Unpredictable Stress Research Articles

The improvement effect of exercise on rats with chronic stress-induced depression-like behavior: a discussion based on the kynurenine pathway.

To observe the effects of 4 weeks of voluntary wheel running on depressive-like behavior in a rat chronic stress-induced depression model to explore the anti-depressive mechanism of exercise. In this observational study, 36 Sprague-Dawley rats were randomly divided into control, stress model, and stress exercise groups (12 rats/group). The control group received no intervention, and the stress model and stress exercise group rats underwent chronic mild unpredictable stress and isolation. The stress exercise group rats also underwent 4 weeks of voluntary wheel running. Behavioral changes and hippocampal protein and mRNA expression levels were detected. Voluntary wheel running significantly increased horizontal and vertical movements, sucrose intake, and the sucrose preference percentage and reduced immobility time in the forced swimming test in depression model rats. The hippocampal tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and quinolinic acid levels were significantly decreased, while the IL-4, IL-10, and kynurenic acid levels were significantly increased. Kynurenine-3-monooxygenase and 3-hydroxyanthranilate-3, 4-dioxygenase mRNA levels were downregulated, and kynurenine aminotransferase mRNA was upregulated. Voluntary wheel running improved depressive-like behavior in depression model rats. The mechanism may be related to a kynurenine pathway metabolite level imbalance, which has neurotoxic and neuroprotective effects, caused by long-term voluntary wheel running.

Effects of Liquid Fructose Supplementation and Chronic Unpredictable Stress on Uterine Contractile Activity in Nonpregnant Rats.

Increased fructose consumption and chronic stress, the major characteristics of modern lifestyle, impact human health; however, the consequences of their combination on the uterus remain understudied. In this study, we investigated contractile activity, morphology, and intracellular activity of antioxidant enzymes in uteri from virgin Wistar rats subjected to liquid fructose supplementation and/or unpredictable stress over 9 weeks. Contractile activity and uterine response to oxytocin or adrenaline were examined ex vivo using isolated bath chambers. Fructose supplementation, irrespective of stress, affected uterine morphology by increasing endometrium while decreasing myometrium volume density, attenuated uterine response to increasing doses of oxytocin, and increased glutathione peroxidase activity. Stress, irrespective of fructose, attenuated dose-dependent adrenaline-induced uterine relaxation. Stress, when applied solely, decreased mitochondrial superoxide dismutase activity. In the combined treatment, irregular estrous cycles and both reduced response to oxytocin and to adrenaline (as a consequence of fructose consumption and exposure to stress), along with fructose-related alteration of uterine morphology, were detected. In conclusion, fructose and stress affect uterine contractile activity, irrespective of each other, by inducing completely distinct responses in isolated uteri. In the combined treatment, the effects of both factors were evident, suggesting that the combination exerts more detrimental effects on the uterus than each factor individually.

L-type calcium channel regulation of depression, anxiety and anhedonia-related behavioral phenotypes following chronic stress exposure

Exposure to chronic and unpredictable stressors can precipitate mood-related disorders in humans, particularly in individuals with pre-existing mental health challenges. L-type calcium channels (LTCCs) have been implicated in numerous neuropsychiatric disorders, as LTCC encoding genes have been identified as candidate risk factors for neuropsychiatric illnesses. In these sets of experiments, we sought to examine the ability of LTCC blockade to alter depression, anxiety, and anhedonic-related behavioral responses to chronic unpredictable stress (CUS) exposure in female and male rats. Rats first underwent either 21 days of CUS or no exposure to chronic stressors, serving as home cage controls (HCC). Then rats were examined for anhedonia-related behavior, anxiety and depression-like behavioral responses as measured by the sucrose preference test (SPT), elevated plus maze (EPM), and forced swim test (FST). CUS exposed females and males showed anhedonic and anxiogenic-like behavioral responses on the SPT and EPM, respectively, when compared to HCCs. In female and male rats, systemic administration of the LTCC blocker isradipine (0.4 mg/kg and 1.2 mg/kg, I.P.) attenuated the CUS-induced decrease in sucrose preference and reversed the CUS-induced decrease in open arm time. In the FST, systemic isradipine decreased immobility time across all groups, consistent with an antidepressant-like response. However, there were no significant differences in forced swim test immobility time between HCC and CUS exposed animals. Taken together, these data point to a role of LTCCs in the regulation of mood disorder-related behavioral phenotype responses to chronic stress exposure.

