Parathyroid hormone (PTH) is a critical endocrine regulator of calcium homeostasis and bone remodeling and is widely employed in clinical settings through synthetic analogs for the treatment of osteoporosis. Although traditionally considered a peripheral regulator, emerging evidence indicates that PTH also exerts effects through the central nervous system (CNS). This study investigated the neuropsychiatric impact of elevated PTH and explored potential CNS involvement using multiple murine models of hyperparathyroidism (HPT). Distinct behavioral phenotypes were observed across models, indicating that psychiatric symptoms vary depending on disease etiology and progression. The effects of hPTH(1-34), a clinically approved PTH analog, were further assessed in male and female mice. Under pharmacological concentrations, hPTH(1-34) enhanced locomotor activity in males but induced mild anxiety-like behavior in females. These behavioral changes in females were independent of the estrus cycle and were amplified by ovariectomy. Metabolic analysis indicates PTH affects the basic metabolism by inhibiting the respiratory exchange ratio, promotes the energy expenditure and locomotion without affecting the food consumption in a 48hr range. To further investigate the molecular effect of PTH in the brain, a PTH1R-Cre mouse line was generated to map PTH receptor-1 (PTH1R) expression. Widespread expression of PTH1R was detected across the brain, including in both neuronal and non-neuronal cell populations. These findings suggest that PTH may influence behavior through interactions with PTH1R-expressing cells in brain vasculature and circumventricular regions. However, further studies are warranted to define the specific brain nuclei and cell types involved in PTH-driven modulation of neurobehavioral function.

Abstract Background Neuropsychiatric comorbidities are highly prevalent in chronic kidney disease (CKD), yet the underlying neural mechanisms remain poorly defined. Methods We established multiple mouse models of CKD and identified an adenine-induced model as the most suitable platform to study neurobehavioral alterations. Anxiety susceptibility was operationalized as the emergence of anxiety-like behavior after subthreshold unpredictable stress (SUS) and was assessed using the SUS paradigm combined with behavioral assays. Region-focused c-Fos mapping, fiber photometry, and chemogenetic manipulation were used to interrogate neural circuit activity. Pharmacological and genetic approaches were applied to investigate the role of angiotensin II (Ang II) signaling. Finally, hypothalamic paraventricular nucleus (PVN) activation was used to explore brain-to-kidney feedback by using in vivo multiphoton microscopy imaging techniques. Results CKD mice showed no consistent baseline anxiety-like phenotype across standard assays but developed robust anxiety-like behavior after subthreshold unpredictable stress. Region-focused c-Fos profiling and fiber photometry identified the central amygdala (CeA) as a stress-sensitized limbic node in CKD. Chemogenetic inhibition of CeA GABAergic neurons attenuated anxiety-like behavior, supporting a functional role for CeA activity. Mechanistically, CKD elevated circulating Ang II and enhanced CeA accumulation of peripherally administered FAM-Ang II-associated signal. CeA-specific Agtr1a knockdown attenuated anxiety-like behavior and exaggerated stress-evoked CeA calcium responses. Exploratory experiments further showed that sustained PVN glutamatergic activation aggravated early renal injury markers in a mild renal injury model. These findings support a kidney-to-brain model in which CKD primes CeA stress circuits, while local Ang II–AT1R signaling contributes to the behavioral expression of stress-induced anxiety-like behavior, with a potential brain-to-kidney feedback component. Conclusions CKD promotes stress-induced anxiety susceptibility through a CeA-centered mechanism involving local Ang II–AT1R signaling. These findings identify CeA Ang II–AT1R signaling as a potential contributor to CKD-associated stress-related affective vulnerability. Abstract graph

