Elevated Corticosterone Levels Research Articles

Modulation of noradrenergic signalling reverses stress-induced changes in the hippocampus: Involvement of orexinergic systems.

Stress can be beneficial for adapting to dangerous situations in the short term but can be damaging in the long term, especially in the hippocampus. The noradrenergic and orexinergic systems play important roles in stress response. This study investigated the effect of noradrenergic activation on changes induced by chronic stress in the hippocampus and the involvement of orexinergic modulation in this process. This study examined five groups of 40 male Wistar rats (4 + 4 animals/ group): control, chronic stress, acute stress, control with noradrenergic activation, and chronic stress with noradrenergic activation. Hippocampal tissue and blood plasma were the primary specimens analyzed. The researchers measured plasma corticosterone (CORT) using a fluorometric method, examined the expression of prepro-orexin (prepro-OX), orexin receptor-1 (OXr1), and glucocorticoid receptor (GR) through RT-PCR, and quantified neuronal populations using Nissl staining. Acute and chronic stress increased plasma CORT levels and gene expression of prepro-OX, OXr1, and GR, while decreasing neuronal numbers, with chronic stress having a more pronounced effect. Yohimbine-treated and/or stressed rats exhibited elevated plasma CORT levels. Chronic stress substantially upregulated GR and increased prepro-OX and OXr1 expressions whereas yohimbine recovered those profiles in chronically stressed animals. Conversely, chronic stress reduced hippocampal neuronal populations, and chronic stress combined with yohimbine partially compensated for the neuronal numbers compared to chronic stress alone. These results suggest that noradrenergic signalling can reverse chronic stress-induced impairments in prepro-OX, OXr1, GR, and neuronal populations.

Acute and chronic cannabis vapor exposure influences basal and stress-induced release of glucocorticoids in male and female rats.

Management of stress and anxiety is often listed as the primary motivation behind cannabis use. Human research has found that chronic cannabis use is associated with increased basal cortisol levels but blunted neuroendocrine responses to stress. Preclinical research has demonstrated mixed effects of Δ9-tetrahydrocannabinol (THC; the psychoactive constituent of cannabis), much of which is suggestive of dose-dependent effects; however, the predominance of this work has employed an injection method to deliver cannabis. As inhalation is the most common route of administration in humans, we employed a translationally relevant model of inhaled cannabis vapor exposure to help characterize the extent to which acute and chronic cannabis exposure modulates neuroendocrine responses to stress. Male and female Sprague-Dawley rats were acutely (single day) or chronically (10 days) exposed to cannabis or vehicle vapor, and the stress hormone, corticosterone, was analyzed prior to and following an acute 30-min restraint stress. Our results indicate that initial exposure to the vapor chambers, regardless of vehicle or cannabis exposure, is sufficient to elevate corticosterone levels in male and female rodents. Further, acute cannabis exposure was capable of increasing corticosterone levels in both male and female rats, however, this effect was modified by the habituation to the vapor chambers differentially in males and females. Regardless of sex, chronic cannabis exposure is sufficient to both elevate basal corticosterone levels and blunt stress-induced increases in corticosterone following a restraint stressor. Collectively, these data help characterize the impacts of cannabis vapor exposure on basal and stress-induced activation of the hypothalamic-pituitary-adrenal axis.

Prenatal Constant Light Exposure Induces Behavioral Deficits in Male and Female Rat Offspring: Effects of Prenatal Melatonin Treatment

Prenatal constant light exposure (CLE) impaired the anxiety response and circadian rhythms of testicular enzymes in adult male rat offspring, while melatonin corrected these deficiencies. However, the mechanism by which CLE induces these long-term behavioral consequences and the impact of melatonin system have not been examined. The aim of the present study was to investigate the effects of prenatal CLE and melatonin treatment on anxiety- and depression-like behaviors, and the melatonin system in male and female adult rat offspring. Six groups of male and female rat offspring (P60) exposed to either light/dark (LD) or CL regimes, and treated with vehicle or melatonin (10 mg/kg, s.c.) were evaluated for anxiety by open field (OF), elevated plus maze (EPM), and light/dark (LD) tests, and depressive-like response by splash test and sucrose preference test. Plasma adrenocorticotropic hormone (ACTH), corticosterone (CORT) and melatonin expression, and hippocampal MT1A and MT1b receptor expression were assessed by ELISA. Prenatal CLE induced behavioral deficits and elevated plasma CORT levels, while melatonin levels, their circadian rhythmicity, and hippocampal MT receptor expression were not altered in male and female offspring in the CLE regime. However, prenatal melatonin treatment corrected behavioral deficits in a sex-specific manner by up-regulating hippocampal MT receptors, even without altering systemic melatonin levels or normalizing CORT in either sex. The results of this study suggest critical insights into how prenatal environmental factors and therapeutic interventions shape physiological and behavioral outcomes.