Effects of sublethal methylmercury and food stress on songbird energetic performance: metabolic rates, molt and feather quality.

Organisms regularly adjust their physiology and energy balance in response to predictable seasonal environmental changes. Stressors and contaminants have the potential to disrupt these critical seasonal transitions. No studies have investigated how simultaneous exposure to the ubiquitous toxin methylmercury (MeHg) and food stress affects birds' physiological performance across seasons. We quantified several aspects of energetic performance in song sparrows, Melospiza melodia, exposed or not to unpredictable food stress and MeHg in a 2×2 experimental design, over 3 months during the breeding season, followed by 3 months post-exposure. Birds exposed to food stress had reduced basal metabolic rate and non-significant higher factorial metabolic scope during the exposure period, and had a greater increase in lean mass throughout most of the experimental period. Birds exposed to MeHg had increased molt duration, and increased mass:length ratio of some of their primary feathers. Birds exposed to the combined food stress and MeHg treatment often had responses similar to the stress-only or MeHg-only exposure groups, suggesting these treatments affected physiological performance through different mechanisms and resulted in compensatory or independent effects. Because the MeHg and stress variables were selected in candidate models with a ΔAICc lower than 2 but the 95% confidence interval of these variables overlapped zero, we found weak support for MeHg effects on all measures except basal metabolic rate, and for food stress effects on maximum metabolic rate, factorial metabolic scope and feather mass:length ratio. This suggests that MeHg and food stress effects on these measures are statistically identified but not simple and/or were too weak to be detected via linear regression. Overall, combined exposure to ecologically relevant MeHg and unpredictable food stress during the breeding season does not appear to induce extra energetic costs for songbirds in the post-exposure period. However, MeHg effects on molt duration could carry over across multiple annual cycle stages.

Chronic unpredictable stress (CUS) reduced phoenixin expression, induced abnormal sperm and testis morphology in male rats

Chronic stress caused by prolonged emotional pressure can lead to various physiological issues, including reproductive dysfunction. Although reproductive problems can also induce chronic stress, the impact of chronic stress-induced reproductive dysfunction remains contentious. This study investigates the effects of chronic unpredictable stress (CUS) on reproductive neuropeptides, sperm quality, and testicular morphology. Sixteen twelve-week-old Sprague Dawley rats were divided into two groups: a non-stress control group and a CUS-induced group. The CUS regimen involved various stressors over 28 days, with both groups undergoing behavioural assessments through sucrose-preference and forced-swim tests. Hypothalamic gene expression levels of CRH, PNX, GPR173, kisspeptin, GnRH, GnIH, and spexin neuropeptides were measured via qPCR, while plasma cortisol, luteinizing hormone (LH), and testosterone concentrations were quantified using ELISA. Seminal fluid and testis samples were collected for sperm analysis and histopathological evaluation, respectively. Results showed altered behaviours in CUS-induced rats, reflecting stress impacts. Hypothalamic corticotropin-releasing hormone (CRH) expression and plasma cortisol levels were significantly higher in CUS-induced rats compared to controls (p < 0.05). Conversely, phoenixin (PNX) expression decreased in the CUS group (p < 0.05), while kisspeptin, spexin, and gonadotropin-inhibitory hormone (GnIH) levels showed no significant differences between groups. Despite a significant increase in GnRH expression (p < 0.05), plasma LH and testosterone concentrations were significantly lower (p < 0.05) in CUS-induced rats. Histopathological analysis revealed abnormal testis morphology in CUS-induced rats, including disrupted architecture, visible interstitial spaces between seminiferous tubules, and absence of spermatogenesis. In conclusion, CUS affects reproductive function by modulating PNX and GnRH expression, influencing cortisol levels, and subsequently reducing plasma LH and testosterone concentrations. This study highlights the complex interplay between chronic stress and reproductive health, emphasizing the significant impact of stress on reproductive functions.