The brain acts as a central integrator that enables organisms to interpret environmental stimuli and coordinate adaptive responses across the body. While enriched environments are known to enhance neural plasticity and cognitive function, their impact on peripheral organ systems remains less understood. Here, we show that enriched environmental conditions activate a peri–locus coeruleus (peri–LC) neuronal ensemble that preserves CD31 hi EMCN hi type H endothelium, a specialized bone-associated endothelial subtype, against age-associated decline, thereby enhancing femoral bone density. Chemogenetic activation and ablation experiments further revealed that this peri-LC ensemble is functionally distinct from other sympathetic regulatory brain regions in its control of bone endothelial heterogeneity and skeletal mass. Three-dimensional bone clearing and spatial analyses showed that CD31 hi EMCN hi endothelium is closely associated with sympathetic nerve terminals. The peri-LC mediates this process through sympathetic signaling and β2-adrenergic receptors on bone vascular endothelial cells. In vivo imaging further demonstrated that norepinephrine release is spatially restricted, with sprouting endothelial cells near the growth plate exhibiting the highest sensitivity. Together, these findings reveal a refined brain–periphery regulatory logic in which distinct sympathetic brain circuits engage spatially restricted norepinephrine signaling to coordinate organ-specific vascular and skeletal adaptations.

Chronic stress disrupts homeostasis in the brain and body, leading to anxiety, depression, and cardiovascular and metabolic dysfunction. Although exercise can counter these effects, the mechanisms are scattered across fields and not yet integrated. This review proposes a multi-scale framework. Exercise is not only stress-relieving; it is also a controllable challenge that can recalibrate the system when repeated bouts are matched by sufficient recovery and bioenergetic support. We propose that repeated exercise engages a stress response–adaptation–recovery cycle, in which peripheral signals from skeletal muscles, liver, adipose tissue and gut convey body metabolic state to the brain and are consolidated into durable plasticity only when mitochondrial capacity, substrate availability, and redox balance permit recovery. These signals pass through the blood-brain barrier and engage plasticity switches, including neurotrophic signals, epigenetic modification and metabolic coupling, thus stabilizing the neural circuits of threat appraisal, reward processing and contextual memory. By integrating these dimensions, we clarify how exercise can transform short-term physical stress into lasting resilience and provide direction for future research.

Stress is a major precipitating factor for emotional disorders, including anxiety. To cope with stress, individuals frequently engage in hedonic behaviors, such as eating palatable food, which provide transient relief from psychological distress and may protect against the development of pathology. However, the neural mechanisms by which hedonic experience counteracts stress-induced anxiety remain poorly understood. Here, we identify a neural circuit functionally connecting the prefrontal cortex (PFC) to the paraventricular nucleus (PVN) of the hypothalamus that mediates stress mitigation through palatable food intake. Activation of this circuit suppresses stress-induced hyperactivity of PVN corticotropin-releasing factor (CRF) neurons and prevents the development of anxiety-like behaviors. This effect is driven by palatable-food-induced dopamine release in the PFC, which activates dopamine D1 receptor (D1R)-expressing neurons projecting to corticotropin-releasing factor receptor 1 (CRFR1)-expressing neurons in the PVN and peri-PVN. Notably, GABAergic CRFR1 neurons are enriched in the peri-PVN, with minimal presence within the PVN proper, suggesting that inhibition of PVNCRF neurons is mediated indirectly via peri-PVN GABAergic inputs. These findings define a previously uncharacterized PFC→peri-PVN→PVN circuit through which hedonic experience modulates stress responses and reveal a neural substrate for behavioral resilience, providing a potential avenue for anxiety intervention.

Chronic hypoxia at high altitudes disrupts emotional and metabolic homeostasis. However, the underlying mechanisms remain unclear. Using mice chronically exposed to 11.35

Background and Objective: Adult diffuse gliomas are common primary brain tumors requiring accurate grading according to the World Health Organization classification (Grades 2–4) to guide treatment planning and prognosis. When surgical resection is unsafe, biopsy remains invasive and provides limited sampling, whereas preoperative magnetic resonance imaging helps target representative regions. However, current MRI-based grading methods lack accuracy and efficiency. Therefore, this study aimed to develop a novel deep-learning-based method for intelligent grading of adult diffuse gliomas.Methods: We propose an innovative approach that fuses deep features extracted from a three-dimensional U-Net segmentation model with handcrafted radiomic features. An optimized multilayer perceptron is used to achieve efficient decision-level fusion.Results: Our method achieved a classification accuracy of 82% on a multicenter validation set, outperforming conventional methods by 6%. Comprehensive validation confirmed strong generalizability and clinical relevance across the tested datasets.Conclusion: The key contributions of this study are: (1) developing a high-accuracy multimodal fusion framework operable with limited computational resources; (2) achieving a novel integration of 3D U-Net deep features and radiomic features; and (3) validating the method on two public datasets (EGD and TCIA) and an internal clinical dataset, demonstrating strong generalizability and clinical relevance.