Chronic unpredictable stress induces anxiety-like behavior and oxidative stress, leading to diminished ovarian reserve

Chronic stress can adversely affect the female reproductive endocrine system, potentially leading to disorders and impairments in ovarian function. However, current research lacks comprehensive understanding regarding the biochemical characteristics and underlying mechanisms of ovarian damage induced by chronic stress. We established a stable chronic unpredictable stress (CUS)-induced diminished ovarian reserve (DOR) animal model. Our findings demonstrated that prolonged CUS treatment over eight weeks resulted in increased atresia follicles in female mice. This atresia was accompanied by decreased AMH and increased FSH levels. Furthermore, we observed elevated levels of corticosterone both in the peripheral blood and within the ovary. Additionally, we detected abnormalities in ATP metabolism within the ovarian tissue. CUS exposure led to oxidative stress in the ovaries, fostering a microenvironment characterized by oxidative damage to mouse ovarian granulosa cells (mGCs) and heightened levels of reactive oxygen species. Furthermore, CUS prompted mGCs to undergo apoptosis via the mitochondrial pathway. These findings indicate a direct association between the fundamental physiological alterations leading to DOR and the oxidative phosphorylation processes within mGCs. The diminished ATP production by mGCs, triggered by CUS, emerges as a pivotal indicator of CUS-induced DOR. Our study establishes an animal model to investigate the impact of chronic stress on ovarian reserve function and sheds light on potential mechanisms underlying this phenomenon.

Constant light and high fat diet alter daily patterns of activity, feed intake and fecal corticosterone levels in pregnant and lactating female ICR mice.

The prevalence of constant light exposure and high-fat diet in modern society raises concerns regarding their impact on maternal and offspring health outcomes. In rodents, exposure to maternal high-fat diet or continuous light negatively program metabolic and stress response outcomes of offspring. A 2x3 factorial study was conducted to investigate the impact of diet (control-CON, 10% fat, or high fat-HF, 60% fat) and exposure to different lighting conditions: regular 12-hour light-dark cycles (LD), continuous dim light (L5), or continuous bright light (L100) on female ICR mice daily patterns of time in and out of the nest, feed intake, and fecal corticosterone levels during gestation and lactation. Our previous analysis of these mice found HF diet decreased number of pups born, but increased litter growth rate to postnatal (PN) d12. Whereas continuous light increased gestation length and tended to increase PN litter growth. Here we report that patterns of grams of feed intake, an indicator of feeding activity, were affected by light, diet, period of the day (day versus night) and physiological state (gestation and lactation), with significant interactions among all these variables (P<0.05). HF diet and light treatment increased fecal corticosterone output (P<0.05) during lactation. Dams exhibited significant 12 h and 24 h rhythms of activity out of the nest in the first 48 h postnatal, with time outside of the nest greater in the second 24 h period. L100 treatment and HF diet attenuated rhythms and shifted phase of rhythms relative to LD and CON, respectively (P<0.05). Alterations in behavior affect maternal physiology, including level and timing of release of corticosteroids. Elevated fecal corticosterone levels due to high-fat diet and continuous light may have potential implications on maternal-offspring health, and potentially underlie some of the adverse effects of modern lifestyle factors on maternal and offspring health.

The Interaction Of Diet-Induced Obesity And Chronic Stress In A Mouse Model Of Menopause.

