitric oxide modulators and antioxidants on endocrine and cellular markers of acute stress in rats

The effects of nitric oxide modulators (NO-modulators) and antioxidants on acute (RSx1) restraint stress induced endocrine, cellular and oxidative/nitrosative stress markers was studied in Wistar rats. The results of our study revealed that exposure to RS(x1) enhanced malondialdehyde (MDA), heat shock protein (HSP-70), corticosterone, nuclear factor kappa B (NF-κB) levels and suppressed glutathione (GSH), superoxide dismutase (SOD) and total nitrites and nitrates (NOx) levels. NO precursor and NO synthase inhibitors were found to differentially modulate stress mechanisms, by altering NF-κB, HSP-70 and corticosterone levels. l-Ascorbic acid significantly suppressed acute stress induced elevation of NF-κB and HSP-70 levels depicting protective effects, as also evidenced by reversal of elevated plasma corticosterone levels. Therefore, modulation of oxidative and nitrosative pathways, offers an approach in modulating stress induced changes associated with various disorders.

Melatonin alleviates hippocampal GR inhibition and depression-like behavior induced by constant light exposure in mice

Light pollution has become a potential health risk factor worldwide. Chronic exposure to constant light (CCL) leads to depressive-like behavior, yet the mechanism remains unclear. In this study, mice exposed to CCL for 3 weeks exhibited depression-like behaviors, with decreased melatonin in plasma and increased oxidative stress in hippocampus. Meanwhile, CCL-exposed mice showed elevated plasma corticosterone (CORT) levels and diminished glucocorticoid receptor (GR) phosphorylation in hippocampus. Concurrently, glycogen synthase kinase 3 beta (GSK3β) was inactivated with increased phosphorylation at Ser9. The interrelationship of GSK3β and GR was clarified in mouse hippocampal neuron (HT-22) cells. GSK3β inhibitor CHIR-99021 induced GR inhibition with diminished phosphorylation, while GR inhibitor RU486 did not affect GSK3β expression or phosphorylation. Furthermore, GSK3β-mediated GR inhibition was reproduced in vitro in HT-22 cells treated with melatonin receptor antagonist luzindole and H2O2 in combination. Finally, melatonin reversed GSK3β-mediated GR inhibition in hippocampus and improved CCL-induced depression-like behavior in mice. These results indicate that CCL induces melatonin deficiency and oxidative stress in hippocampus, which in turn leads to GSK3β-mediated GR inhibition and depression-like behavior in mice.

Investigation of the effects of maternal separation on the pancreatic oxidative and inflammatory damages along with metabolic impairment in response to chronic social defeat stress in young adult male rats.

Chronic glucocorticoid release during the stress response has been proposed to initiate certain damages, which in turn produce metabolic disorders. The present study is the first work to test whether maternal separation (MS) would impact the metabolic alterations associated with pancreatic oxidative and inflammatory damages under chronic exposure to social defeat stress (CSDS) in adulthood. During the first 2weeks of life, male Wistar rats were exposed to MS or left undisturbed with their mothers (Std). Starting on postnatal day 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent CSDS for 3weeks. Thus, there were 4 groups (n = 7/group): Std-Con, Ms-Con, Std-CSDS, MS-CSDS. Each animal was weighed and then decapitated so that we could collect trunk blood for assessment of fasting plasma corticosterone, insulin, glucose, lipid profile, and insulin resistance. Plasma and pancreatic catalase activity, reduced glutathione (GSH), malondialdehyde levels and pancreatic interleukin-1 beta (IL-1β) content were also measured. MS-CSDS animals showed elevated plasma corticosterone and insulin levels (P < 0.01) along with insulin resistance (P < 0.05). According to one-way ANOVA results, chronic exposure to early or adult life adversity decreased body weight (P < 0.0001), Catalase activity and GSH levels (P < 0.0001) and increased malondialdehyde level (P = 0.0006) in plasma. Pancreatic MDA and IL-1β contents elevated just in MS-CSDS rats (P < 0.05). Maternal separation shapes vulnerability to develop corticosterone hypersecretion, insulin resistance, pancreatic oxidative, and inflammatory damages associated with chronic exposure to later social challenges, which could potentially trigger metabolic disorders. The online version contains supplementary material available at 10.1007/s40200-021-00902-3.

