Serotonin (5-HT) regulates neurodevelopment and behavior. Whereas central 5-HT is synthesized by tryptophan hydroxylase (TPH)-2, the TPH1 isoform produces 5-HT peripherally. Although these systems are anatomically segregated, TPH1 gene polymorphisms have been linked to neuropsychiatric vulnerability, suggesting that peripheral 5-HT may influence behavior through indirect pathways, potentially involving the gut-immune-brain axis. Here, we examined how lifelong peripheral 5-HT deficiency shapes behavior and cross-system communication in a sex-specific manner using adult TPH1 knockout (TPH1-/-) rats. Animals underwent behavioral testing combined with neurochemical and gene expression profiling, gut microbiome sequencing, and peripheral leukocyte phenotyping. TPH1-/- males and females displayed reduced anxiety-like behavior and enhanced attentional performance. TPH1-/- males also showed improved sociability and cognitive flexibility. These behavioral alterations were accompanied by attenuation of monoaminergic and GABA/glutamatergic signaling, alongside changes in HPA-axis and neuroplasticity-related pathways across cortico-limbic regions. Peripheral 5-HT deficiency further reshaped gut microbiome ecology, selectively reducing α-diversity in males and altering microbial community composition in both sexes. In the colon, TPH1 deficiency downregulated pro-inflammatory cytokines while upregulating adhesion marker expression. Circulating leukocyte populations were also altered, with reductions in γδ T cells, CD127+ CD8+ T cells, and B cells, and an increase in eosinophils. Integrative analyses showed that individual differences in anxiety-like behavior and cognition were associated with variation spanning neurochemical, microbial, and immune domains. Together, these findings support a role for peripheral 5-HT in behavioral regulation and reveal cross-system associations consistent with sex-specific modulation along the gut-immune-brain axis, while identifying TPH1-dependent signaling as a potential contributor to neuropsychiatric disorders’ pathophysiology.
Major depressive disorder (MDD) is increasingly recognized as involving both neuroinflammatory alterations and synaptic pathology. While (2R,6R)-hydroxynorketamine (HNK) exerts rapid antidepressant effects via synaptic modulation, memantine (MEM) shows complementary neuroprotective properties. However, whether their combination offers complementary benefits in inflammation-associated depressive-like phenotypes remains unclear. We investigated MEM combined with low-dose HNK (MEM + 1/2HNK) using an acute LPS-induced model of depressive-like behavior in male mice and primary cortical neuron cultures. Behavioral assessments included sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), and open field test (OFT). Proteomic profiling, western blotting, immunocytochemistry, and microelectrode array (MEA) recordings were performed. K252a, a broad-spectrum kinase inhibitor commonly used to interfere with Trk receptor-associated signaling, was used to assess the involvement of BDNF/TrkB-related signaling. MEM + 1/2HNK alleviated LPS-induced behavioral deficits in the SPT, FST, and TST, producing effects broadly comparable to full-dose HNK, whereas reduced-dose HNK and MEM alone showed limited efficacy. Proteomic profiling of the medial prefrontal cortex (mPFC) revealed upregulation of glutamatergic synapse and mTOR signaling proteins. MEM + 1/2HNK restored excitatory synapse density and activated the BDNF-TrkB-PI3K-AKT-mTOR signaling pathway in vivo and in vitro. MEA recordings demonstrated that MEM + 1/2HNK reversed LPS-induced disruptions in neuronal network firing rates and synchrony. K252a treatment attenuated the behavioral, synaptic, and electrophysiological improvements induced by MEM + 1/2HNK, supporting the involvement of Trk receptor-associated signaling. Together, these findings suggest that MEM and low-dose HNK counteract inflammation-associated neural dysfunction in association with Trk-related signaling. These proof-of-concept findings do not establish a safety or overall drug-burden advantage over full-dose HNK and require validation in both sexes before translational advantages can be inferred.