Menopause is characterized by the cessation of ovarian hormone production. During postmenopause, cisgender women face increased risks of obesity, cognitive decline, and mood disorder. Mood disorders are associated with exposure to chronic stress. We investigated the combined effects of a high-fat diet (HFD) and chronic stress exposure in a mouse model of menopause using 4-vinylcyclohexene diepoxide (VCD), a selective ovotoxicant that gradually depletes ovarian follicles and hormones. Starting at 6 months, 82 female WT C57BL/6J mice received saline or VCD (130 mg/kg i.p.) 5 days per week for 3 weeks. One month after injection, mice were fed either low-fat diet (LFD) or HFD for 8 weeks followed by 6 weeks of chronic variable mild stress (CVMS). Post-CVMS, mice were either processed for gene expression of the anterodorsal BNST or behavior tests to assess cognitive and anxiety-related behaviors. Plasma samples were collected to analyze metabolic hormones and corticosterone levels. VCD-treated HFD-fed mice had higher fat and body mass, and elevated fasting glucose levels compared to controls and more pronounced avoidance behaviors and cognitive impairments. LFD-fed, VCD-treated mice exhibited less exploration of novel objects and open spaces compared to OIL and HFD counterparts. VCD elevated corticosterone levels on LFD and increased BNST Pacap gene expression on HFD. These findings highlight cognitive repercussions of estrogen deficiency and suggest a potential protective effect of a HFD against some of the adverse outcomes associated with menopause. Our study emphasizes the importance of considering dietary and hormonal interactions in the development of therapeutic strategies.

Hypothalamic corticotropin-releasing hormone neurons modulate sevoflurane anesthesia and the post-anesthesia stress responses

General anesthesia (GA) is an indispensable procedure necessary for safely and compassionately administering a significant number of surgical procedures and invasive diagnostic tests. However, the undesired stress response associated with GA causes delayed recovery and even increased morbidity in the clinic. Here, a core hypothalamic ensemble, corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVHCRH neurons), is discovered to play a role in regulating sevoflurane GA. Chemogenetic activation of these neurons delay the induction of and accelerated emergence from sevoflurane GA, whereas chemogenetic inhibition of PVHCRH neurons accelerates induction and delays awakening. Moreover, optogenetic stimulation of PVHCRH neurons induce rapid cortical activation during both the steady and deep sevoflurane GA state with burst-suppression oscillations. Interestingly, chemogenetic inhibition of PVHCRH neurons relieve the sevoflurane GA-elicited stress response (e.g., excessive self-grooming and elevated corticosterone level). These findings identify PVHCRH neurons modulate states of anesthesia in sevoflurane GA, being a part of anesthesia regulatory network of sevoflurane.

Hypothalamic corticotropin-releasing hormone neurons modulate sevoflurane anesthesia and the post-anesthesia stress responses.

General anesthesia (GA) is an indispensable procedure necessary for safely and compassionately administering a significant number of surgical procedures and invasive diagnostic tests. However, the undesired stress response associated with GA causes delayed recovery and even increased morbidity in the clinic. Here, a core hypothalamic ensemble, corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVHCRH neurons), is discovered to play a role in regulating sevoflurane GA. Chemogenetic activation of these neurons delay the induction of and accelerated emergence from sevoflurane GA, whereas chemogenetic inhibition of PVHCRH neurons accelerates induction and delays awakening. Moreover, optogenetic stimulation of PVHCRH neurons induce rapid cortical activation during both the steady and deep sevoflurane GA state with burst-suppression oscillations. Interestingly, chemogenetic inhibition of PVHCRH neurons relieve the sevoflurane GA-elicited stress response (e.g., excessive self-grooming and elevated corticosterone level). These findings identify PVHCRH neurons modulate states of anesthesia in sevoflurane GA, being a part of anesthesia regulatory network of sevoflurane.