Behavioral Deficits Induced by Somatostatin-Positive GABA Neuron Silencing Are Rescued by Alpha 5 GABA-A Receptor Potentiation.

IntroductionDeficits in somatostatin-positive gamma-aminobutyric acid interneurons (SST+ GABA cells) are commonly reported in human studies of mood and anxiety disorder patients. A causal link between SST+ cell dysfunction and symptom-related behaviors has been proposed based on rodent studies showing that chronic stress, a major risk factor for mood and anxiety disorders, induces a low SST+ GABA cellular phenotype across corticolimbic brain regions; that lowering Sst, SST+ cell, or GABA functions induces depressive-/anxiety-like behaviors (a rodent behavioral construct collectively defined as “behavioral emotionality”); and that disinhibiting SST+ cells has antidepressant-like effects. Recent studies found that compounds preferentially potentiating receptors mediating SST+ cell functions, α5-GABAA receptor positive allosteric modulators (α5-PAMs), achieved antidepressant-like effects. Together, the evidence suggests that SST+ cells regulate mood and cognitive functions that are disrupted in mood disorders and that rescuing SST+ cell function via α5-PAM may represent a targeted therapeutic strategy.MethodsWe developed a mouse model allowing chemogenetic manipulation of brain-wide SST+ cells and employed behavioral characterization 30 minutes after repeated acute silencing to identify contributions to symptom-related behaviors. We then assessed whether an α5-PAM, GL-II-73, could rescue behavioral deficits.ResultsBrain-wide SST+ cell silencing induced features of stress-related illnesses, including elevated neuronal activity and plasma corticosterone levels, increased anxiety- and anhedonia-like behaviors, and impaired short-term memory. GL-II-73 led to antidepressant- and anxiolytic-like improvements among behavioral deficits induced by brain-wide SST+ cell silencing.ConclusionOur data validate SST+ cells as regulators of mood and cognitive functions and demonstrate that bypassing low SST+ cell function via α5-PAM represents a targeted therapeutic strategy.

Memantine treatment exerts an antidepressant-like effect by preventing hippocampal mitochondrial dysfunction and memory impairment via upregulation of CREB/BDNF signaling in the rat model of chronic unpredictable stress-induced depression

Mitochondrial and cognitive dysfunctions have long been associated with major depressive disorders (MDDs). Studies have shown that Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, possesses an antidepressant-like effect. Hence, the NMDA receptor can be a better therapeutic target for MDD. Therefore, the present study was designed to study the impact of Memantine on mitochondrial functional status and depression-like symptoms in the chronic unpredictable stress (CUS) model of depression. CUS for 28 days resulted in depression-like symptoms (as indicated by increased immobility time in the forced swim test) and a decline in the spatial learning and retention memory in the Morris water maze (MWM) test, which was prevented by Memantine (10 mg/kg/day) treatment. We observed elevated plasma corticosterone (CORT) levels, microdialysates glutamate concentration, and synaptosomal calcium (Ca2+) ion levels after 28 days of CUS. Memantine treatment prevented only increased plasma CORT and synaptosomal Ca2+ ion levels. Memantine treatment also restored CUS induced increase in oxidative stress parameters [increased neuronal nitric oxide synthase (nNOS) expression, nitric oxide (NO) levels, lipid peroxidation (LPO) and superoxide dismutase (SOD) activity], decrease in mitochondrial electron transport chain (ETC) enzymes activity and mitochondrial membrane potential (MMP). CUS also reduced the expression of cell survival genes, cyclic-AMP response element-binding protein (CREB), and brain-derived nerve growth factor (BDNF), which was reversed by treatment with Memantine. CUS, however, caused a non-significant decrease in the hippocampal adenosine triphosphate (ATP) levels and a non-significant increase in the expression of pro-apoptotic genes, Caspase 3, and the number of TUNEL positive cells, indicating that hippocampal mitochondrial dysfunction caused due to CUS was not severe enough to affect overall energy production, mitochondrial integrity, and cellular apoptosis status. Thus, Memantine treatment exerts an antidepressant-like effect by preventing CUS induced excitotoxicity, oxidative stress, and enhancing CUS induced decrease in mitochondrial functioning and expression of cell survival genes via upregulation of stress-responsive CREB/BDNF signaling.

Bacopa monnieri alleviates aluminium chloride-induced anxiety by regulating plasma corticosterone level in Wistar rats.

