CircAKT3 alleviates postoperative cognitive dysfunction by stabilizing the feedback cycle of miR-106a-5p/HDAC4/MEF2C axis in hippocampi of aged mice.

Circular RNAs (circRNAs) have garnered significant attention in the field of neurodegenerative diseases including Alzheimer's diseases due to their covalently closed loop structure. However, the involvement of circRNAs in postoperative cognitive dysfunction (POCD) is still largely unexplored. To identify the genes differentially expressed between non-POCD (NPOCD) and POCD mice, we conducted the whole transcriptome sequencing initially in this study. According to the expression profiles, we observed that circAKT3 was associated with hippocampal neuronal apoptosis in POCD mice. Moreover, we found that circAKT3 overexpression reduced apoptosis of hippocampal neurons and alleviated POCD. Subsequently, through bioinformatics analysis, our data showed that circAKT3 overexpression in vitro and in vivo elevated the abundance of miR-106a-5p significantly, resulting in a decrease of HDAC4 protein and an increase of MEF2C protein. Additionally, this effect of circAKT3 was blocked by miR-106a-5p inhibitor. Interestingly, MEF2C could activate the transcription of miR-106a-5p promoter and form a positive feedback loop. Therefore, our findings revealed more potential modulation ways between circRNA-miRNA and miRNA-mRNA, providing different directions and targets for preclinical studies of POCD.

Farnesol Exerts Protective Effects against Chronic Sleep Deprivation-Induced Cognitive Impairment via Activation SIRT1/Nrf2 Pathway in the Hippocampi of Adult Mice.

SCOPE: Sleep deprivation (SD) negatively affects all aspects of health, with one serious consequence being impaired cognition. Farnesol (FOL) is a sesquiterpene synthesized by plants and mammals that has antioxidant, anti-inflammatory, and neuroprotective properties. This study investigates the mechanism underlying the neuroprotective effect of FOL on SD-induced cognitive impairment. METHODS AND RESULTS: Administration of FOL dramatically ameliorates chronic sleep deprivation (CSD)-induced cognitive impairment. In addition, FOL notably attenuates oxidative stress damage, pro-inflammatory cytokines activation, and microglial activation in the hippocampi of the CSD-exposed mice. Further examination indicates that administration of FOL after the CSD significantly increases the protein expressions of silent information regulator factor 2-related enzyme 1 (Sirt1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (Gpx4) in the hippocampi. Sirt1 agonist resveratrol (RES) has a similar neuroprotective effect, indicating that FOL could exert neuroprotective effects through the activation of the Sirt1/Nrf2 signaling pathway. CONCLUSION: The results reveal that FOL could protect against CSD-induced cognitive impairment by activating the Sirt1/Nrf2 signaling pathway.

Contribution of preoperative gut microbiota in postoperative neurocognitive dysfunction in elderly patients undergoing orthopedic surgery.

Objective: To investigate the role of gut microbiota and metabolites in POCD in elderly orthopedic patients, and screen the preoperative diagnostic indicators of gut microbiota in elderly POCD. Method: 40 elderly patients undergoing orthopedic surgery were enrolled and divided into Control group and POCD group following neuropsychological assessments. Gut microbiota was determined by 16S rRNA MiSeq sequencing, and metabolomics of GC-MS and LC-MS was used to screen the differential metabolites. We then analyzed the pathways enriched by metabolites. Result: There was no difference in alpha or beta diversity between Control group and POCD group. There were significant differences in 39 ASV and 20 genera bacterium in the relative abundance. Significant diagnostic efficiency analyzed by the ROC curves were found in 6 genera bacterium. Differential metabolites in the two groups including acetic acid, arachidic acid, pyrophosphate etc. were screened out and enriched to certain metabolic pathways which impacted the cognition function profoundly. Conclusion: Gut microbiota disorders exist preoperatively in the elderly POCD patients, by which there could be a chance to predict the susceptible population. Clinical Trial Registration: [http://www.chictr.org.cn/edit.aspx?pid=133843&htm=4], identifier [ChiCTR2100051162].

Sulforaphane improves cognitive dysfunction after surgery and anesthesia in mice: The role of Keap1-Nrf2 signaling.