Corticosterone-Mediated BDNF Changes and Their Effects on Adult Neurogenesis in Depression

Adult neurogenesis, the process of generating functional neurons from neural precursor cells in the adult brain, is essential for cognitive function and emotional regulation. Major Depressive Disorder (MDD), characterized by persistent sadness and decreased psychosocial function, is associated with impaired adult hippocampal neurogenesis (AHN). Elevated levels of corticosterone (CORT), a glucocorticoid released in response to stress, have been shown to downregulate brain-derived neurotrophic factor (BDNF), a crucial regulator of neurogenesis, thereby inhibiting AHN. Despite significant advances in understanding the impact of CORT and BDNF on neurogenesis, the precise molecular and cellular pathways involved remain unclear. This review highlights key gaps in the research, particularly the need for a deeper understanding of how glucocorticoid and mineralocorticoid receptors regulate BDNF transcription, the role of autophagic pathways in BDNF degradation, and the influence of glutamatergic signaling on these processes. Future research should focus on elucidating these mechanisms to develop targeted therapeutic strategies, including pharmacological interventions that modulate BDNF and CORT levels and lifestyle modifications like exercise and adequate sleep to enhance neurogenesis. Understanding these complex interactions will be crucial for advancing treatments for depression and improving mental health outcomes.

Chronic psychosocial stress affects insulin-like growth factor 1 and its receptors in mouse ovaries.

Context Chronic psychosocial stress negatively affects folliculogenesis and oogenesis. Intraovarian mechanisms mediating these effects are poorly understood. Aims This work aimed to find out how chronic psychosocial stress affects ovarian IGF1 and its receptor (IGF1R), as well as Igf1 and Igf1r gene expression in cumulus-oocyte complexes (COCs). It also aimed to address possible protective effects of gonadotropin stimulation on IGF1 ovarian signalling. Methods Female CD1 mice experienced chronic psychosocial stress of 11-day isolation followed by overcrowding for 10days. To verify the model, blood corticosterone levels and the quality of oocytes were evaluated in stressed females. The levels of IGF1/IGF1R, blood IGF1 concentration, and expression of Igf1 /Igf1r in the ovaries were compared in stressed and unstressed females. Key results Psychosocial stress caused an elevation of corticosterone level, which was alleviated by gonadotropin treatment. The stressed mice showed a decreased IGF1 level in the ovaries and a decreased expression of Igf1 and Igf1r in COCs. In the unstressed females, gonadotropin injection decreased the expression of Igf1 and Igf1r ; in the stressed females, the same treatment increased Igf1r expression. Neither stress nor ovarian stimulation with gonadotropins affected the serum IGF1 level. Conclusions Psychosocial stress suppresses IGF1 signalling in the ovaries. Gonadotropin treatment modulates these effects differently in stressed and unstressed animals. Implications The results may have translational value for human reproduction. Ovarian IGF1 can be considered a candidate for further improvement of IVF results in women under conditions of chronic stress.

Physiological and behavioral variation by urbanization and climate in an urban-tolerant toad

The distribution of a species is best understood by examining the organism-environment interaction. Climate and anthropogenic habitat degradation, including urbanization, are salient features of the environment that can limit species distributions, especially for ectotherms. Comparative studies of the capacity of individuals to cope with rapid environmental change can help us understand the future success or failure of local populations or even the species. Studies of the glucocorticoid stress response are commonly used to understand how species cope with environmental stressors. Glucocorticoids modulate many aspects of physiological homeostasis including changes in energetic allocation and behavior. In a time of global amphibian decline the Gulf Coast Toad (Incilius nebulifer) is increasing its distribution and abundance. To understand how this species deals with thermal and urban stressors, we studied glucocorticoid regulation, hop performance, and lipid storage in I. nebulifer juveniles across nine populations that differed in average annual temperature and level of imperviousness (as an indication of urbanization). We measured corticosterone release rates at baseline, during agitation stress, and during recovery; then measured locomotor performance and whole-body lipids. We tested if I. nebulifer in hotter temperatures and more urbanized habitats exhibits elevated baseline corticosterone levels and either a reduced corticosterone stress response (“stress resistance” hypothesis) or quick post-stress recovery by negative feedback (“on again, off again” hypothesis). We also tested whether they exhibit reduced fat stores and decreased locomotor performance as costs of dealing with thermal and urban stressors. We found that I. nebulifer showed elevated baseline and agitation (stressed-induced) corticosterone release rates, and higher lipid storage with increasing urbanization. Climate had quadratic effects on these traits, such that populations living at the lowest and highest temperatures had the lowest corticosterone release rates and lipid stores, and the highest hop performance was observed in the least urbanized site at the warmest climate. Additionally, the rate of glucocorticoid recovery after agitation (negative feedback) decreased with increasing temperature and increased with increasing urbanization. These results indicate that I. nebulifer follows the “on again, off again” hypothesis in an adaptive pattern, which may help them cope with environmental change in terms of urbanization and climatic differences.