NMT2 alleviates depression-like behavior in a rat model of chronic unpredictable stress: An integrated proteomic and phosphoproteomic analysis

Proteomics has been widely used to investigate multiple diseases. Combining the analyses of proteomics with phosphoproteomics can be used to further explain the pathological mechanisms of depression. In this study, depression-like behavior was induced in a rat model of chronic unpredictable mild stress (CUMS). We subsequently conducted the sucrose preference test, open field experiment, and forced swimming test to assess depressive-like behavior. Proteomic and phosphoproteomic sequencing of the hippocampal tissues from depressive-like behavior and normal rats were analyzed to identify differentially expressed proteins (DEPs) and differentially phosphorylated proteins (DPPs). Differentially expressed phosphorylated proteins (DEPPs) were obtained by intersecting the DEPs and DPPs, and functional enrichment analysis, as well as ingenuity pathway analysis (IPA), were subsequently performed. The study also investigated correlations among the DEPPs and used qRT-PCR to quantify the expression levels of key genes. Five DEPPs were identified, Gys1, Nmt2, Lrp1, Bin1, and Atp1a1, which were found to activate the synaptogenesis signaling pathway, induce mitochondrial dysfunction, and activate the phosphoinositide biosynthesis and degradation pathways. The qRT-PCR results confirmed the proteomic findings for Gys1, Nmt2, Lrp1, and Atp1a1. Importantly, inhibiting Nmt2 was found to alleviate depression-like behavior and alleviate neuronal apoptosis in the hippocampus of CUMS rats. In conclusion, we identified five DEPPs associated with the synaptogenesis signaling pathway, mitochondrial dysfunction, and phosphoinositide biosynthesis and degradation in depression. Furthermore, NMT2 may be a potential target for the treatment or diagnosis of depression. Our findings provide novel insights into the molecular mechanisms of depression.

Effects of season and sex on the concentrations of fecal glucocorticoid metabolites in captive and free-ranging endangered mountain gazelles (Gazella gazella).

The aim of our study was to measure fecal glucocorticoid metabolite (FGM) concentrations in captive and free-ranging male and female mountain gazelles (Gazella gazella) during their circannual cycle. In addition, FGM concentrations were used to track the intensity of the adrenocortical response in mountain gazelles during the same period. Fecal samples were collected from the ground in the Hatay Mountain Gazelle Wildlife Development Area in the Hatay Province of Türkiye (36°32' N, 36°32' E) in each season of the year (December, April, July, September). The sex of the animals was determined by detecting the SRY gene of the Y chromosome in DNA isolated from the fecal samples. FGM was extracted from dried fecal samples with methanol, and its concentration was measured using a previously partially validated ELISA. The results indicate that season is the most important factor explaining the variability in FGM concentrations in mountain gazelles. In animals of both sexes, the highest concentrations of FGM were observed in September. The values were significantly higher in the captive population, perhaps due to unpredictable stress. In July, FGM concentrations were low in both populations. As a result of the overall analysis across seasons, the comparison of FGM concentrations between captive and free-ranging animals revealed higher concentrations in captive animals only in September but not in other seasons, although higher concentrations have been previously reported for several wild captive species. Due to predation risk, the presence of offspring can be considered a critical point in the biological cycle for the welfare of free-ranging mountain gazelles, as suggested by the higher FGM concentrations in the free-ranging population in July. The high number of visitors could be a challenge for mountain gazelles in captivity, as indicated by higher FGM concentrations during September. Sex had no effect on the FGM concentrations of either population.

Long-term Environmental Enrichment Normalizes Schizophrenia-like Abnormalities and Promotes Hippocampal Slc6a4 Promoter Demethylation in Mice Submitted to a Two-hit Model

Here, we explored the impact of prolonged environmental enrichment (EE) on behavioral, neurochemical, and epigenetic changes in the serotonin transporter gene in mice subjected to a two-hit schizophrenia model. The methodology involved administering the viral mimetic PolyI:C to neonatal Swiss mice as a first hit during postnatal days (PND) 5–7, or a sterile saline solution as a control. At PND21, mice were randomly assigned either to standard environment (SE) or EE housing conditions. Between PND35-44, the PolyI:C-treated group was submitted to various unpredictable stressors, constituting the second hit. Behavioral assessments were conducted on PND70, immediately after the final EE exposure. Following the completion of behavioral assessments, we evaluated the expression of proteins in the hippocampus that are indicative of microglial activation, such as Iba-1, as well as related to neurogenesis, including doublecortin (Dcx). We also performed methylation analysis on the serotonin transporter gene (Slc6a4) to investigate alterations in serotonin signaling. The findings revealed that EE for 50 days mitigated sensorimotor gating deficits and working memory impairments in two-hit mice and enhanced their locomotor and exploratory behaviors. EE also normalized the overexpression of hippocampal Iba-1 and increased the expression of hippocampal Dcx. Additionally, we observed hippocampal demethylation of the Slc6a4 gene in the EE-exposed two-hit group, indicating epigenetic reprogramming. These results contribute to the growing body of evidence supporting the protective effects of long-term EE in counteracting behavioral disruptions caused by the two-hit schizophrenia model, pointing to enhanced neurogenesis, diminished microglial activation, and epigenetic modifications of serotonergic pathways as underlying mechanisms.