Transcranial focused ultrasound (tFUS) enables non-invasive neuromodulation, yet its underlying molecular mechanisms remain largely elusive. Here, we show that transient receptor potential canonical 4 (TRPC4) and transient receptor potential canonical 5 (TRPC5) channels are critical mediators of tFUS-induced neuronal modulation in the mouse brain. Applying tFUS to the retrosplenial cortex (RSC) in male mice desensitizes mechanical and thermal sensitivity while robustly elicits early growth response 1 (Egr1) expression. Inhibiting these tFUS-induced Egr1 ensembles blocks the somatic sensory effects. Transcriptomic analysis identifies Trpc4 enrichment in tFUS-activated Egr1-positive cells. Both pharmacological inhibition and genetic knockdown of TRPC4 abolish tFUS-mediated sensory modulation. Targeted knockdown further demonstrates that the highly homologous TRPC5 plays a comparable role. In situ proximity ligation assay, co-immunoprecipitation, and live-cell calcium imaging confirm that TRPC4 and TRPC5 form a protein complex in the RSC that facilitates the tFUS response. These findings establish TRPC4/TRPC5 as essential molecular components for tFUS neuromodulation.

Visceral hypersensitivity is a hallmark feature of irritable bowel syndrome (IBS), yet its underlying mechanisms remain incompletely understood. In the present study, we found that miRNA-let7b5p was downregulated in the spinal cord of IBS model rats induced by neonatal colorectal distension. Concurrently, microglia exhibited a shift toward a pro-inflammatory M1 phenotype and selectively engulfed inhibitory synapses, resulting in impaired GABAergic neuronal function and disruption of the excitatory/inhibitory balance. Intrathecal administration of a miRNA-let7b5p agomir suppressed M1-type microglial activation in the spinal cord, reduced pro-inflammatory cytokine levels, and alleviated visceral hypersensitivity, whereas antagomir treatment induced visceral hypersensitivity in control rats. Mechanistically, MAP3K3 was identified as a direct target of miRNA-let7b5p, and its knockdown recapitulated the protective effects conferred by miRNA upregulation. Collectively, these findings demonstrate that miRNA-let7b5p attenuates IBS-associated visceral hypersensitivity by downregulating MAP3K3, thereby inhibiting spinal microglial activation and restoring GABAergic neuronal function. This study provides novel insights into the pathogenesis of IBS-related visceral hypersensitivity and highlights a potential therapeutic target for drug development.

Parathyroid hormone (PTH) is critical for regulating calcium and phosphate homeostasis, and its dysregulation contributes to osteoporosis. Current methods for precise control of PTH secretion are limited. This study explores chemogenetic tools to regulate PTH secretion in parathyroid chief cells via Gq/Gi signaling. In vitro, we found that activation of hM3Dq-expressing cells increased PTH release, while hM4Di inhibited it. In vivo, hM3Dq activation improved bone structure and reduced bone loss in an ovariectomized rat model. These findings suggest chemogenetics as a promising approach for modulating PTH and offering potential therapeutic strategies for bone health and related disorders.

