The role of thyroid-stimulating hormone in regulating lipid metabolism: Implications for body-brain communication.

Thyroid-stimulating hormone (TSH) is a pituitary hormone that stimulates the thyroid gland to produce and release thyroid hormones, primarily thyroxine and triiodothyronine. These hormones are key players in body-brain communication, influencing various physiological processes, including the regulation of metabolism (both peripheral and central effects), feedback mechanisms, and lipid metabolism. Recently, the increasing incidence of abnormal lipid metabolism has highlighted the link between thyroid function and lipid metabolism. Evidence suggests that TSH can affect all bodily systems through body-brain communication, playing a crucial role in growth, development, and the regulation of various physiological systems. Lipids serve dual purposes: they are involved in energy storage and metabolism, and they act as vital signaling molecules in numerous cellular activities, maintaining overall human health or contributing to various diseases. This article reviews the role of TSH in regulating lipid metabolism via body-brain crosstalk, focusing on its implications for common lipid metabolism disorders such as obesity, atherosclerosis, nonalcoholic fatty liver disease, neuropsychiatric disorders (including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and depression), and cerebrovascular disorders such as stroke.

Effects of arketamine on depression-like behaviors and demyelination in mice exposed to chronic restrain stress: A role of transforming growth factor-ß1.

BACKGROUND: Chronic restrain stress (CRS) induces depression-like behaviors and demyelination in the brain; however, the relationship between these depression-like behaviors and demyelination remains unclear. Arketamine, the (R)-enantiomer of ketamine, has shown rapid antidepressant-like effects in CRS-exposed mice. METHODS: We examined whether arketamine can improve both depression-like behaviors and demyelination in the brains of CRS-exposed mice. Additionally, we investigated the role of transforming growth factor ß1 (TGF-ß1) in the beneficial effects of arketamine. RESULTS: A single dose of arketamine (10 mg/kg) improved both depression-like behavior and demyelination in the corpus callosum of CRS-exposed mice. Correlations were found between depression-like behaviors and demyelination in this region. Furthermore, pretreatment with RepSox, an inhibitor of TGF-ß1 receptor, significantly blocked the beneficial effects of arketamine on depression-like behaviors and demyelination in CRS-exposed mice. Finally, a single intranasal administration of TGF-ß1 ameliorated both depression-like behaviors and demyelination in CRS-exposed mice. LIMITATIONS: The precise mechanisms by which TGF-ß1 contributes to the effects of arketamine remain unclear. CONCLUSIONS: These data suggest that CRS-induced demyelination in the corpus callosum may contribute to depression-like behaviors, and that arketamine can mitigate these changes through a TGF-ß1-dependent mechanism.

Relationship between hearing loss and depression: A cross-sectional analysis from the National Health and Nutrition Examination Survey 2015-2018.

BACKGROUND: Hearing loss is a prevalent issue resulting from loud noise exposure, aging, diseases, and genetic differences. As individuals age, the likelihood of experiencing hearing loss and depression escalates; yet, the link between hearing loss and the risk of depression remains ambiguous. This study explores the relationship between hearing and depression risk, taking into account sociodemographic and health-related factors. METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES) 2015-2018, a cross-sectional analysis was conducted, focusing on adult participants. It evaluated their hearing status and depression levels using the Patient Health Questionnaire-9 (PHQ-9). The study examined a range of variables, such as age, gender, socioeconomic status, lifestyle choices, and comorbidities, to understand their influence on the link between hearing loss and depression. RESULTS: Analysis indicated a significant association between moderate to severe hearing loss and an increased risk of depression, notably in older adults. This relationship remained significant even after adjusting for a variety of sociodemographic and health factors. LIMITATIONS: This is a study using the NHANES database using self-reported surveys. CONCLUSION: The findings of this study emphasize the need to integrate hearing health in the holistic assessment and treatment of depression, particularly advocating for combined care strategies for the elderly.

Comparison of Patient Outcomes Between Leadless vs Transvenous Pacemakers Following Transcatheter Aortic Valve Replacement.