Life on both environment in semi-aquatic frogs: Impact of aquatic microplastic (MP) from MP enrichment to growth, immune function and physiological stress

The pervasive distribution of microplastics (MPs) in aquatic ecosystems presents a significant threat to wildlife, with amphibians being particularly vulnerable due to their complex life cycles and ecological roles. This study investigates physiological and ecological impacts of aquatic MP exposure on juvenile black-spotted pond frogs (Pelophylax nigromaculatus), focusing on juvenile frog stage, history of life after metamorphosis. MP examinations in the intestine and body revealed accumulation primarily in the gastrointestinal tracts without evidence of systemic distribution. Experimental exposure to different concentrations of MPs demonstrated adverse effects on growth, physiological stress, and immune function. Notably, higher MP concentrations led to significant reductions in growth and innate immunity, indicative of compromised health. High concentrations of MPs were associated with elevated levels of corticosterone and antioxidant enzymes, indicating physiological stress. However, there was no evidence of extreme hormonal surges or imbalances in antioxidant enzyme activity, suggesting that amphibians were able to effectively cope with the levels of MPs used in the study. Changes in gastrointestinal morphology and fecal microbiota composition were observed, reflecting response of metabolic adaptation to MP exposure. At low concentrations of MPs, adaptive changes in digestive tract morphology and the maintenance of gut microbiota balance were observed, indicating that the frogs were able to manage the exposure below a certain threshold. In contrast, high concentrations of MPs had clear negative effects on amphibians, which could impact biodiversity and ecosystem stability. These findings also suggest that MPs may trigger adaptive responses at lower concentrations, while still posing significant environmental risks at higher levels.

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.

Sperm miR-142-3p Reprogramming Mediates Paternal Pre-Pregnancy Caffeine Exposure-Induced Non-Alcoholic Steatohepatitis in Male Offspring Rats.

Numerous studies have suggested a strong association between paternal adverse environmental exposure and increased disease susceptibility in offspring. However, the impact of paternal pre-pregnant caffeine exposure (PPCE) on offspring health remains unexplored. This study elucidates the sperm reprogramming mechanism and potential intervention targets for PPCE-induced non-alcoholic steatohepatitis (NASH) in offspring. Here, male rats are administrated caffeine (15-60mgkg-1/d) by gavage for 8 weeks and then mated with females to produce offspring. This study finds that NASH with transgenerational inheritance occurred in PPCE adult offspring. Mechanistically, a reduction of miR-142-3p is implicated in the occurrence of NASH, characterized by hepatic lipid metabolism dysfunction and chronic inflammation through an increase in ACSL4. Conversely, overexpression of miR-142-3p mitigated these manifestations. The origin of reduced miR-142-3p levels is traced to hypermethylation in the miR-142-3p promoter region of parental sperm, induced by elevated corticosterone levels rather than by caffeine per se. Similar outcomes are confirmed in offspring conceived via in vitro fertilization using miR-142-3pKO sperm. Overall, this study provides the first evidence of transgenerational inheritance of NASH in PPCE offspring and identifies miR-142-3p as a potential therapeutic target for NASH induced by paternal environmental adversities.

The anxiogenic drug yohimbine is a reinforcer in male and female rats.

The indole alkaloid yohimbine is an anxiogenic drug that activates stress-responsive systems in the brain. However, because yohimbine also elicits approach behaviors, this study employed male and female Sprague-Dawley rats to explore its potential reinforcing effects. Thus, it was first determined if intravenous (IV) infusions of yohimbine (0.25 mg/kg/infusion) could maintain lever pressing, whether intake could be modulated by dose/infusion, and if lever pressing would persist in the absence of yohimbine or yohimbine-paired cues. Next, to assess yohimbine's effect on memory consolidation, 0.3, 1.25 or 3 mg/kg yohimbine was administered post-training using an object recognition memory task. Finally, place conditioning assessed whether doses of yohimbine that elevate blood serum corticosterone levels (1.25 or 3 mg/kg) couldelicit a conditioned place preference. It was found that both sexes acquired yohimbine IV self-administration, that intake was modulated by dose/infusion, and that lever pressing persisted during extinction and in the absence of the yohimbine-paired cue. As well, post-training injections of 1.25 mg/kg yohimbine enhanced consolidation of object memory, and 1.25 and 3 mg/kg elevated corticosterone levels and elicited a place preference in both sexes. Finally, in behavioral tests of psychomotor functions, acute yohimbine increased lever pressing for a visual cue and elevated locomotor activity. These findings reveal a profile of yohimbine's behavioral effects that is consistent with that of psychostimulant reinforcing drugs.