Anesthesia and surgery are likely causing cognitive dysfunction in patients, especially the elderly. However, the underlying pathogenic mechanisms largely remain unclear. Accumulating evidence suggest that signaling between Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) plays an important role in the pathogenesis and treatment of brain dysfunction, while sulforaphane (SFN), a natural compound acting as an Nrf2 agonist, can improve brain function. In the present study, we used 9-month-old mice to perform tibial fracture surgery under isoflurane general anesthesia. Hierarchical cluster analysis of Morris water maze test (MWMT) analysis was performed to classify mice into post-operative cognitive dysfunction (POCD) versus non-POCD phenotypes. Expression levels of Keap1 and Nrf2 were significantly decreased in the medial prefrontal cortex (mPFC), hippocampus and liver, but not in the nucleus accumbens, muscle and gut of POCD mice compared to control and non-POCD mice. Interestingly, both pretreatment and posttreatment with SFN significantly improved the abnormal behaviors of mice in the MWMT, in parallel with the up-regulated levels of Keap1-Nrf2 signaling in the mPFC, hippocampus and liver. In conclusion, these results suggest that decreased Keap1-Nrf2 signaling in the mPFC, hippocampus and liver may contribute to the onset of POCD, and that SFN exerts facilitating effects on POCD symptoms by increasing Keap1-Nrf2 signaling.

CAR-T Cells Targeting TSHR Demonstrate Safety and Potent Preclinical Activity Against Differentiated Thyroid Cancer.

BACKGROUND: Chimeric antigen receptor T cells (CAR-Ts) have demonstrated remarkable efficacy in hematological cancers but have not yet translated in treating solid tumors. The significant hurdles limiting CAR-T therapy were from a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present TSH receptor (TSHR) as a putative target for CAR-T therapy of differentiated thyroid cancer (DTC). METHODS: We undertook a large-scale screen on thyroid cancer tissues and multiple internal organs through bioinformatical analysis and immunohistochemistry to date TSHR expression. Using 3 previously described monoclonal antibodies, we generated 3 third-generation CAR-Ts. We tested anti-TSHR CAR-T in vitro activity by T-cell function and killing assay. Then we tested preclinical therapeutical efficacy in a xenograft mouse model of DTC and analyzed mice's physical conditions and histological abnormalities to evaluate anti-TSHR CAR-T's safety. RESULTS: TSHR is highly and homogeneously expressed on 90.8% (138/152) of papillary thyroid cancer, 89.2% (33/37) of follicular thyroid cancer, 78.2% (18/23) of cervical lymph node metastases, and 86.7% of radioactive iodine resistance diseases. We developed 3 novel anti-TSHR CAR-Ts from monoclonal antibodies M22, K1-18, and K1-70; all 3 CAR-Ts mediate significant antitumor activity in vitro. Among these, we demonstrate that K1-70 CAR-T can have therapeutical efficacy in vivo, and no apparent toxicity has been observed. CONCLUSION: TSHR is a latent target antigen of CAR-T therapy for DTC. Anti-TSHR CAR-T could represent a therapeutic option for patients with locoregional relapsed or distant metastases of thyroid cancer and should be tested in carefully designed clinical trials.

Cefazolin Improves Anesthesia and Surgery-Induced Cognitive Impairments by Modulating Blood-Brain Barrier Function, Gut Bacteria and Short Chain Fatty Acids.

Emerging evidence suggests that anesthesia and surgery may induce gut dysbiosis. Gut dysbiosis leads to imbalance in circulating contents of microbiota-derived metabolites and disrupts the integrity of the blood-brain barrier (BBB), contributing to postoperative cognitive dysfunction (POCD). The composition of gut microbiota may be influenced by various antibiotics. However, how perioperative use of antibiotics affects POCD needs more explorations. In the present study, we explored the effect of cefazolin, a common antibiotic used in perioperative period, on cognitive function, BBB integrity, gut bacteria and short chain fatty acids (SCFAs), a group of widely studied metabolites in aged mice, using 18-month-old male mice. Significant BBB disruptions and decreased levels of tight junction proteins, zonula occludens-1 (ZO-1) and Occludin (OCLN) were seen in the mice of POCD model. Cefazolin treatment attenuated these changes induced by anesthesia and surgery. Furthermore, cefazolin reversed the changes in several fecal bacteria (ß-, γ/δ-, ε-Proteobacteria, and Bacteroidetes) as determined by qPCR tests. Analysis of plasma SCFAs showed that almost all types of SCFAs were reduced in POCD and cefazolin administration reversed the changes in expression of the two most abundant SCFAs (acetic and propionic acids). In conclusion, this study demonstrated that cefazolin improved POCD. Mechanistically, cefazolin suppressed the disruption of BBB, gut microbiota or SCFAs, thereby ameliorating POCD.