BACKGROUND: Evidence is limited regarding the effectiveness of leadless pacemaker implantation for conduction disturbance following transcatheter aortic valve replacement (TAVR). OBJECTIVES: This study sought to examine the national trends in the use of leadless pacemaker implantation following TAVR and compare its performance with transvenous pacemakers. METHODS: Medicare fee-for-service beneficiaries aged ≥65 years who underwent leadless or transvenous pacemakers following TAVR between 2017 and 2020 were included. Outcomes included in-hospital overall complications as well as midterm (up to 2 years) all-cause death, heart failure hospitalization, infective endocarditis, and device-related complications. Propensity score overlap weighting analysis was used. RESULTS: A total of 10,338 patients (730 leadless vs 9,608 transvenous) were included. Between 2017 and 2020, there was a 3.5-fold increase in the proportion of leadless pacemakers implanted following TAVR. Leadless pacemaker recipients had more comorbidities, including atrial fibrillation and end-stage renal disease. After adjusting for potential confounders, patients with leadless pacemakers experienced a lower rate of in-hospital overall complications compared with patients who received transvenous pacemakers (7.2% vs 10.1%; P = 0.014). In the midterm, we found no significant differences in all-cause death (adjusted HR: 1.13; 95% CI: 0.96-1.32; P = 0.15), heart failure hospitalization (subdistribution HR: 0.89; 95% CI: 0.74-1.08; P = 0.24), or infective endocarditis (subdistribution HR: 0.98; 95% CI: 0.44-2.17; P = 0.95) between the 2 groups, but leadless pacemakers were associated with a lower risk of device-related complications (subdistribution HR: 0.37; 95% CI: 0.21-0.64; P < 0.001). CONCLUSIONS: Leadless pacemakers are increasingly being used for conduction disturbance following TAVR and were associated with a lower rate of in-hospital complications and midterm device-related complications compared to transvenous pacemakers without a difference in midterm mortality.

Splenic nerve denervation attenuates depression-like behaviors in Chrna7 knock-out mice via the spleen-gut-brain axis.

BACKGROUND: Growing evidence highlights the role of the spleen-brain axis in inflammation-associated depression. The α7-subtype of nicotinic acetylcholine receptor (α7 nAChR, encoded by the Chrna7 gene) is implicated in systemic inflammation, with Chrna7 knock-out (KO) mice displaying depression-like behaviors. Yet, the influence of spleen nerve on depression-like behaviors in these KO mice remains to be elucidated. METHODS: We investigated the effects of the splenic nerve denervation (SND) on depression-like behaviors, the protein expression in the prefrontal cortex (PFC), and the gut microbiota composition in Chrna7 KO mice. RESULTS: SND markedly alleviated depression-like behaviors and the reduced expression of GluA1 and postsynaptic density protein-95 (PSD-95) in the PFC of Chrna7 KO mice. No changes in α-diversity of gut microbiota were noted among the control, KO + sham, and KO + SND groups. However, significant differences in ß-diversity of gut microbiota were noted among the groups. Notable alterations in various microbiota (e.g., Fluviimonas_pallidilutea, Maribacter_arcticus, Parvibacter_caecicola) and plasma metabolites (e.g., helicide, N-acetyl-L-aspartic acid, α-D-galactose 1-phosphate, choline, creatine) were observed between KO + sham and KO + SND groups. Interestingly, correlations were found between the relative abundance of specific microbiota and other outcomes, including synaptic proteins, metabolites and behavioral data. LIMITATIONS: The underlying mechanisms remain to be fully understood. CONCLUSIONS: Our findings indicate that the splenic nerve contributes to depression-like phenotypes in Chrna7 KO mice via the spleen-gut-brain axis.

Role of oxidative phosphorylation in the antidepressant effects of arketamine via the vagus nerve-dependent spleen-brain axis.

Arketamine, the (R)-enantiomer of ketamine, exhibits antidepressant-like effects in mice, though the precise molecular mechanisms remain elusive. It has been shown to reduce splenomegaly and depression-like behaviors in the chronic social defeat stress (CSDS) model of depression. This study investigated whether the spleen contributes to the antidepressant-like effects of arketamine in the CSDS model. We found that splenectomy significantly inhibited arketamine's antidepressant-like effects in CSDS-susceptible mice. RNA-sequencing analysis identified the oxidative phosphorylation (OXPHOS) pathway in the prefrontal cortex (PFC) as a key mediator of splenectomy's impact on arketamine's effects. Furthermore, oligomycin A, an inhibitor of the OXPHOS pathway, reversed the suppressive effects of splenectomy on arketamine's antidepressant-like effects. Specific genes within the OXPHOS pathways, such as COX11, UQCR11 and ATP5e, may contribute to these inhibitory effects. Notably, transforming growth factor (TGF)-ß1, along with COX11, appears to modulate the suppressive effects of splenectomy and contribute to arketamine's antidepressant-like effects. Additionally, SRI-01138, an agonist of the TGF-ß1 receptor, alleviated the inhibitory effects of splenectomy on arketamine's antidepressant-like effects. Subdiaphragmatic vagotomy also counteracted the inhibitory effects of splenectomy on arketamine's antidepressant-like effects in CSDS-susceptible mice. These findings suggest that the OXPHOS pathway and TGF-ß1 in the PFC play significant roles in the antidepressant-like effects of arketamine, mediated through the spleen-brain axis via the vagus nerve.

