Estradiol valerate elicits antidepressant-like effects in middle-aged female rats under chronic mild stress

Spinal cord injury (SCI) results in significant loss of sublesional bone, adding to the comorbidity of SCI with an increased risk of fracture and post-fracture complications. Unfortunately, the effect of SCI on skeletal health is also likely to rise, as the average age of SCI has increased and there are well-known negative effects of age on bone. To date, however, the impact of age and age-associated inflammation (inflammaging) on skeletal health after SCI remains largely unknown. To address this, we compared bone parameters in young (3 month) and middle-aged (9 month) male and female rats with a moderate thoracic contusion injury, to age- and sex-matched sham-operated controls. Skeletal parameters, locomotor function, and serum cytokine levels were assessed at both subchronic (30 days) and chronic (180 days) time points post-injury. We hypothesized that SCI would lead to a dramatic loss of bone immediately after injury in all SCI groups, with inflammaging leading to greater loss in middle-aged SCI rats. We also predicted that whereas younger rats might re-establish bone properties in more chronic phases of SCI, middle-aged rats would not. Supporting these hypothesis, trabecular bone volume was significantly lower in male and young female SCI rats early after injury. Contrary to our hypothesis, however, there was greater loss of trabecular bone volume, relative to age-matched shams, in young compared with middle-aged SCI rats, with no effects of SCI on trabecular bone volume in middle-aged female rats. Moreover, despite recovery of weight-supported locomotor activity, bone loss persisted into the chronic phase of injury for the young rats. Bone formation rates were lower in young male SCI rats, regardless of the time since injury, whereas both young and middle-aged female SCI rats had lower bone formation in the subchronic but not the chronic phase of SCI. In middle-aged rats, SCI-induced higher osteoclast surfaces, which also persisted into the chronic phase of SCI in middle-aged females. Neither age nor SCI-induced increases in inflammation seemed to be associated with bone loss. In fact, SCI had more dramatic and persistent effects on bone in male rats, whereas aging and SCI elevated serum cytokines only in female rats. Overall, this study demonstrates SCI-induced loss of bone and altered bone turnover in male and female rats that persists into the chronic phase post-injury. The sex- and age-dependent variations in bone turnover and serum cytokines, however, underscore the need to further explore both mechanisms and potential therapeutics in multiple demographics.

Chronic mild stress impact: Are females more vulnerable?

Corticotropin-releasing hormone mRNA levels in response to chronic mild stress rise in male but not in female rats while tyrosine hydroxylase mRNA levels decrease in both sexes.

Cognitive deficits in the rat chronic mild stress model for depression: Relation to anhedonic-like responses

89. The effect of acute metabolic stress on anhedonia and IL-1 beta expression following chronic stress

Objective Recent studies suggest that chronic stress exposure can ameliorate the progression of diet-induced prediabetic disease, by inhibiting an increase in weight gain, caloric intake and efficiency and insulin resistance. To determine the underlying mechanism by which chronic stress improves the progression of type 2 diabetes, we developed a model of chronic mild stress in high-fat diet(HFD)-fed mice which are resistant to obesity and exhibit a healthy-like metabolic phenotype.
 Methods High-fat diet (HFD): 45% kcal derived from fat (Research Diets, Inc.).Mice experienced one stressor during the day and a different stressor during the night. Stressors were randomly chosen from the following list : cage tilt on a 45° angle for 1 to 16 h; food deprivation for 12 to 16 h; white noise for 1 to 16 h; strobe light illumination for 1 to 16 h; crowded housing; light cycle (continuous illumination) for 24 to 36 h; dark cycle (continuous darkness) for 24 to 36 h; water deprivation for 12 to 16 h; damp bedding (200 ml water poured into sawdust bedding) for 12 to 16 h.Recombinant adeno-associated virus (AAV): AAV9 vectors encoding myonectin under the control of the ubiquitous CMV promoter (AAV9-CMV-Vip) or an equal dose of the AAV9-CMV-null vector were delivered to C57BL/6 mice by the tail vein. Mice were deprived of food for 16 h and then subjected to test 7 days after AAV injection.
 Results Chronic stress improved glucose intolerance and sympathetic overactivity in HFD-fed mice. Chronic stress attenuated epinephrine(EPI)-stimulated glycerol release into blood in vivo and accelerated glycerol release from white adipose tissue followed by in vitro incubation with EPI. Chronic stress reduced plasma triglyceride but increased the levels of plasma insulin and myonectin. We further found that adeno-associated virus 9 (AAV9)-mediated myonectin overexpression improved glucose homeostasis and reduced epinephrine sensitivity. Myonectin overexpression reduced plasma norepinephrine, EPI and leptin levels, and increased insulin sensitivity in brown and white adipose tissue. Intense sympathetic activity with high-intensity running inhibited myonectin expression in skeletal muscle, whereas medium and low-intensity exercise running increased myonectin expression.
 Conclusions These findings suggest that chronic mild stress can improve glucose homeostasis via myonectin-mediated suppression of sympathetic activity in high-fat diet-fed mice.