The Role of Perioperative Sleep Disturbance in Postoperative Neurocognitive Disorders.

Postoperative neurocognitive disorder (PND) increases the length of hospital stay, mortality, and risk of long-term cognitive impairment. Perioperative sleep disturbance is prevalent and commonly ignored and may increase the risk of PND. However, the role of perioperative sleep disturbances in PND remains unclear. Nocturnal sleep plays an indispensable role in learning, memory, and maintenance of cerebral microenvironmental homeostasis. Hospitalized sleep disturbances also increase the incidence of postoperative delirium and cognitive dysfunction. This review summarizes the role of perioperative sleep disturbances in PND and elucidates the potential mechanisms underlying sleep-deprivation-mediated PND. Activated neuroinflammation and oxidative stress; impaired function of the blood-brain barrier and glymphatic pathway; decreased hippocampal brain-derived neurotrophic factor, adult neurogenesis, and sirtuin1 expression; and accumulated amyloid-beta proteins are associated with PND in individuals with perioperative sleep disorders. These findings suggest that the improvement of perioperative sleep might reduce the incidence of postoperative delirium and postoperative cognitive dysfunction. Future studies should further investigate the role of perioperative sleep disturbance in PND.

Gut Microbiome and Plasma Metabolome Signatures in Middle-Aged Mice With Cognitive Dysfunction Induced by Chronic Neuropathic Pain.

Patients with chronic neuropathic pain (CNP) often complain about their terrible memory, especially the speed of information processing. Accumulating evidence suggests a possible link between gut microbiota and pain processing as well as cognitive function via the microbiota-gut-brain axis. This study aimed at exploring the fecal microbiome and plasma metabolite profiles in middle-aged spared nerve injury (SNI) mice model with cognitive dysfunction (CD) induced by CNP. The hierarchical cluster analysis of performance in the Morris water maze test was used to classify SNI mice with CD or without CD [i.e., non-CD (NCD)] phenotype. 16S rRNA sequencing revealed a lower diversity of gut bacteria in SNI mice, and the increase of Actinobacteria, Proteus, and Bifidobacterium might contribute to the cognitive impairment in the CNP condition. The plasma metabolome analysis showed that the endocannabinoid (eCB) system, disturbances of lipids, and amino acid metabolism might be the dominant signatures of CD mice. The fecal microbiota transplantation of the Sham (not CD) group improved allodynia and cognitive performance in pseudo-germ-free mice via normalizing the mRNA expression of eCB receptors, such as cn1r, cn2r, and htr1a, reflecting the effects of gut bacteria on metabolic activity. Collectively, the findings of this study suggest that the modulation of gut microbiota and eCB signaling may serve as therapeutic targets for cognitive deficits in patients with CNP.

Whole brain radiotherapy induces cognitive dysfunction in mice: key role of gut microbiota.

RATIONALE: Approximately 20-40% of patients with cancer will experience brain metastasis (BM), which has a great impact on the quality of life and survival rates of patients. Whole brain radiotherapy (WBRT) is an effective method for the treatment of BM. However, it cannot be ignored that WBRT might induce a series of neuropsychiatric side effects, including cognitive dysfunction (CD). Accumulating evidence shows that the gut microbiota and the gut-microbiota-brain axis may play a vital role in the pathogenesis of CD. OBJECTIVE AND METHODS: We adopted WBRT to mimic CD after a hierarchical cluster analysis of the Morris water maze test (MWMT) results. In addition, we observed the effects of antibiotics and prebiotics on WBRT-induced CD. Variations were revealed via the 16S rRNA sequencing analysis at different levels. RESULTS: The 16S rRNA sequencing analysis revealed an altered composition of gut microbiota between CD and non-CD phenotypes. Furthermore, we observed a decrease in the levels of Phylum-Bacteroidete, Class-Bacteroidia, and Order-Bacteroidales in the CD group and an increase in the Genus-Allobaculum level after WBRT. Pretreatment with antibiotics caused a significant decrease in the level of Phylum-TM7 01, whereas an increase in the levels of Class-Gammaproteobacteria, Order-Enterobacteriales, and Species-Escherichia coli. After pretreatment with probiotics, the levels of Phylum-Cyanobacteria, Class-4C0d-2, and Order-YS2 were decreased, while the levels of Family-Bacteroidaceae, Genus-Bacteroides, and Species-Parabacteroides distasonis were increased. CONCLUSIONS: WBRT-induced CD might be highly related to abnormal composition of gut microbiota. Strategies improving the composition of the gut microbiota may provide beneficial effects on CD in individuals exposed to WBRT.