Dietary sulforaphane glucosinolate mitigates depression-like behaviors in mice with hepatic ischemia/reperfusion injury: A role of the gut-liver-brain axis.

Nutrition has been increasingly recognized for its use in mental health. Depression is commonly observed in patients with chronic liver disease (CLD). Building on our recent findings of depression-like behaviors in mice with hepatic ischemia/reperfusion (HI/R) injury, mediated by the gut-liver-brain axis, this study explored the potential influence of dietary sulforaphane glucosinolate (SGS) on these behaviors. Behavioral assessments for depression-like behaviors were conducted 7 days post either sham or HI/R injury surgery. Dietary intake of SGS significantly prevented splenomegaly, systemic inflammation, depression-like behaviors, and downregulation of synaptic proteins in the prefrontal cortex (PFC) of HI/R-injured mice. Through 16S rRNA analysis and untargeted metabolomic analyses, distinct bacterial profiles and metabolites were identified between control + HI/R group and SGS + HI/R group. Correlations were observed between the relative abundance of gut microbiota and both behavioral outcomes and blood metabolites. These findings suggest that SGS intake could mitigate depression-like phenotypes in mice with HI/R injury, potentially through the gut-liver-brain axis. Additionally, SGS, found in crucial vegetables like broccoli, could offer prophylactic nutritional benefits for depression in patients with CLD.

The role of BDNF transcription in the antidepressant-like effects of 18ß-glycyrrhetinic acid in a chronic social defeat stress model.

BACKGROUND: Xiaoyaosan (XYS), a traditional Chinese medicine formulation, has been used in the treatment of depression. However, no studies have yet identified the active compounds responsible for its antidepressant effects in the brain. STUDY DESIGN: We investigated the antidepressants effects of XYS and identified 18ß-glycyrrhetinic acid (18ß-GA) as the primary compound present in the brain following XYS injection. Furthermore, we explored the molecular mechanisms underlying the antidepressant-like effects of both XYS and 18ß-GA. METHODS: To investigate the antidepressant-like effects of XYS and elucidate the associated molecular mechanisms, we employed various methodologies, including cell cultures, the chronic social defeat stress (CSDS) model, behavioral tests, immunoprecipitation, quantitative PCR (qPCR) assays, Western blotting assays, luciferase assays, chromatin immunoprecipitation (ChIP) assays, immunofluorescence staining, and dendritic spine analysis. RESULTS: We identified 18ß-GA as the primary compound in the brain following XYS injection. In vitro, 18ß-GA was found to bind with ERK (extracellular signal-regulated kinase), subsequently activating ERK kinase activity toward both c-Jun and cAMP response element binding protein (CREB). Moreover, 18ß-GA activated brain-derived neurotrophic factor (BDNF) transcription by stimulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2), c-Jun, and CREB, while also inhibiting methyl CpG binding protein 2 (MeCP2) both in vitro and in vivo. Chronic intraperitoneal (i.p.) administration of 18ß-GA exhibited prophylactic antidepressant-like effects in a CSDS model, primarily by activating BDNF transcription in the medial prefrontal cortex (mPFC). Interestingly, a single i.p. injection of 18ß-GA produced rapid and sustained antidepressant-like effects in CSDS-susceptible mice by engaging the BDNF-tropomyosin receptor kinase B (TrkB) signaling pathway in the mPFC. CONCLUSION: These findings suggest that the activation of BDNF transcription in the mPFC underlies the antidepressant-like effects of 18ß-GA, a key component of XYS in the brain.

Biped Robots Control in Gusty Environments with Adaptive Exploration Based DDPG.