The interaction between muscles and fat tissue has a significant impact on human health. The speed of muscle atrophy and fat infiltration varies in different genders and age groups. The study aims to observe the changes of fat and muscle parameters of abdominal tissue and paravertebral muscle with age and gender, and further to explore the characteristics of muscle atrophy and fat infiltration with age and gender through changes in the proportion of paravertebral muscle content to abdominal tissue content. 713 subjects who came to our hospital for physical examination of chest low-dose Computed Tomography (LDCT) scanning from September 1, 2021 to September 1, 2022 were collected. The scanning sequence and post-processing of quantitative Computed Tomography (QCT) were performed on them. The contents (including mass and area) of abdominal overall fat, visceral fat, visceral soft tissue, paravertebral intramuscular fat and paravertebral intramuscular muscle at the central level of L2 vertebrae were obtained. Then calculate the proportion of paravertebral intramuscular fat content to overall fat content, paravertebral intramuscular fat content to visceral fat content, and paravertebral intramuscular muscle content to visceral soft tissue content. Group the subjects by age and gender and observe the characteristics of changes in each parameter with age and gender. There was a significant positive correlation (r = 0.637–0.999, P<0.001) between the mass and area in the overall fat, visceral fat, visceral soft tissue, as well as paravertebral intramuscular fat and muscle. The content of visceral fat (for mass: F = 3.645, P = 0.006; for area: F = 3.406, P = 0.009) and paravertebral intramuscular fat (for mass: F = 3.455, P = 0.009; for area: F = 3.750, P = 0.005) in males increased with age, while the muscle content of paravertebral muscle (for mass: F = 4.556, P = 0.001; for area: F = 4.077, P = 0.003) decreased. The percentage of paravertebral intramuscular fat content to overall fat content (for mass: F = 3.522, P = 0.008; for area: F = 3.454, P = 0.009), paravertebral intramuscular fat content to visceral fat content (for mass: F = 2.485, P = 0.043; for area: F = 2.503, P = 0.042) in males increased with age, and the percentage of paravertebral intramuscular muscles content to visceral soft tissue content (for mass: F = 3.408, P = 0.009; for area: F = 2.956, P = 0.020) decreased with age. For females, the content of overall fat (for mass: F = 12.476, P<0.001; for area: F = 12.301, P<0.001), visceral fat (for mass: F = 17.878, P<0.001; for area: F = 17.861, P<0.001) and paravertebral intramuscular fat (for mass: F = 6.399, P<0.001; for area: F = 6.960, P<0.001) increased with age, the percentage of paravertebral intramuscular fat content to overall fat content (for mass: F = 4.342, P = 0.002; for area: F = 4.068, P = 0.003), paravertebral intramuscular fat content to visceral fat content (for mass: F = 2.986, P = 0.019; for area: F = 2.801, P = 0.026) decreased before 60y and increased after 61y. The fat and muscle content of abdominal tissues and paravertebral muscles have different characteristics in different age groups. Age and gender factors should be paid attention to when solving the problems of fat and muscle changes in clinic.

Progranulin (PGRN) is a secreted glycoprotein with cytokine-like properties, exerting tripartite mechanisms of inflammation suppression, tissue repair promotion, and metabolic regulation. This multifaceted functionality positions PGRN as a potential “multi-effect therapeutic strategy” for metabolic disorders characterised by cartilage degradation and imbalanced bone remodelling, potentially establishing it as a novel therapeutic target for such conditions. Osteoarthritis, rheumatoid arthritis, intervertebral disc degeneration, osteoporosis, periodontitis, and diabetes-related complications—representing the most prevalent metabolic diseases—currently lack effective treatments due to incomplete understanding of their precise pathogenic mechanisms. Recent studies have revealed that PGRN expression levels are closely associated with the onset and progression of these metabolic disorders. However, the exact regulatory role of PGRN in these diseases remains elusive, partly owing to its tissue-specific actions and context-dependent dual roles (anti-inflammatory vs. pro-inflammatory). In this review, we summarise the structure and functions of PGRN, explore its involvement in neurological disorders, immune-inflammatory diseases, and metabolic conditions, and specifically focus on its molecular mechanisms in metabolic diseases. Furthermore, we consolidate advances in targeting PGRN and the application of its engineered derivative, Atsttrin, in metabolic bone disorders. We also discuss potential unexplored mechanisms through which PGRN may exert influence within this field or other therapeutic domains. Collectively, this work aims to provide a new framework for elucidating PGRN’s role in disease pathogenesis and advancing strategies for the prevention and treatment of metabolic disorders.