Effects of post-ovariectomy time frame and age on the antidepressant-like actions of estradiol and prolame in female rats

Diurnal Variation in the Effect of Chronic Mild Stress on Sucrose Intake and Preference

Background:Chronic stress is a major risk factor for psychiatric disorders, including anxiety, depression, and post-traumatic stress disorder. Chronic stress can cause structural alterations like grey matter atrophy in key emotion-related areas such as the prefrontal cortex (PFC). To identify biological pathways affected by chronic stress in the PFC, researchers have performed transcriptional profiling (RNA-sequencing, microarray) to measure gene expression in rodent models. However, transcriptional signatures in the PFC that are shared across different chronic stress paradigms and laboratories remain relatively unexplored.Methods:We performed a meta-analysis of publicly available transcriptional profiling datasets within the Gemma database. We identified six datasets that characterized the effects of either chronic social defeat stress (CSDS) or chronic unpredictable mild stress (CUMS) on gene expression in the PFC or medial prefrontal cortex (mPFC) in mice (n=117). We fit a random effects meta-analysis model to the chronic stress effect sizes (log(2) fold changes) for each transcript (n=21,379) measured in most datasets. We then compared our results with two other published chronic stress meta-analyses, as well as transcriptional signatures associated with psychiatric disorders.Results:We identified 133 genes that were consistently differentially expressed across chronic stress studies and paradigms (false discovery rate (FDR)<0.05). Fast Gene Set Enrichment Analysis (fGSEA) revealed 53 gene sets enriched with differential expression (FDR<0.05), dominated by glial and neurovascular markers (e.g., oligodendrocyte, astrocyte, endothelial/vascular) and stress-related signatures (e.g., major depressive disorder, hormonal responses). Immediate-early gene markers of neuronal activity (Fos, Junb, Arc, Dusp1) were consistently suppressed. Many of the identified effects resembled those seen in previous meta-analyses characterizing stress effects (CSDS, early life stress), despite minimal overlap in included samples. Moreover, some of the differential gene expression resembled previous observations from stress-related psychiatric disorders, including alcohol abuse disorder, major depressive disorder, bipolar disorder, and schizophrenia.Conclusion:Our study demonstrates that chronic stress induces a robust, cross-paradigm PFC signature characterized by down-regulation of glia/myelin and vascular pathways and suppression of immediate-early gene activity, highlighting cellular processes linking chronic stress exposure, PFC dysfunction, and the onset of psychiatric disorders.

The aim of this study was to assess the effects of genistein (G) and daidzein (D) on the histological, hormonal, and functional parameters of the pituitary-ovarian axis in middle-aged female rats, and to compare these effects with the effects of estradiol (E), commonly used in the prevention and treatment of menopausal symptoms. Middle-aged (12 month old) Wistar female rats subcutaneously received 35 mg/kg of G, or 35 mg/kg of D, or 0.625 mg/kg of E every day for 4 weeks. Each of the treated groups had a corresponding control group. An intact control group was also established. G and D did not change the intracellular protein content within gonadotropic and lactotropic cells, but vacuolization was observed in all the cell types. In contrast, E caused an inhibition of gonadotropic and stimulation of lactotropic cells. Also, ovaries of middle-aged female rats exposed to G or D have more healthy primordial and primary follicles and less atretic follicles. E treatment in the ovaries had a mostly negative effect, which is reflected by the increased number of atretic follicles in all tested classes. G and D provoked decrease in CuZnSOD and CAT activity, while E treatment increased MnSOD and decreased CuZnSOD and GSHPx activity. All the treatments increased serum estradiol and decreased testosterone levels, while D and E increased the serum progesterone level. In conclusion, soy phytoestrogens exhibited beneficial effects on pituitary-ovarian function in middle-aged female rats, as compared to estradiol.

The prevalence of depression in menopausal women in China: A meta-analysis of observational studies