As technology rapidly evolves, the application of bipedal robots in various environments has widely expanded. These robots, compared to their wheeled counterparts, exhibit a greater degree of freedom and a higher complexity in control, making the challenge of maintaining balance and stability under changing wind speeds particularly intricate. Overcoming this challenge is critical as it enables bipedal robots to sustain more stable gaits during outdoor tasks, thereby increasing safety and enhancing operational efficiency in outdoor settings. To transcend the constraints of existing methodologies, this research introduces an adaptive bio-inspired exploration framework for bipedal robots facing wind disturbances, which is based on the Deep Deterministic Policy Gradient (DDPG) approach. This framework allows the robots to perceive their bodily states through wind force inputs and adaptively modify their exploration coefficients. Additionally, to address the convergence challenges posed by sparse rewards, this study incorporates Hindsight Experience Replay (HER) and a reward-reshaping strategy to provide safer and more effective training guidance for the agents. Simulation outcomes reveal that robots utilizing this advanced method can more swiftly explore behaviors that contribute to stability in complex conditions, and demonstrate improvements in training speed and walking distance over traditional DDPG algorithms.

Neurocognition and NMDAR co-agonists pathways in individuals with treatment resistant first-episode psychosis: a 3-year follow-up longitudinal study.

This study aims to determine whether 1) individuals with treatment-resistant schizophrenia display early cognitive impairment compared to treatment-responders and healthy controls and 2) N-methyl-D-aspartate-receptor hypofunction is an underlying mechanism of cognitive deficits in treatment-resistance. In this case‒control 3-year-follow-up longitudinal study, n = 697 patients with first-episode psychosis, aged 18 to 35, were screened for Treatment Response and Resistance in Psychosis criteria through an algorithm that assigns patients to responder, limited-response or treatment-resistant category (respectively resistant to 0, 1 or 2 antipsychotics). Assessments at baseline: MATRICS Consensus Cognitive Battery; N-methyl-D-aspartate-receptor co-agonists biomarkers in brain by MRS (prefrontal glutamate levels) and plasma (D-serine and glutamate pathways key markers). Patients were compared to age- and sex-matched healthy controls (n = 114). Results: patient mean age 23, 27% female. Treatment-resistant (n = 51) showed lower scores than responders (n = 183) in processing speed, attention/vigilance, working memory, verbal learning and visual learning. Limited responders (n = 59) displayed an intermediary phenotype. Treatment-resistant and limited responders were merged in one group for the subsequent D-serine and glutamate pathway analyses. This group showed D-serine pathway dysregulation, with lower levels of the enzymes serine racemase and serine-hydroxymethyltransferase 1, and higher levels of the glutamate-cysteine transporter 3 than in responders. Better cognition was associated with higher D-serine and lower glutamate-cysteine transporter 3 levels only in responders; this association was disrupted in the treatment resistant group. Treatment resistant patients and limited responders displayed early cognitive and persistent functioning impairment. The dysregulation of NMDAR co-agonist pathways provides underlying molecular mechanisms for cognitive deficits in treatment-resistant first-episode psychosis. If replicated, our findings would open ways to mechanistic biomarkers guiding response-based patient stratification and targeting cognitive improvement in clinical trials.

Ketamine and its enantiomers for depression: a bibliometric analysis from 2000 to 2023.

Ketamine has demonstrated rapid and sustained antidepressant effects, marking its emergence as an innovative treatment of depression. Despite the growing number of preclinical and clinical studies exploring the antidepressant effects of ketamine and its enantiomers, a comprehensive bibliometric analysis in this field has yet to be conducted. This study employs bibliometric methods and visualization tools to examine the literature and identify key topics related to the antidepressant effects of ketamine and its enantiomers. We sourced publications on the antidepressant effects of ketamine and its enantiomers from the Web of Science Core Collection (WOSCC) database, covering the period from 2000 to 2023. Tools such as VOSviewer, CiteSpace and the R package "bibliometrix" were utilized for visual analysis. The study included 4,274 publications, with a notable increase in publications peaking in 2022. Co-occurrence analysis highlighted two primary research focal points: the efficacy and safety of ketamine and its enantiomers in treating depression, and the mechanisms behind their antidepressant effects. In conclusion, this analysis revealed a significant increase in research on the antidepressant effects of ketamine and its enantiomers over the past two decades, leading to the approval of esketamine nasal spray for treatment-resistant depression. The rapid antidepressant effects of ketamine have spurred further studies into its mechanisms of action and the search for new antidepressants with fewer side effects.

Identification of novel endoplasmic reticulum-related genes and their association with immune cell infiltration in major depressive disorder.