Effects of Multivitamin-Mineral Supplementation on Chronic Stress-Induced Oxidative Damage in Swiss Albino Mice.

Stress is a hazardous occurrence that causes a variety of physiological and behavioral responses in a person. It increases energy metabolism and enhances oxidative stress, both of which are implicated in the pathophysiology of several diseases. Numerous vitamins and minerals have the ability to modulate oxidative stress. The present investigation aimed to evaluate the effectiveness of a multivitamin-mineral (MM) supplement in addressing oxidative imbalances caused by chronic stress in the plasma, hepatic, and renal tissues of Swiss albino mice. Thirty healthy male Swiss albino mice were randomly assigned to one of the three groups, with 10 animals each: control, unpredictable chronic stress (UCS), and MM + UCS. The experiment lasted for four weeks, after which all the animals underwent cervical decapitation, and samples of their blood, liver, and kidney were taken for biochemical studies. DNA damage analysis was performed on lymphocytes. Exposure to UCS negatively affected all biochemical markers, as indicated by reduced levels of antioxidants (superoxide dismutase, catalase, glutathione S-transferase, glutathione reductase, and reduced glutathione) in the plasma, liver, and kidney tissues, along with enhanced levels of lipid peroxidation and marker enzymes. MM supplementation normalized the deranged biochemical markers in stress-exposed mice. The results of DNA damage supported the biochemical findings mentioned above. The findings suggest that MM supplementation could help reduce oxidative disturbances caused by stress in both healthy and diseased conditions.

Urbanisation-associated shifts in the avian metabolome within the annual cycle

While organisms have evolved to cope with predictable changes in the environment, the rapid rate of current global change presents numerous novel and unpredictable stressors to which organisms have had less time to adapt. To persist in the urban environment, organisms must modify their physiology, morphology and behaviour accordingly. Metabolomics offers great potential for characterising organismal responses to natural and anthropogenic stressors at the systems level and can be applied to any species, even without genomic knowledge. Using metabolomic profiling of blood, we investigated how two closely related species of passerine bird respond to the urban environment. Great tits Parus major and blue tits Cyanistes caeruleus residing in urban and forest habitats were sampled during the breeding (spring) and non-breeding (winter) seasons across replicated sites in southern Sweden. During breeding, differences in the plasma metabolome between urban and forest birds were characterised by higher levels of amino acids in urban-dwelling tits and higher levels of fatty acyls in forest-dwelling tits. The suggested higher rates of fatty acid oxidation in forest tits could be driven by habitat-associated differences in diet and could explain the higher reproductive investment and success of forest tits. High levels of amino acids in breeding urban tits could reflect the lack of lipid-rich caterpillars in the urban environment and a dietary switch to protein-rich spiders, which could be of benefit for tackling inflammation and oxidative stress associated with pollution. In winter, metabolomic profiles indicated lower overall levels of amino acids and fatty acyls in urban tits, which could reflect relaxed energetic demands in the urban environment. Our metabolomic profiling of two urban-adapted species suggests that their metabolism is modified by urban living, though whether these changes represent adaptative or non-adaptive mechanisms to cope with anthropogenic challenges remains to be determined.