The aberrant activation of the canonical Wnt/(3-catenin signaling has been identified as a significant contributor to the pathogenesis of osteoarthritis (OA), exacerbating OA symptoms and driving OA progression. Despite its potential as a therapeutic target, clinical translation is impeded by the lack of a targeting delivery system and effective drug candidate that can modulate steady-state protein levels of (3-catenin at post-translational level. Our study addresses these challenges by offering a new approach for OA treatment. To overcome these challenges, we introduced a novel delivery system using human serum albumin (HSA) to deliver a small molecule (3-catenin inhibitor, Methyl-Sulfonyl AB (MSAB). This system is designed to enhance the bioavailability of MSAB, ensuring its accumulation inside the joint space, and facilitating the degradation of (3-catenin protein. We have demonstrated that MSAB, when delivered via HSA, not only effectively inhibits cartilage damage but also ameliorates OA-related pain in an OA mouse model. We then performed proteomic analysis and biochemical studies to determine the molecular mechanisms underlying the therapeutic effects of MSAB. We identified that discoidin domain receptor 2 (DDR2), a critical mediator in OA pathology, is a downstream molecule of (3-catenin signaling and (3-catenin/TCF7 directly controls DDR2 gene transcription. MSAB suppressed the DDR2 expression in chondrocytes. MSAB ameliorated OA progression and OA-associated pain through inhibition of (3-catenin-DDR2 signaling. This study underscores the efficacy of MSAB/HSA in OA treatment, providing new insights into its molecular mechanism of OA. It suggests that targeted therapies with MSAB/HSA could be a new OA management strategy.

Anxiety, whilst often viewed as a disorder, is an evolutionarily conserved mechanism that facilitates threat detection and survival. However, when stress regulation becomes maladaptive, this adaptive response can shift into pathology. Here, we identify the claustrum (CLA) as a key hub for allostasis following stress, integrating Gad2 (GABAergic)-vGluT1 (glutamatergic) microcircuits. We report that acute social defeat stress activated the CLA and induced hypervigilance and anxiety-like behaviors. Multimodal analyses revealed transcriptional plasticity in CLA neurons, and fiber photometry revealed anticipatory activation of Gad2 neurons and reactive activation of vGluT1+ neurons. We further delineated a reciprocal GABAergic-glutamatergic circuit between the CLA and the anterior cingulate cortex (ACC) that orchestrates allostasis following stress via opposing mechanisms: (1) glutamatergic CLA−ACC projections that amplify threat responses, and (2) two distinct GABAergic inhibitory pathways – intrinsic CLAGad2+ activity and top-down ACC−CLAGad2+ modulation. Chronic stress drives persistent hyperactivation of CLAGad2+ neurons, suppressing CLA glutamatergic activity and leading to depression-like behaviors. Our results identify a dynamic CLA circuit that gates stress responses via CLAGad2+ neurons acting as a brake under acute stress. Chronic stress amplifies this inhibition, thereby disturbing circuit balance and driving behavioral despair affective pathology. ### Competing Interest Statement The authors have declared no competing interest. National Key R&D Program of China, 2024YFC3406700, 2024YFC3406701 Shenzhen Medical Research Fund, B2402018 National Natural Science Foundation of China, 32371070 Guangdong Provincial Key S&T Program, 2018B030336001 Shenzhen Science and Technology Program, JCYJ20241202125015020, JCYJ20220818101615033, JCYJ20210324101813035

Osteoarthritis (OA) is a degenerative joint disease accompanied with the loss of cartilage and consequent nociceptive symptoms. Normal articular cartilage maintains at aneural state. Neuron guidance factor Semaphorin 3A (Sema3A) is a membrane-associated secreted protein with chemorepulsive properties for axons. However, the role of Sema3A in articular cartilage is still not clear. In the present studies, we investigated the functions of Sema3A in OA development in mice, non-human primates, and patients with OA. Sema3A has a protective effect on cartilage degradation, validated by the organoid culture in vitro and confirmed in chondrocyte-specific Sema3A conditional knockout mice. We demonstrated that Sema3A is a key molecule in maintaining cartilage homeostasis from chondrocyte hypertrophy via activating the PI3K pathway. The potential usage of Sema3A for OA treatment was validated in mouse and Rhesus macaque OA models through intra-articular injection of Sema3A, and also in patients by administering Sema3A containing platelet-rich plasma into the knee joints. Our studies demonstrated that Sema3A exerts a critical role in inhibiting neurite ingrowth and preventing chondrocyte hypertrophy in cartilage, and could be potentially used for OA treatment.