BACKGROUND: Several lines of evidence point to an interaction between genetic predisposition and environmental factors in the onset of major depressive disorder (MDD). This study is aimed to investigate the pathogenesis of MDD by identifying key biomarkers, associated immune infiltration using bioinformatic analysis and human postmortem sample. METHODS: The Gene Expression Omnibus (GEO) database of GSE98793 was adopted to identify hub genes linked to endoplasmic reticulum (ER) stress-related genes (ERGs) in MDD. Another GEO database of GSE76826 was employed to validate the novel target associated with ERGs and immune infiltration in MDD. Moreover, human postmortem sample from MDD patients was utilized to confirm the differential expression analysis of hub genes. RESULTS: We discovered 12 ER stress-related differentially expressed genes (ERDEGs). A LASSO Cox regression analysis helped construct a diagnostic model for these ERDEGs, incorporating immune infiltration analysis revealed that three hub genes (ERLIN1, SEC61B, and USP13) show the significant and consistent expression differences between the two groups. Western blot analysis of postmortem brain samples indicated notably higher expression levels of ERLIN1 and SEC61B in the MDD group, with USP13 also tending to increase compared to control group. LIMITATIONS: The utilization of the MDD gene chip in this analysis was sourced from the GEO database, which possesses a restricted number of pertinent gene chip samples. CONCLUSIONS: These findings indicate that ERDEGs especially including ERLIN1, SEC61B, and USP13 associated the infiltration of immune cells may be potential diagnostic indicators for MDD.

Efficacy and safety of esketamine for perioperative depression in patients undergoing elective surgery: A meta-analysis of randomized controlled trials.

BACKGROUND: Depression is a prevalent mood disorder during the perioperative period, with both preoperative concurrent depression and new-onset postoperative depression impacting postoperative recovery. Recent studies have indicated that the dissociative anesthetic esketamine may alleviate perioperative depressive symptoms. OBJECTIVE: This meta-analysis aimed to assess the efficacy and safety of esketamine in treating perioperative depression. METHODS: We selected randomized controlled trials comparing esketamine to placebo in terms of postoperative depressive symptoms. The primary outcome was postoperative depression scores, with secondary outcomes including the prevalence of postoperative depression, pain scores using the Visual Analogue Scale or Numeric Rating Scale, and incidences of adverse reactions such as nausea/vomiting, dizziness, dreams/nightmares, hallucinations. RESULTS: We enrolled a total of 17 studies involving 2462 patients. The esketamine group demonstrated a significant reduction in postoperative depression scores within one week after surgery (SMD -0.47, 95% CI (-0.66, -0.27), P < 0.001) and over the long term (SMD -0.44, 95% CI (-0.79, -0.09), P = 0.01). Furthermore, esketamine significantly decreased the prevalence of postoperative depression both within one week (RR 0.46, 95% CI (0.33, 0.63), P < 0.001) and over the long term (RR 0.50, 95% CI (0.36, 0.70), P < 0.001). Additionally, esketamine effectively relieved pain on the first postoperative day compared to control. However, it also increased the risks of dizziness and hallucinations for a short time. CONCLUSION: This meta-analysis suggests that the intraoperative or postoperative application of esketamine could be a potentially effective treatment for perioperative depression, although the increased risk of adverse reactions should be considered.

Viewpoints Sigma-1 receptor agonist fluvoxamine for multiple sclerosis.

Accumulating evidence suggests that the Epstein-Barr virus (EBV) plays a key role in the development of multiple sclerosis (MS). Additionally, depressive symptoms often precede the onset of MS. Given the role of the XBP1-sigma-1 receptor complex in the endoplasmic reticulum during EBV reactivation, the author proposes that fluvoxamine, an antidepressant with sigma-1 receptor agonism, could be a suitable therapeutic drug for MS.

Autophagy-related gene model as a novel risk factor for schizophrenia.

Autophagy, a cellular process where cells degrade and recycle their own components, has garnered attention for its potential role in psychiatric disorders, including schizophrenia (SCZ). This study aimed to construct and validate a new autophagy-related gene (ARG) risk model for SCZ. First, we analyzed differential expressions in the GSE38484 training set, identifying 4,754 differentially expressed genes (DEGs) between SCZ and control groups. Using the Human Autophagy Database (HADb) database, we cataloged 232 ARGs and pinpointed 80 autophagy-related DEGs (AR-DEGs) after intersecting them with DEGs. Subsequent analyses, including metascape gene annotation, pathway and process enrichment, and protein-protein interaction enrichment, were performed on the 80 AR-DEGs to delve deeper into their biological roles and associated molecular pathways. From this, we identified 34 candidate risk AR-DEGs (RAR-DEGs) and honed this list to final RAR-DEGs via a constructed and optimized logistic regression model. These genes include VAMP7, PTEN, WIPI2, PARP1, DNAJB9, SH3GLB1, ATF4, EIF4G1, EGFR, CDKN1A, CFLAR, FAS, BCL2L1 and BNIP3. Using these findings, we crafted a nomogram to predict SCZ risk for individual samples. In summary, our study offers deeper insights into SCZ's molecular pathogenesis and paves the way for innovative approaches in risk prediction, gene-targeted diagnosis, and community-based SCZ treatments.