Intermittent access to sugary drinks associated with fasting induces overeating and depressive-like behavior in female C57BL/6J mice

Binge eating disorder is the most prevalent eating disorder, affecting both sexes but more commonly found in women. Given the frequent co-occurrence of psychiatric disorders, this study aimed to establish a standardized experimental intermittent protocol to investigate overeating associated with depression. A 10-day protocol induced uncontrolled eating behavior in C57BL/6J female mice. The first experiment included the following groups: naive group (chow ad libitum), control group (chow and sucrose solution ad libitum), and fasting groups (16 and 20 h) exposed to an intermittent sucrose solution (10 %) and chow regimen. Subsequently, the feeding test, open field test, elevated plus maze test, tail suspension test, and light/dark conflict test were conducted. Furthermore, monoamine oxidase (MAO) A and B activities in brain structures and plasma corticosterone levels were assessed. Food overconsumption and depressive-like behavior were observed in both sucrose fasting groups, while risk-taking behaviors were specifically observed in the 20-hour fasting sucrose group. While both fasting sucrose groups caused reduced hippocampal MAO-A activity, only the F20 sucrose group inhibited MAO-B in the cortex and hypothalamus. Moreover, both fasting sucrose groups exhibited elevated corticosterone levels. In a separate design (Experiment 2), groups with 16 and 20 h of fasting alone (without sucrose) did not show the same behavioral results as the intermittent fasting sucrose groups, thus avoiding fasting bias. Based on these results, the 20-hour sucrose fasting group was chosen as the ideal protocol for mimicking overeating behavior associated with depression to investigate future therapeutic approaches for this comorbidity.

Ameliorative effect of α-tocopherol and tocotrienol-rich palm oil extract on menopause-associated mood disorder in ovariectomized mice

Menopause-associated mood disorder is characterized by emotional depression, anxiety, and stress, which accompany hypogonadism in women in the menopausal phase. The current treatment for menopause-associated mood disorder provides only symptomatic relief and is associated with many side effects. Supplementation with vitamin E has been shown to be effective in ameliorating anxiety and depression. However, the effects of vitamin E and its underlying mechanism in ameliorating menopause-associated mood disorders remain uncertain. This work evaluated the effects of α-tocopherol and tocotrienol-rich palm oil extract on depressive and anxiety-related phenotypes induced by estrogen deficiency through ovariectomy in mice. Our study revealed that ovariectomized mice exhibited alterations in behavior indicative of depressive- and anxiety-like behaviors. The serum corticosterone level, a glucocorticoid hormone associated with stress, was found to be elevated in ovariectomized mice as compared to the sham group. Oral administration of α-tocopherol (50 and 100 mg/kg) and tocotrienol-rich palm oil extract (100 and 200 mg/kg) for 14 days alleviated these behavioral changes, as observed in open field, social interaction, and tail suspension tests. However, treatment with tocotrienol-rich palm oil extract, but not α-tocopherol, modulated the depressive- and anxiety-like responses in ovariectomized mice subjected to chronic restraint stress. Both treatments suppressed the elevated serum corticosterone level. Our findings suggested that α-tocopherol and tocotrienol-rich palm oil extract alleviated menopause-associated mood disorder, at least in part, by modulating the hypothalamic-pituitary-adrenal (HPA) axis. The findings of this study can provide a new foundation for the treatment of menopause-associated depressive- and anxiety-like phenotypes, for the betterment of psychological wellbeing.