The Role of Bacteria and Its Derived Metabolites in Chronic Pain and Depression: Recent Findings and Research Progress.

BACKGROUND: Chronic pain is frequently comorbid with depression in clinical practice. Recently, alterations in gut microbiota and metabolites derived therefrom have been found to potentially contribute to abnormal behaviors and cognitive dysfunction via the "microbiota-gut-brain" axis. METHODS: PubMed was searched and we selected relevant studies before October 1, 2019. The search keyword string included "pain OR chronic pain" AND "gut microbiota OR metabolites"; "depression OR depressive disorder" AND "gut microbiota OR metabolites". We also searched the reference lists of key articles manually. RESULTS: This review systematically summarized the recent evidence of gut microbiota and metabolites in chronic pain and depression in animal and human studies. The results showed the pathogenesis and therapeutics of chronic pain and depression might be partially due to gut microbiota dysbiosis. Importantly, bacteria-derived metabolites, including short-chain fatty acids, tryptophan-derived metabolites, and secondary bile acids, offer new insights into the potential linkage between key triggers in gut microbiota and potential mechanisms of depression. CONCLUSION: Studying gut microbiota and its metabolites has contributed to the understanding of comorbidity of chronic pain and depression. Consequently, modulating dietary structures or supplementation of specific bacteria may be an available strategy for treating chronic pain and depression.

Differential Levels of Hippo Signaling in Selected Brain and Peripheral Tissues in Streptozotocin-Induced Cognitive Dysfunction in Mice.

Increasing studies have revealed that metabolic disorders, especially diabetes, are high risk factors for the development of Alzheimer's disease (AD) and other neurodegenerative diseases. It has been reported that patients with diabetes are prone to suffer from cognitive dysfunction (CD). Although abnormal glucose metabolism and deposition of amyloid ß (Aß) are proven to have a closely relationship with diabetes-induced CD, its exact mechanism is still undetermined. In this study, a total of 14 mice were intraperitoneally injected with streptozotocin for 5 consecutive days to mimic diabetic models, and then hierarchical cluster analysis was adopted to classify the diabetic mice into CD and Non-CD phenotypes by the results of Morris water maze test (MWMT). Furthermore, we detected Hippo signaling including mammalian sterile 20-like protein kinases1 (MST1), large tumor suppressors 1 (LATS1), Yes-associated protein (YAP) and phosphorylation of YAP (p-YAP) in brain and peripheral tissues. As compared with control mice, the levels of MST1, LATS1 and p-YAP/YAP ratio were increased in medial prefrontal cortex (mPFC), striatum and hippocampus of CD mice, while these proteins were decreased in gut tissue of CD mice. Additionally, there were significant positive correlations between escape latency and p-YAP/YAP ratio in mPFC, anterior cingulate cortex (ACC) and hippocampus, as well as the level of LATS1 in liver, kidney and gut tissues. In conclusion, alterations in Hippo signaling may contribute to CD induced by diabetes. Therefore, therapeutic interventions improving Hippo signaling might be beneficial to the treatment of diabetes-induced CD and other neurodegenerative diseases.

Contribution of skeletal muscular glycine to rapid antidepressant effects of ketamine in an inflammation-induced mouse model of depression.