Dynamic regulation of phosphorylation of NMDA receptor GluN2B subunit tyrosine residues mediates ketamine rapid antidepressant effects

The rapid antidepressant effects of ketamine depend on the N-methyl-D-aspartate (NMDA) receptor containing 2B subunit (NR2B), whose function is influenced by its phosphorylated regulation and distribution within and outside synapses. It remains unclear if ketamine’s rapid onset of antidepressant effects relies on the dynamic phosphorylated regulation of NR2B within and outside synapses. Here, we show that ketamine rapidlyalleviated depression-like behaviors and normalized abnormal expression of pTyr1472NR2B and striatal-enriched protein tyrosine phosphatase (STEP) 61 within and outside synapses in the medial prefrontal cortex (mPFC) induced by chronic unpredictable stress (CUS) and conditional knockdown of STEP 61, a key phosphatase of NR2B, within 1 hour after administration Together, our results delineate the rapid initiation of ketamine’s antidepressant effects results from the restoration of NR2B phosphorylation homeostasis within and outside synapses. The dynamic regulation of phosphorylation of NR2B provides a new perspective for developing new antidepressant strategies.

Curcumin mitigates stress induced depression and hippocampal damage through upregulation of BDNF expression and adult neurogenesis.

Chronic stress, recognized as a major precipitant of depression, has been linked to various neural alterations, including cell death, neuronal atrophy, and compromised hippocampal neurogenesis and plasticity. This study aim to scrutinize curcumin's influence on glucocorticoid hormone secretion and its subsequent effects on the structural integrity and neurogenesis of the hippocampal neurons. A total of 30 adult albino Wistar rats, each weighing between 200-250 g, were utilized for the study. The rats, excluding those in the control group, underwent a 42-day regimen of modified Chronic Unpredictable Stress (CUS) to induce depressive-like states. After inducing CUS, these rats were categorized into six groups, each receiving different oral treatments for two weeks. The treatments included 30 mg/kg body weight of curcumin, 20 mg/kg body weight of fluoxetine, or a combination of both, along with a control group that received distilled water and an olive oil treated group. The rats were tested for behavioural despair using the forced swim test and their blood samples were obtained for serum corticosterone test. Afterwards, the rats were anesthetized, transcardially perfused and the hippocampus dissected and prepared for histopathological study. The study's multi-faceted approach encompassed behavioral, biochemical, and histological evaluations. Behavioral despair, gauged through the forced swimming test, displayed a marked reduction in the curcumin-treated rats compared to controls (p&lt;0.05). Additionally, curcumin significantly lowered serum corticosterone levels, aligning them closely with the control levels. Histomorphological analysis of the hippocampus showed that the curcumin- treated rats exhibited substantially less neurodegeneration, as evidenced by fewer cytoplasmic vacuolations and more intact neuronal structures. Increased cell proliferation and BDNF level were also observed in curcumin treated rats. This study has illuminated a multifaceted approach through which curcumin mitigates hippocampal neurodegeneration, thus showing possible therapeutic potential of curcumin in ameliorating depressive symptoms.

Amygdala-specific changes in Cacna1c, Nfat5, and Bdnf expression are associated with stress responsivity in mice: A possible mechanism for psychiatric disorders

The CACNA1C gene encodes the alpha-1c subunit of the Cav1.2 calcium channel, a regulator of neuronal calcium influx involved in neurotransmitter release and synaptic plasticity. Genetic data show a role for CACNA1C in depressive symptoms underlying different psychiatric diagnoses. However, the mechanisms involved still require further exploration. This study aimed to investigate sex and region-specific changes in the Cacna1c gene and behavioral outcomes in mice exposed to chronic stress. Moreover, we evaluated the Nuclear factor of activated T-cells 5 (Nfat5) and the Brain-derived neurotrophic factor (Bdnf) as potential upstream and downstream Cacna1c targets and their correlation in stressed mice and humans with depression. Male and female Swiss mice were exposed to chronic unpredictable stress (CUS) for 21 days. Animal-integrated emotionality was assessed using the sucrose splash test, the tail suspension, the open-field test, and the elevated-plus-maze. Gene expression analysis was performed in the amygdala, prefrontal cortex, and hippocampus. Human data for in silico analysis was obtained from the Gene Expression Omnibus. CUS-induced impairment in integrated emotional regulation was observed in males. Gene expression analysis showed decreased levels of Cacna1c and Nfat5 and increased levels of Bdnf transcripts in the amygdala of stressed male mice. In contrast, there were no major changes in behavioral responses or gene expression in female mice after stress. The expression of the three genes was significantly correlated in the amygdala of mice and humans. The strong and positive correlation between Canac1c and Nfat5 suggests a potential role for this transcription factor in Canac1c expression. These changes could impact amygdala reactivity and emotional responses, making them a potential target for psychiatric intervention.