Parental developmental experience affects vocal learning in offspring

Cultural and genetic inheritance combine to enable rapid changes in trait expression, but their relative importance in determining trait expression across generations is not clear. Birdsong is a socially learned cognitive trait that is subject to both cultural and genetic inheritance, as well as being affected by early developmental conditions. We sought to test whether early-life conditions in one generation can affect song acquisition in the next generation. We exposed one generation (F1) of nestlings to elevated corticosterone (CORT) levels, allowed them to breed freely as adults, and quantified their son’s (F2) ability to copy the song of their social father. We also quantified the neurogenetic response to song playback through immediate early gene (IEG) expression in the auditory forebrain. F2 males with only one corticosterone-treated parent copied their social father’s song less accurately than males with two control parents. Expression of ARC in caudomedial nidopallium (NCM) correlated with father-son song similarity, and patterns of expression levels of several IEGs in caudomedial mesopallium (CMM) in response to father song playback differed between control F2 sons and those with a CORT-treated father only. This is the first study to demonstrate that developmental conditions can affect social learning and neurogenetic responses in a subsequent generation.

Omega-3 alleviates behavioral and molecular changes in a mouse model of stress-induced juvenile depression

IntroductionDepression is increasingly diagnosed in adolescence, necessitating specific prevention and treatment methods. However, there is a lack of animal models mimicking juvenile depression. This study explores a novel model using ultrasound (US) stress in juvenile mice. MethodsWe employed the US stress model in one-month-old C57/BL6 mice, exposing them to alternating ultrasound frequencies (20–25 kHz and 25–45 kHz) for three weeks. These frequencies correspond to negative and neutral emotional states in rodents and can induce a depressive-like syndrome. Concurrently, mice received either an omega-3 food supplement (FS) containing eicosapentaenoic acid (EPA; 0.55 mg/kg/day) and docosahexaenoic acid (DHA; 0.55 mg/kg/day) or a vehicle. Post-stress, we evaluated anxiety- and depressive-like behaviors, blood corticosterone levels, brain expression of pro-inflammatory cytokines, and conducted metabolome analysis of brain, liver and blood plasma. ResultsUS-exposed mice treated with vehicle exhibited decreased sucrose preference, a sign of anhedonia, a key feature of depression, increased anxiety-like behavior, elevated corticosterone levels, and enhanced TNF and IL-1β gene expression in the brain. In contrast, US-FS mice did not display these changes. Omega-3 supplementation also reduced anxiety-like behavior in non-stressed mice. Metabolomic analysis revealed US-induced changes in brain energy metabolism, with FS increasing brain sphingomyelin. Liver metabolism was affected by both US and FS, while plasma metabolome changes were exclusive to FS. Brain glucose levels correlated positively with activity in anxiety tests. ConclusionChronic omega-3 intake counteracted depressive- and anxiety-like behaviors in a US model of juvenile depression in mice. These effects likely stem from the anti-inflammatory properties of the supplement, suggesting potential therapeutic applications in juvenile depression.

Enriched housing differentially alters allostatic load and cardiopulmonary responses to wildfire-related smoke in male and female mice

ABSTRACT Living conditions are an important modifier of individual health outcomes and may lead to higher allostatic load (AL). However, housing-induced cardiovascular and immune effects contributing to altered environmental responsiveness remain understudied. This investigation was conducted to examine the influence of enriched (EH) versus depleted housing (DH) conditions on cardiopulmonary functions, systemic immune responses, and allostatic load in response to a single wildfire smoke (WS) exposure in mice. Male and female C57BL/6J mice were divided into EH or DH for 22 weeks, and cardiopulmonary assessments measured before and after exposures to either one-hr filtered air (FA) or flaming eucalyptus WS exposure. Male and female DH mice exhibited increased heart rate (HR) and left ventricular mass (LVM), as well as reduced stroke volume and end diastolic volume (EDV) one week following exposure to WS. Female DH mice displayed significantly elevated levels of IL-2, IL-17, corticosterone and hemoglobin A1c (HbA1c) following WS, while female in EH mice higher epinephrine levels were detected. Female mice exhibited higher AL than males with DH, which was potentiated post-WS exposure. Thus, DH increased susceptibility to extreme air pollution in a gender-dependent manner suggesting that living conditions need to be evaluated as a modifier of toxicological responses.