A role of gut-brain axis on prophylactic actions of arketamine in male mice exposed to chronic restrain stress.

The gut-brain axis, which includes gut microbiota and microbiome-derived metabolites, might be implicated in depression. We reported the sustained prophylactic effects of a new antidepressant arketamine in chronic restrain stress (CRS) model of depression. In this study, we investigated the role of gut-brain axis on the prophylactic effects of arketamine in the CRS (7 days) model. Pretreatment with arketamine (10 mg/kg, 1 day prior to the CRS onset) significantly prevented CRS-induced body weight loss, increased immobility time of forced swimming test, decreased sucrose preference of sucrose preference test, and reduced expressions of synaptic proteins (GluA1 and PSD-95) in the prefrontal cortex (PFC) in the male mice. Gut microbiota analysis showed that pretreatment with arketamine might restore altered abundance of gut microbiota in CRS-exposed mice. An untargeted metabolomics analysis revealed four metabolites (e.g., L-leucine, N-acetyl-l-glutamine, 2-(2,4-dichlorophenyl)-3-[4-(dimethylamino)phenyl]acrylonitrile, L-threonine amide) that were altered between control and CRS group; however, there were found to be altered between the saline + CRS group and the arketamine + CRS group. Network analysis demonstrated correlations among synaptic proteins in the PFC and certain microbiota, and blood metabolites. These findings suggest that gut-brain axis, including its metabolites, might partially contribute to the persistent prophylactic effects of arketamine in the CRS model.

Repeated (S)-ketamine administration ameliorates the spatial working memory impairment in mice with chronic pain: role of the gut microbiota-brain axis.

Chronic pain is commonly linked with diminished working memory. This study explores the impact of the anesthetic (S)-ketamine on spatial working memory in a chronic constriction injury (CCI) mouse model, focusing on gut microbiome. We found that multiple doses of (S)-ketamine, unlike a single dose, counteracted the reduced spontaneous alteration percentage (%SA) in the Y-maze spatial working memory test, without affecting mechanical or thermal pain sensitivity. Additionally, repeated (S)-ketamine treatments improved the abnormal composition of the gut microbiome (ß-diversity), as indicated by fecal 16S rRNA analysis, and increased levels of butyrate, a key gut - brain axis mediator. Protein analysis showed that these treatments also corrected the upregulated histone deacetylase 2 (HDAC2) and downregulated brain-derived neurotrophic factor (BDNF) in the hippocampi of CCI mice. Remarkably, fecal microbiota transplantation from mice treated repeatedly with (S)-ketamine to CCI mice restored %SA and hippocampal BDNF levels in CCI mice. Butyrate supplementation alone also improved %SA, BDNF, and HDAC2 levels in CCI mice. Furthermore, the TrkB receptor antagonist ANA-12 negated the beneficial effects of repeated (S)-ketamine on spatial working memory impairment in CCI mice. These results indicate that repeated (S)-ketamine administration ameliorates spatial working memory impairment in CCI mice, mediated by a gut microbiota - brain axis, primarily through the enhancement of hippocampal BDNF - TrkB signaling by butyrate.

(R)-ketamine restores anterior insular cortex activity and cognitive deficits in social isolation-reared mice.

Chronic social isolation increases the risk of mental health problems, including cognitive impairments and depression. While subanesthetic ketamine is considered effective for cognitive impairments in patients with depression, the neural mechanisms underlying its effects are not well understood. Here we identified unique activation of the anterior insular cortex (aIC) as a characteristic feature in brain-wide regions of mice reared in social isolation and treated with (R)-ketamine, a ketamine enantiomer. Using fiber photometry recording on freely moving mice, we found that social isolation attenuates aIC neuronal activation upon social contact and that (R)-ketamine, but not (S)-ketamine, is able to counteracts this reduction. (R)-ketamine facilitated social cognition in social isolation-reared mice during the social memory test. aIC inactivation offset the effect of (R)-ketamine on social memory. Our results suggest that (R)-ketamine has promising potential as an effective intervention for social cognitive deficits by restoring aIC function.