Metagenome of Tibetan kefir grains and its alleviating effect on dysfunction of gut microbiome and depressive colorectal cancer comorbidity induced by chronic stress and AOM/DSS

The prevalence of major depression in cancer patients ranges from 5% to 26%. The research on the screening of neurotrophic and anticancer psychoprobiotics is way of important. The aim of this work was to demonstrate the interventional effect of Tibetan kefir fermented goat milk on colorectal cancer and a co-morbidity model established by chronic unpredictable stress (CUMS). The results showed that the Tibetan kefir fermented milk significantly alleviated the manifestations of depressive behavior and altered the level of corticotropin-releasing factor (CRF), serum corticosterone, and inflammatory factors (IL-6, IL-17, TNF-α and IL-1β) in serum, hippocampus and colon Moreover, the Tibetan kefir fermented milk could alleviate the inflammatory response and the hyperactivity of the HPA axis and inhibite the disturbance of 5-hydroxytryptamine system caused by colorectal cancer and CUMS to prevent the progress of depressive colorectal cancer. These results interpreted the potential mechanism of Tibetan kefir on antidepressant and anticancer. It provided a theoretical basis for the exploitation of psychotropic probiotic dairy products and enriched patients' dietary supplement.

Sex- Specific Effects of Chronic Unpredictable Stress on Renal Mitochondrial Function in C57BL/6 Mice

Background: The kidneys play a central role in long term control of blood pressure. Chronic psychological stress has been linked to hypertension, inflammation, and is associated with both an increased prevalence and progression of renal disease. However, the molecular and cellular mechanisms by which chronic stress alters renal function are not fully understood, and data on sex specific differences in renal and blood pressure responses to stress are limited. The impact of stress to cause local inflammation and mitochondrial dysfunction in the kidneys is not clear and represents a potential mechanism leading to renal dysfunction and hypertension. The chronic unpredictable stress (CUS) model induces psychological stress in rodents thus allowing the study of integrated physiological changes to the kidney in response to stress. Hypothesis: Exposing mice to CUS will lead to increased blood pressure that is associated with decreased renal mitochondrial function and renal inflammation. Methods: To investigate the link between stress, renal mitochondrial function, inflammation, and blood pressure, we exposed adult male and female C57BL/6 mice to CUS for 28 consecutive days. Blood pressure was measured via tail cuff on the 28th day of stress. 24 hours later, mice were euthanized and estrous cycle phase in females was determined by vaginal cytology. Kidney mitochondrial oxygen consumption was assessed using the Oroboros respirometer on the pole ends of the left kidneys. NLR family pyrin domain containing 3 (NLRP3) expression was measured in the right kidney using Real-Time TaqMan PCR. Results: Mean arterial pressure was elevated in both stressed males (in mmHg, 106±4 vs 87±4, n&lt;11, p&lt;0.01) and females (131± 6 vs 94±11 n&lt;4, p&lt;0.01) compared to non-stressed mice. While maximal electron transport capacity (ETS), a measure of mitochondrial function, was unchanged in CUS male kidneys, stressed females in the receptive (estrus and proestrus) phase of the estrous cycle exhibited a significant decrease in renal ETS compared to non-stressed females (in pmol O2/mg protein, 14.4±0.9 vs 11.4±0.7, n=11, p&lt;0.05). Renal mRNA expression of NLRP3 was increased in CUS males (35%± 7.7, n=8, p&lt;0.01) but unchanged in CUS females. Conclusion: These data suggest potential mechanistic differences in stress-induced hypertension in renal mitochondria (decreased ETS in stressed females) and inflammasome level (increased NLRP3 in stressed males) between male and female mice. This work was supported by P20GM109091 (F.H.), R01HL130972-01A1, R01HL5949, BX000168-10A1, BX005320 (F.G.S.), R01DK132948 (C.W. &amp; F.P.) R01 MH129798 (SKW); VA VISN7 RDA (F.H.),, 1U54HL169191-01 &amp; BX002604 (M.J.R.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the abstract. 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.