RATIONALE: Basic and clinical studies have reported rapid and long-lasting antidepressant effects of ketamine. Although previous studies have proposed several mechanisms underlying the antidepressant effects of ketamine, these mechanisms have not been completely elucidated. OBJECTIVES: The present study evaluated the effects of systemically administered ketamine treatment in a lipopolysaccharide (LPS)-induced mouse model of depression. METHODS: Non-targeted metabolomics, western blotting, and behavioral tests (locomotion, tail suspension, and forced swimming tests) were performed. RESULT: Ketamine significantly attenuated the abnormally increased immobility time in a lipopolysaccharide (LPS)-induced mouse model of depression. Aminomalonic acid, glutaraldehyde, glycine, histidine, N-methyl-L-glutamic acid, and ribose levels in skeletal muscle were altered following ketamine administration. Furthermore, ketamine significantly decreased the LPS-induced increase in glycine receptor A1 (GlyA1) levels. However, the glycine receptor antagonist strychnine did not elicit any pharmacological effects on ketamine-induced alterations in behaviors or muscular GlyA1 levels. Exogenous glycine and L-serine significantly improved depression-like symptoms in LPS-induced mice. CONCLUSIONS: Our findings suggest that skeletal muscular glycine contributes to the antidepressant effects of ketamine in inflammation. Effective strategies for improving skeletal muscular glycine levels may be a novel approach to depression treatment.

Alterations in the BDNF-mTOR Signaling Pathway in the Spinal Cord Contribute to Hyperalgesia in a Rodent Model of Chronic Restraint Stress.

Stress is a non-specific, systemic, physiological response of the body to strong internal and external environmental stimuli. Accumulating evidence has suggested that stress, particularly chronic restraint stress (CRS), can reduce pain threshold and increase pain sensitivity. However, pathogenic and therapeutic mechanisms underlying CRS remain unclear. Here, we aimed to investigate roles of the brain-derived neurotrophic factor (BDNF)-mammalian target of rapamycin (mTOR) signaling pathway in CRS-induced abnormal pain sensitivity. CRS was successfully mimicked 7 days after model development, and paw withdrawal mechanical threshold (PWMT) and tail-flick latency (TFL) were evaluated. CRS significantly altered BDNF and mTOR phosphorylation in the anterior cingulate cortex and spinal cord but not in the hippocampus. On day 7, a single dose of 7,8-dihydroxyflavone, an activator of BDNF-tropomyosin receptor kinase B, was administered via intraperitoneal or intrathecal injection. Notably, only the intrathecal injection improved PWMT and TFL. Additionally, an intraperitoneal injection of rapamycin, an mTOR inhibitor, failed to induce any behavioral changes, whereas a single intrathecal injection of rapamycin improved abnormal CRS-induced PWMT and TFL. In conclusion, CRS can induce abnormal pain sensitivity, probably by altering the BDNF-mTOR signaling pathway in the spinal cord.

Anesthesia and surgery induce cognitive dysfunction in elderly male mice: the role of gut microbiota.

It is well known that the incidence of postoperative cognitive dysfunction (POCD) is high in elderly patients. The pathogenesis and therapeutic mechanisms of POCD, however, have not yet been completely elucidated. The effects of gut microbiota, particularly in terms of regulating brain function, have gradually attracted increasing attention. In this study, we investigated the potential role of gut microbiota in POCD in aged male mice and attempted to determine whether alterations in gut microbiota would be helpful in the diagnosis of POCD. POCD and non-POCD mice were classified by hierarchical cluster analysis of behavioral results. Additionally, α- and ß-diversity of gut microbiota showed a differential profile between the groups. In total, 24 gut bacteria were significantly altered in POCD mice compared with those in non-POCD mice, in which 13 gut bacteria were significantly correlated with escape latency in the Morris water maze test (MWMT). Remarkably, receiver operating characteristic curves revealed that the Dehalobacteriaceae family and Dehalobacterium genus are potentially important bacteria for the diagnosis of POCD. These findings indicate that alterations in the composition of gut microbiota are probably involved in the pathogenesis of POCD in aged mice. Novel therapeutic strategies regulating specific gut bacteria may be helpful for the prevention and treatment of POCD.

Ketamine Alleviates Postoperative Depression-Like Symptoms in Susceptible Mice: The Role of BDNF-TrkB Signaling.