Objective: Distraction osteogenesis (DO) has been widely used to treat bone defects as its effectiveness in bone regeneration. Currently, distraction devices for establishing DO models are mainly developed for rats or large animals. However, a mouse DO model is in great need for in-depth mechanistic investigations using various transgenic mice. The current study reports the development of a reproducible murine DO model. Methods: A mini-titanium lengthener was designed and fabricated. The mini-lengthener was applied on the murine femur with four threaded pins using a designed clamp as the drilling and insertion guide. After transverse osteotomy using a Gigli saw, and after 5 days of latency, DO procedures started at 0.3 mm/day for 10 days, and the consolidation period was left for 28 days. The bone formation was monitored by radiography and histology. Potential effects on animal locomotion during DO were also measured by behavior tests. Results: Separated bone segments maintained good alignment during the entire DO phases. New bone formation was found as early as the end of the distraction phase. Active bone remodeling was found between the separated bone segments at late distraction and early consolidation phases. At the mature consolidation phase, bone remodeling was mainly observed in the contact cortical bone. Mice underwent DO procedure did not have significant impairment in their locomotion. Conclusion: We have successfully developed a murine femoral DO model, which may be used to study the biological processes of DO. We also developed the mini-lengthener and the guide clamp to ensure the standardization and reproducibility of the mouse DO model. The translational potential of this article: Current study reports the development of a murine femoral DO model. A well-established murine DO model will facilitate further investigations of the biological mechanisms of DO in various transgenic and normal mice.

The aberrant activation of the canonical Wnt/β-catenin signaling has been identified as a significant contributor to the pathogenesis of osteoarthritis (OA), exacerbating OA symptoms and driving OA progression. Despite its potential as a therapeutic target, clinical translation is impeded by the lack of a targeting delivery system and effective drug candidate that can modulate steady-state protein levels of β-catenin at post-translational level. Our study addresses these challenges by offering a new approach for OA treatment. To overcome these challenges, we introduced a novel delivery system using human serum albumin (HSA) to deliver a small molecule β-catenin inhibitor, Methyl-Sulfonyl AB (MSAB). This system is designed to enhance the bioavailability of MSAB, ensuring its accumulation inside the joint space, and facilitating the degradation of β-catenin protein. We have demonstrated that MSAB, when delivered via HSA, not only effectively inhibits cartilage damage but also ameliorates OA-related pain in an OA mouse model. We then performed proteomic analysis and biochemical studies to determine the molecular mechanisms underlying the therapeutic effects of MSAB. We identified that discoidin domain receptor 2 (DDR2), a critical mediator in OA pathology, is a downstream molecule of β-catenin signaling and β-catenin/TCF7 directly controls DDR2 gene transcription. MSAB suppressed the DDR2 expression in chondrocytes. MSAB ameliorated OA progression and OA-associated pain through inhibition of β-catenin-DDR2 signaling. This study underscores the efficacy of MSAB/HSA in OA treatment, providing new insights into its molecular mechanism of OA. It suggests that targeted therapies with MSAB/HSA could be a new OA management strategy.