Chronic Unpredictable Stress Induces Mitochondrial Dysfunction in Hypothalamic Pituitary Adrenal Axis Regions

Background: Stress elicits physiological and behavioral responses via adaptive responses like the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) activation. Under chronic stress, however, these responses become dysfunctional leading to pathological changes in behavior and health. Mitochondria are dynamic organelles that provide cellular energy, activate immune responses, and synthesize glucocorticoids in the adrenal glands in response to stress. Thus, the mitochondrion is a key candidate linking the effects of chronic stress and health, however, the effects of chronic stress on mitochondrial function in the HPA axis, particularly with respect to sex differences, are largely unexplored. Hypothesis: Chronic unpredictable stress (CUS) decreases mitochondrial function and dynamics in key regions within the HPA axis. Methods: Adult male and female C57Bl6/J mice were exposed to 28 consecutive days of CUS or handling (non-CUS) with weekly weighing. Mice were euthanized 24h after the last stress exposure and the brain and adrenal glands dissected and weighed. Mitochondrial function was assessed using high resolution respirometry in hypothalamus and adrenal tissues. Protein expression was assessed by immunoblot. Results: CUS decreased mitochondrial respiration within key stress centers, with stressed males exhibiting decreased respiration in the amygdala (20%, p=0.05), and stressed females exhibiting decreased respiration in the hypothalamus (20%, p=0.004) and adrenal glands (17%, p=0.06). CUS increased mitochondrial complex protein in male adrenal gland (47%, p=0.01) and mitochondrial mass in hypothalamus (p=0.007). Finally, cleaved Gasdermin D expression was increased nearly 2-fold in male hypothalamus (p=0.03). Conclusions: Our data show sex- and region-dependent decreases in HPA axis mitochondrial function concurrent with upregulated protein expression and pore formation. These observations point to sex-specific effects of CUS to induce mitochondrial dysfunction. This work was supported by P20GM109091 (F.H.), R01HL130972-01A1, R01HL5949, BX000168-10A1, BX005320 (F.G.S.), R01DK132948 (C.W. &amp; F.P.) R01 MH129798 (SKW); VA VISN7 RDA (F.H.), 1U54HL169191-01 &amp; BX002604 (M.J.R.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the abstract. 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.

Protective Effects of Long-Term Escitalopram Administration on Memory and Hippocampal BDNF and BCL-2 Gene Expressions in Rats Exposed to Predictable and Unpredictable Chronic Mild Stress.

Stress and escitalopram (an anti-stress medication) can affect brain functions and related gene expression. This study investigated the protective effects of long-term escitalopram administration on memory, as well as on hippocampal BDNF and BCL-2 gene expressions in rats exposed to predictable and unpredictable chronic mild stress (PCMS and UCMS, respectively). Male rats were randomly assigned to different groups: control (Co), sham (Sh), predictable and unpredictable stress (PSt and USt, respectively; 2 h/day for 21 consecutive days), escitalopram (Esc; 10 mg/kg for 21 days), and predictable and unpredictable stress with escitalopram (PSt-Esc and USt-Esc, respectively). The passive avoidance test was used to assess behavioral variables. The expressions of the BDNF and BCL-2 genes were assessed using real-time quantitative PCR. Latency significantly decreased in the PSt and USt groups. Additionally, latency showed significant improvement in the PSt-Esc group compared to the PSt group. The expression of the BDNF gene significantly decreased only in the USt group. BDNF gene expression significantly increased in the PSt-Esc and USt-Esc groups compared to their respective stress-related groups, whereas the expression of the BCL-2 gene did not change significantly in both PSt-Esc and USt-Esc groups. PCMS and UCMS had devastating effects on memory. Escitalopram improved memory only under PCMS conditions. PCMS and UCMS exhibited fundamental differences in hippocampal BDNF and BCL-2 gene expressions. Furthermore, escitalopram increased hippocampal BDNF gene expression in the PCMS and UCMS subjects. Hence, neurogenesis occurred more significantly than anti-apoptosis under both PCMS and UCMS conditions with escitalopram.