Patients are more likely to suffer from central nervous system (CNS) complications after anesthesia and surgery. However, postoperative depression (POD) has not yet received sufficient attentions, and its pathogenesis and therapeutic strategies remain poorly understood. We here aimed to investigate whether brain derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling plays an important role in POD. BDNF-TrkB signaling was altered in brain and peripheral tissues, including medial prefrontal cortex (mPFC), hippocampus, liver, and muscle, among control, POD susceptible, and resilient groups. Additionally, we demonstrated that 7,8-dihydroxyflavone (7,8-DHF), a TrkB agonist, could exert its pharmacologic property to alleviate POD-like symptoms. More importantly, ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, also has significant antidepressant effects in POD model, associating with the improving effects on levels of BDNF-TrkB signaling in brain and peripheral tissues. Interestingly, the beneficial effects of ketamine on POD-like symptoms are fully attenuated by a TrkB antagonist. These findings suggest that abnormal expressions of BDNF-TrkB signaling in brain and peripheral tissues are implicated in the pathogenesis of POD, and that therapeutic agents targeting BDNF-TrkB, particularly ketamine, could favor the beneficial effects for POD.

Role of Actinobacteria and Coriobacteriia in the antidepressant effects of ketamine in an inflammation model of depression.

Ketamine, an N-methyl-d-aspartic acid receptor (NMDAR) antagonist, elicits rapid-acting and sustained antidepressant effects in treatment-resistant depressed patients. Accumulating evidence suggests that gut microbiota via the gut-brain axis play a role in the pathogenesis of depression, thereby contributing to the antidepressant actions of certain compounds. Here we investigated the role of gut microbiota in the antidepressant effects of ketamine in lipopolysaccharide (LPS)-induced inflammation model of depression. Ketamine (10 mg/kg) significantly attenuated the increased immobility time in forced swimming test (FST), which was associated with the improvements in α-diversity, consisting of Shannon, Simpson and Chao 1 indices. In addition to α-diversity, ß-diversity, such as principal coordinates analysis (PCoA), and linear discriminant analysis (LDA) coupled with effect size measurements (LEfSe), showed a differential profile after ketamine treatment. Furthermore, a total of 30 bacteria were significantly altered in the LPS + saline treated mice and LPS + ketamine treated mice. Interestingly, two bacteria, including the phylum Actinobacteria and the class Coriobacteriia were significantly correlated with the immobility time of FST. Importantly, the receiver operating characteristic (ROC) curves demonstrated that the phylum Actinobacteria and the class Coriobacteriia were potential biomarker for the antidepressant effects of ketamine in an inflammation model. These findings suggest that antidepressant effects of ketamine might be related to the regulation of abnormal composition of gut microbiota, and that the phylum Actinobacteria and the class Coriobacteriia might be potential biomarkers for ketamine's antidepressant efficacy.

PGC-1α-FNDC5-BDNF signaling pathway in skeletal muscle confers resilience to stress in mice subjected to chronic social defeat.

Skeletal muscle consumes two thirds of the body's energy and may play a role in stress-related disorders. Evidence suggests that the peroxisome proliferator-activated receptor γ coactivator α (PGC-1α)-fibronectin type III domain-containing 5 (FNDC5)-brain-derived neurotrophic factor (BDNF) signaling pathway in skeletal muscle plays a key role in conferring the beneficial effects of exercise. In this study, we aimed to determine whether this pathway contributes to the resilience or susceptibility of mice subjected to chronic social defeat stress (CSDS). BDNF-tropomyosin receptor kinase B (TrkB) and proBDNF-p75NTR signaling in the medial prefrontal cortex and nucleus accumbens of susceptible but not resilient mice were significantly altered compared with the controls. Furthermore, the levels of PGC-1α, FNDC5, and BDNF, as well as the p-TrkB/TrkB ratio in the skeletal muscle of susceptible but not resilient mice, were significantly lower than those of the controls, but the levels of proBDNF and p75NTR in the skeletal muscle of susceptible mice were significantly higher than those of the controls. Moreover, there were significant positive associations between social interaction test data and the expression of PGC-1α, FNDC5, and BDNF or the p-TrkB/TrkB ratio in skeletal muscle. These results suggest that the downregulation of the PGC-1α-FNDC5-BDNF signaling pathway in skeletal muscle contributes to resilience vs. susceptibility to CSDS. Therefore, alterations in this pathway in skeletal muscle may play a crucial role in mediating stress-related disorders.