Background: Management of intractable constipation is still challenging in children. Fecal impaction has been considered a common cause while retrograde colonic enema(RCE) is an effective method for this condition. Fecal microbiota transplantation(FMT) has also demonstrated great potential in many gastrointestinal diseases. However, the efficacy of RCE with FMT in childhood constipation remains unclear.Methods: A randomized, double-blind, controlled trial with 110 children who met the inclusion criteria was conducted. The subjects were randomly assigned to the FMT with RCE group or the placebo with RCE group. The duration of FMT treatment was 4 weeks, with a 12-week follow-up. The main observations were complete spontaneous bowel movements and bowel function satisfaction, and the adverse effects were assessed based on symptoms.Findings: At the end of follow-up, the effectiveness rates in the FMT with RCE and placebo with RCE groups were 43.64% and 21.82%, respectively (χ2 =11.24, P < 0.05). Compared with the end of treatment, there were eight recurrences (25.00%) in the FMT with RCE group and three recurrences (20.00%) in the placebo with RCE group( P >0.05). Among the primary outcome indicators, 27 patients (49.09%) in the FMT with RCE group and 15 patients (27.27%) in the placebo with RCE group were satisfied with defecation (χ2 =5.55, P <0.05). In total, 22 patients (40.00%) in the FMT with RCE group and 10 patients(18.18%) in the placebo with RCE group had complete spontaneous bowel movements for ≥ 3 weeks (χ2 =6.35, P <0.05). No adverse effects were found in all recruited cases.Interpretation: FMT enhances the efficacy of RCE and the use of RCE based FMT is a safe and effective method in the treatment of intractable constipation in children.Trial Registration Details: The study protocol was registered prospectively (https://clinicaltrials.gov/; registration number: NCT 05035784).Funding Information: This study was supported by the National Natural Science Foundation of China (No. 81570465, 30700917) and the General Funding Project from Department of Education of Liaoning Province (No. JC2019014).Declaration of Interests: We declare no competing interests.Ethics Approval Statement: The Ethics Committee of China Medical University (2018PS427K) approved the protocol, and written informed consent was obtained from all parents.

Assessing and responding to threats is vital in everyday life. Unfortunately, many mental illnesses involve impaired risk assessment, affecting patients, families, and society. The brain processes behind these behaviors are not well understood. We developed a transgenic mouse model (disrupted-in-schizophrenia 1 [DISC1]-N) with a disrupted avoidance response in risky settings. Our study utilized single-nucleus RNA sequencing and path-clamp coupling with real-time RT-PCR to uncover a previously undescribed group of glutamatergic neurons in the basolateral amygdala (BLA) marked by Wolfram syndrome 1 (WFS1) expression, whose activity is modulated by adjacent astrocytes. These neurons in DISC1-N mice exhibited diminished firing ability and impaired communication with the astrocytes. Remarkably, optogenetic activation of these astrocytes reinstated neuronal excitability via D-serine acting on BLAWFS1 neurons’ NMDA receptors, leading to improved risk-assessment behavior in the DISC1-N mice. Our findings point to BLA astrocytes as a promising target for treating risk-assessment dysfunctions in mental disorders.

Ornithine α-ketoglutarate (OKG), a nutritional compound, is an amino acid salt with anti-oxidative and anti-inflammatory effects on humans and animals. Ulcerative colitis (UC), as an inflammatory bowel disease (IBD), leads to chronic intestinal inflammatory dysfunction. This study evaluated the optimal dosage of OKG in healthy mice. Then, a mouse model of acute colitis was established using dextran sodium sulfate (DSS), and the preventive effect of OKG on DSS-induced colitis in mice was explored through analysis of serum inflammatory cytokines and fecal microbiota. Initially, the mice were randomly divided into a control group, a group given a low dose of OKG (LOKG: 0.5%), a group given a medium dose of OKG (MOKG: 1%), and a group given a high dose of OKG (HOKG: 1.5%); they remained in these groups for the entire 14-day experimental period. Our results demonstrated that 1% OKG supplementation increased body weight, serum growth hormone (GH), insulin (INS), alkaline phosphatase (ALP), Tyr, and His and decreased urea nitrogen (BUN), NH3L, and Ile. Then, a 2 × 2 factor design was used for a total of 40 mice, with diet (a standard diet or a 1% OKG diet) and challenge (4% DSS or not) as the main factors. During days 14 to 21, the DSS mice were administered 4% DSS to induce colitis. The results revealed that OKG alleviated weight loss and reversed the increases in colonic histological damage induced by DSS. OKG also increased serum IL-10 secretion. Moreover, OKG enhanced the abundance of Firmicutes and decreased that of Bacteriodetes at the phylum level and particularly enhanced the abundance of Alistipes and reduced that of Parabacterioides at the genus level. Our results indicated that OKG promotes growth performance and hormone secretion and regulates serum biochemical indicators and amino acid concentrations. Furthermore, 1% OKG supplementation prevents DSS-induced colitis in mice via altering microbial compositions and reducing the secretion of inflammatory cytokines in serum.