Ciprofol ameliorates ECS-induced learning and memory impairment by modulating aerobic glycolysis in the hippocampus of depressive-like rats

Electroconvulsive shock (ECS) is utilized to treat depression but may cause learning/memory impairments, which may be ameliorated by anesthetics through the modulation of hippocampal synaptic plasticity. Given that synaptic plasticity is governed by aerobic glycolysis, it remains unclear whether anesthetics modulate aerobic glycolysis to enhance learning and memory function. Depression-like behavior in rats was induced by chronic mild unpredictable stress (CUMS), with anhedonia assessed via sucrose preference test (SPT). Depressive-like behaviors and spatial learning/memory were assessed with forced swim test (FST), open field test (OFT), and Morris water maze (MWM) test. Changes in aerobic glycolysis and synaptic plasticity in the hippocampal region of depressive-like rats post-ECS were documented using immunofluorescence analysis, Western blot, Lactate Assay Kit and transmission electron microscopy. Both the OFT and FST indicated that ECS was effective in alleviating depressive-like behaviors. The MWM test demonstrated that anesthetics were capable of attenuating ECS-induced learning and memory deficits. Immunofluorescence analysis, Western blot, Lactate Assay Kit and transmission electron microscopy revealed that the decline in learning and memory abilities in ECS-induced depressive-like rats was correlated with decreased aerobic glycolysis, and that the additional use of ciprofol or propofol ameliorated these alterations. Adding the glycolysis inhibitor 2-DG diminished the ameliorative effects of the anesthetic. No significant difference was observed between ciprofol and propofol in enhancing aerobic glycolysis in astrocytes and synaptic plasticity after ECS. These findings may contribute to understanding the mechanisms by which anesthetic drugs modulate learning and memory impairment after ECS in depressive-like behavior rats.

Physiological and behavioral contagion/buffering effects of chronic unpredictable stress in a socially enriched environment: A preliminary study

Rodents are sensitive to the emotional state of conspecifics. While the presence of affiliative social partners mitigates the physiological response to stressors (buffering), the partners of stressed individuals show behavioral and endocrine changes indicating that stress parameters can be transmitted across the group members (contagion). In this study, we investigated the social contagion/buffering phenomena in behavior and neuroendocrine mechanisms after exposure to chronic stress, in groups of rats living in the PhenoWorld (PhW). Three groups were tested (8 stressed rats, 8 unstressed rats, and a mixed group with 4 and 4) and these were analyzed under 4 conditions: stressed (pure stress group, n = 8), unstressed (naive control group, n = 8), stressed from mixed group (stressed companion group, n = 8), unstressed from mixed group (unstressed companion group, n = 8. While naive control animals remained undisturbed, pure stress group animals were all exposed to stress. Half of the animals under the mixed-treatment condition were exposed to stress (stressed companion group) and cohabitated with their unstressed partners (unstressed companion group). We confirmed the well-established chronic unpredictable stress (CUS) effects in physiological, behavioral, and neuroendocrine endpoints; body weight gain, open arm entries and time in EPM, and oxytocin receptor expression levels in the amygdala decreased by stress exposure, whereas adrenal weight was increased by stress. Furthermore, we found that playing, rearing and solitary resting behaviors decreased, whereas huddling behavior increased by CUS. In addition, we detected significant increases (stress-buffering) in body weight gain and huddling behaviors between pure stress and stress companion animals, and significant stress contagion effects in emotional behavior and oxytocin receptor expression levels between naive control and control companion groups. Hence, we demonstrate buffering and contagion effects were evident in physiological parameters, emotional behaviors, and social home-cage behaviors of rats and we suggest a possible mediation of these effects by oxytocin neurotransmission. In conclusion, the results herein suggest that the stress status of animals living in the same housing environment influences the behavior of the group.

Heat-Induced Cross-Tolerance to Salinity Due to Thermopriming in Tomatoes.

Global plant production is challenged by unpredictable (a)biotic stresses that occur individually, simultaneously or staggered. Due to an increasing demand for environmentally friendly plant production, new sustainable, universal, and preventive measures in crop protection are needed. We postulate thermopriming as a suitable procedure that fulfills these requirements. Therefore, we performed thermopriming as a pre-conditioning on tomato transplants in combination with two subsequent salt stress treatments to evaluate their single and combined physiological effects on leaves and fruits with regard to plant performance, fruit yield and quality. We identified a cross-tolerance to salinity that was triggered by the preceding thermopriming treatment and resulted in an accumulation of phenols and flavonols in the leaves. Plant growth and fruit yield were initially delayed after the stress treatments but recovered later. In regard to fruit quality, we found an increase in carotenoid and starch contents in fruits due to thermopriming, while sugars and titratable acidity were not affected. Our results indicate that thermopriming can mitigate the impact of subsequent and recurrent stress events on plant performance and yield under production-like conditions.