Objectives Aluminium is present in food preparations, antacids and many medications. It causes neurodegeneration thereby resulting in a spectrum of neurological disorders such as dementia, Alzheimer's disease and anxiety. Bacopa monnieri (BM) is widely used in ayurvedic medicine to improve memory functions. Its anxiolytic property was investigated in this study by using elevated plus maze (EPM) and plasma corticosterone level. Methods Thirty rats were assigned into five groups. Control group received distilled water, and 0.5% tween 80, AlCl3 group received Aluminium Chloride (AlCl3), Protective groups (BM100+AlCl3 group and BM200+AlCl3 group) received AlCl3 and BM at two different doses, and the BM200 group received BM. The EPM experiment was performed at the end of the 4th week of oral administration of BM and AlCl3 followed by the measurement of plasma corticosterone. Results Oral administration of AlCl3 to rats increases the levels of anxiety as seen in a decrease in the percentage of entries into the open arms of EPM, an increase in grooming frequency and defecation index. However, the rats in the protective groups shown an increase in the percentage of open arm entries and rearing frequency, and decreased grooming frequency and defecation index. AlCl3 alone treated group showed a significant increase in the plasma corticosterone levels compared to the control group. Whereas the protective groups have shown a significant decrease in the plasma corticosterone levels than the AlCl3 alone treated group. Conclusions Hence the BM has potential role in reverting the anxiogenic effect of AlCl3 in the amygdala as it is evident from the plasma corticosterone levels and the EPM parameters of different groups under study.

New insights into the effects of caffeine on adult hippocampal neurogenesis in stressed mice: Inhibition of CORT-induced microglia activation.

Chronic stress-evoked depression has been implied to associate with the decline of adult hippocampal neurogenesis. Caffeine has been known to combat stress-evoked depression. Herein, we aim to investigate whether the protective effect of caffeine on depression is related with improving adult hippocampus neurogenesis and explore the mechanisms. Mouse chronic water immersion restraint stress (CWIRS) model, corticosterone (CORT)-established cell stress model, a coculture system containing CORT-treated BV-2 cells and hippocampal neural stem cells (NSCs) were utilized. Results showed that CWIRS caused obvious depressive-like disorders, abnormal 5-HT signaling, and elevated-plasma CORT levels. Notably, microglia activation-evoked brain inflammation and inhibited neurogenesis were also observed in the hippocampus of stressed mice. In comparison, intragastric administration of caffeine (10 and 20mg/kg, 28days) significantly reverted CWIRS-induced depressive behaviors, neurogenesis recession and microglia activation in the hippocampus. Further evidences from both in vivo and in vitro mechanistic experiments demonstrated that caffeine treatment significantly suppressed microglia activation via the A2AR/MEK/ERK/NF-κB signaling pathway. The results suggested that CORT-induced microglia activation contributes to stress-mediated neurogenesis recession. The antidepression effect of caffeine was associated with unlocking microglia activation-induced neurogenesis inhibition.

P.222 Ghrelin enhances dopamine neuronal activity in the ventral tegmental area during food prediction but not consumption

Pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid N-arachidonoylethanolamine (or anandamide, AEA), exerts favourable effects in rodent models of stress-related depression. Yet although depression seems to be more common among women than men and in spite of some evidence of sex differences in treatment efficacy, preclinical development of FAAH inhibitors for the pharmacotherapy of stress-related depression has been predominantly conducted in male animals. Here, adult female rats were exposed to six weeks of social isolation and, starting from the second week, treated with the FAAH inhibitor URB694 (0.3 mg/kg/day, i.p.) or vehicle. Compared to pair-housed females, socially isolated female rats treated with vehicle developed behavioral (mild anhedonia, passive stress coping) and physiological (reduced body weight gain, elevated plasma corticosterone levels) alterations. Moreover, prolonged social isolation provoked a reduction in brain-derived neurotrophic factor (BDNF) and AEA levels within the hippocampus. Together, these changes are indicative of an increased risk of developing a depressive-like state. Conversely, pharmacological inhibition of FAAH activity with URB694 restored both AEA and BDNF levels within the hippocampus of socially isolated rats and prevented the development of behavioral and physiological alterations. These results suggest a potential interplay between AEA-mediated signaling and hippocampal BDNF in the pathogenesis of depression-relevant behaviors and physiological alterations and antidepressant action of FAAH inhibition in socially isolated female rats.