Menopausal women often suffer from depression, which impairs their quality of life. Physical activity has been reported to exert beneficial effects on preventing and treating depression. This meta-analysis aims to explore the effect of leisure-time physical activity on determined depression or depressive symptoms in menopausal women. Relevant studies were searched from PubMed, Embase, Cochrane Library, Web of Science, PsycINFO, CINAHL Plus, China National Knowledge Infrastructure (CNKI), VIP, and WanFang databases. Outcomes were depression or depressive symptoms. Weighted mean difference (WMD) or standard mean difference (SMD) with 95% confidence interval (CI) was used as the statistical measure. Heterogeneity tests were performed for each outcome, and all outcomes were subjected to sensitivity analysis. Subgroup analysis was performed based on depression degree, exercise intensity, exercise form, intervention duration, supervision, sample size, and geographical region. A total of 17 studies were included in this meta-analysis. The results showed that exercise alleviated the depressive symptoms of menopausal women (SMD = -1.23; 95% CI, -2.21 to -0.24). In addition, exercise was found to reduce the depression (SMD = 11.45; 95% CI, -1.75 to -1.15), and depression assessed by the Center for Epidemiologic Studies Depression Scale (CES-D) (WMD = -5.76; 95% CI, -6.63 to -4.89) or Self-Rating Depression Scale (SDS) (WMD = -6.86; 95% CI, -9.24 to -4.49). The results were similar regardless of depression degrees, exercise intensity, intervention duration, exercise form, supervision or not, sample size, and geographical region. Leisure-time physical activity may help alleviate depressive symptoms or depression in menopausal women. However, further high-quality studies are needed to confirm these findings and better understand the specific effects of physical activity on depression in this population. https://www.crd.york.ac.uk/prospero/, identifier CRD42024581087.

The chronic stress model was developed on the basis of the stress-diathesis hypothesis of depression. However, these behavioural responses associated with different stress paradigms are quite complex. This study examined the effects of two chronic stress regimens on anxiety-like and depressive behaviours. C57BL/6 mice were subjected to unpredictable chronic mild stress or to chronic restraint stress for 4 weeks. Subsequently, both anxiety-like behaviours (open field, elevated plus maze and novelty suppressed feeding) and depression-like behaviours (tail suspension, forced swim and sucrose preference) were evaluated. Both chronic stress models generated anxiety-like behaviours, whereas only unpredictable chronic mild stress could induce depressive behaviours such as increased immobility and decreased sucrose consumption. These results of the present study provide additional evidence on how chronic stress affects behavioural responses and point to the importance of the validity of animal models of chronic stress in studying depression.

Major depressive disorder characterized as recurrent negative mood is one of the prevalent psychiatric diseases. Chronic stress plus lack of reward may induce long-term imbalance between reward and penalty circuits in the brain, leading to persistent negative mood. Numerous individuals demonstrate resilience to chronic mild stress. Molecular mechanisms for major depression and resilience in the brain remain unclear. After juvenile mice were treated by the chronic unpredictable mild stress (CUMS) for 4weeks, they were screened by sucrose preference, Y-maze and forced swimming tests to examine whether their behaviors were depression-like or not. mRNA and miRNA profiles were quantified by high-throughput sequencing in amygdala tissues harvested from control, CUMS-susceptible, and CUMS-resilience mice. 1.5-fold ratio in reads per kilo-base per million reads was set to be the threshold to judge the involvement of mRNAs and miRNAs in the CUMS, major depression, or resilience. In the amygdala from CUMS-susceptible mice, the expression of genes relevant to GABAergic, cholinergic, glutamatergic, dopaminergic, and serotonergic synapses was changed, as well as the expression of genes that encoded signal pathways of PI3K-Akt, calcium, cAMP, MAPK, and drug addiction was imbalanced. The expression of these genes in the amygdala form CUMS-resilience mice was less changed. The downregulation of genes relevant to synaptic functions and the imbalance of intra-signaling pathway in the amygdala are associated with major depression. Consistent results through sequencing mRNA and miRNA and using different methods validate our finding and conclusion.

Pulsatile growth hormone (GH) secretion was compared in young (5 months), middle-aged (11 months) and old (25-29 months) female Sprague-Dawley rats under nonanesthetized, free-moving conditions. Mean plasma GH levels were 99.1 +/- 9.3 ng/ml in young rats, 56.3 +/- 5.8 ng/ml in middle-aged rats and 49.7 +/- 4.9 ng/ml in old rats (p less than 0.01 for young vs. middle-aged and old rats). In young females, 10 out of 17 rats had GH pulses with peak levels greater than 200 ng/ml, in 6 middle-aged females all GH peaks were below 200 ng/ml, and in old females 13 out of 17 rats showed GH peaks of less than 100 ng/ml. The average peak (amplitude) of GH pulses in the old rats (69.3 +/- 8.3 ng/ml) was lower than in the young rats (130.4 +/- 17.5 ng/ml, p less than 0.01) and somewhat lower than in the middle-aged rats (87.0 +/- 8.9 ng/ml). There was no change in intervals between GH pulses. Pituitary GH content in middle-aged and old females (1,189 +/- 60 and 1,100 +/- 89 micrograms, respectively) was significantly lower (p less than 0.05 and p less than 0.01, respectively) than in young female rats (1,464 +/- 76 micrograms). Somatostatin content in the median eminence of old rats (22.4 +/- 1.9 ng) was significantly lower than in young rats (28.5 +/- 1.6 ng, p less than 0.05). It is concluded that GH secretion is reduced in aging female rats, but unlike in aging male rats the decrease is seen at an earlier age.(ABSTRACT TRUNCATED AT 250 WORDS)