BACKGROUND:Dysregulation of microbiota-gut-brain axis has been implicated in depression, with immune and inflammatory signalling representing potential pathways linking gut microbial alterations to depressive symptoms. Short-chain fatty acids (SCFAs), namely acetate, propionate and butyrate are promising immunomodulating mediators of systemic inflammation and neuroplasticity. However, clinical trials of this pathway have given inconsistent results. The aim of this research was to conduct a synthesis of evidence for the therapeutic role of SCFAs using two approaches, to assess association between SCFA levels and depressive symptom severity, and to assess the efficacy of interventions targeting SCFA-related pathways for depressive symptoms. METHODS:PubMed, Scopus, PsycINFO, Cochrane Library, and Web of Science were searched from inception till 2 March 2025. Searches were updated on 13 November 2025. For intervention meta-analysis, randomized controlled trials (RCTs) evaluating interventions that have the potential to modulate SCFA production (probiotics, fecal microbiota transplantation (FMT), transcutaneous auricular vagus nerve stimulation (taVNS) and direct SCFA administration were included. For correlation meta-analysis, observational studies correlating the fecal SCFA levels with depression scores and RCT derived dataset were used. Here, correlation coefficients and Standardized Mean Differences (SMD) were pooled using random-effects models. Sensitivity and subgroup analyses were conducted to explore a moderating effect of the intervention type and the metabolic status (BMI). RESULTS:The review included eight randomized controlled trials (N = 430) of which 7 (N = 385) contributed to primary intervention meta-analysis and 7 observational studies (N = 369). Up to 6 datasets contributed to the faecal SCFA correlation meta-analyses. Among non-obese individuals, acetate (p < 0.001) and propionate (p = 0.004) depletion levels were significantly associated with increased severity of depression. SCFA-modulating interventions had a significant beneficial effect on depressive symptoms in comparison to controls (Overall SMD - 0.74, 95% CI - 1.10 to - 0.37; p < 0.0001; I2 = 64%)), k = 7. Across intervention classes, point estimates were largest for FMT (SMD (-1.45), taVNS (SMD (-1.04), and direct sodium butyrate (SMD (-0.84) although formal subgroup differences were not statistically significant (p = 0.44). Exploratory sensitivity analyses suggested that obesity status may be a potential biological moderator of treatment response, although this finding should be considered hypothesis-generating. CONCLUSION:This meta-analysis provides preliminary evidence that targeting the immunometabolic gut-brain axis through SCFA-related pathways may represent a promising approach for depressive symptoms, with exploratory findings suggesting a potential role of metabolic phenotype. The findings support further investigation of phenotype-directed SCFA-related interventions, incorporating metabolic and inflammatory characteristics alongside clinical outcomes. Future precision psychiatry trials should be stratified by metabolic status to identify patient subgroups most likely to respond to this form of immunomodulation.
BACKGROUND:Inflammation in pregnancy induced by chronic disease, infection, or environmental exposures has been associated with neurodevelopmental conditions in observational study designs. OBJECTIVE:To investigate causal effects of pregnancy inflammation on offspring neurodevelopment in the Norwegian Mother, Father and Child Cohort Study (MoBa) using a genetically informed design. METHODS:In pre-registered analyses, we tested potential causal effects of increased C-reactive protein (CRP), interleukin-6 (IL-6), and glycoprotein acetyls (GlycA) in pregnancy on neurodevelopmental outcomes using trio polygenic score (PGS) and intergenerational Mendelian randomization (MR) analyses. PGS and MR genetic instruments were used to predict neurodevelopmental outcomes in the MoBa cohort, which included mother-reported neurodevelopmental traits registered from age 3 to 8 years and diagnoses of ADHD and autism. In both the trio PGS and intergenerational MR analyses, simultaneous inclusion of mothers', fathers', and children's genotypes allowed for effects consistent with the hypothesized causal pathway (maternal inflammation) to be estimated independent of familial confounding factors. RESULTS:Validation analyses of genetic instruments only showed strong predictive value for CRP. Trio PGS in 41,531 complete trios did not reveal maternal indirect effects of genetic liability to higher CRP on offspring neurodevelopmental outcomes. The results of the trio MR also failed to support a causal link between maternal inflammation, proxied by higher CRP, during pregnancy and offspring neurodevelopment. CONCLUSION:This study provided no evidence consistent with causal effects of higher CRP in pregnancy on offspring neurodevelopment. This may imply that observational links are driven by genetic confounding, though other factors - such as selective participation in MoBa - cannot be ruled out as alternative explanations for our null findings.
Background and aims Post-traumatic stress disorder (PTSD) comorbid with depression is a prevalent, treatment-refractory clinical syndrome. Emerging evidence indicates shared microglial alterations in PTSD and depression, suggesting it may represent a common pathological substrate. However, the underlying neuroimmune mechanisms remain unclear. Methods PTSD- and depression-like behaviors were induced in rats by using single prolonged stress combined with foot shock (SPS&S). Cellular activity, spatial distribution, and morphology were assessed using qPCR, immunofluorescence, and Golgi-Cox staining. Microglial activity was inhibited using clodronate liposomes (CDSlip) and minocycline. Bulk RNA sequencing was performed to profile neuroimmune-related signaling molecules. Results Stress induced PTSD- and depression-like behaviors, accompanied by region-specific enhanced microglial activity in the anterior-medial NAC core (amNACc) and lateral NAC shell (LNACsh). Selective depletion of microglia in amNACc and LNACsh via CDSlip specifically alleviated stress induced PTSD- and depression-like behaviors, respectively. Morphological and functional analyses in each region revealed that microglia reshaped the spatial pattern of neuronal structure and function, manifested by enhanced in amNAC and inhibited in LNACsh, via differentially pruning adjacent inhibitory synapses in corresponding region. Further transcriptomic analysis of synaptic pruning relevant signaling pathway showed upregulated expression of “Eat me” signal molecules (particularly Mertk) in the amNAC and downregulated expression of “Find me” signal molecules (particularly Cx3cr1) in the LNACsh, consistent with the observed spatial synaptic pruning profiles. Minocycline administration reversed stress-induced PTSD and depression-like behaviors while normalizing the region-specific alterations in synaptic pruning signaling molecules. Conclusion Stress may elicit two regionally heterogeneous microglial subpopulations within NAC: phagocytosis-enhanced and recognition-impaired, which remodel the structure and function of local neural networks by differential pruning of inhibitory synapses, thereby driving the manifestation of PTSD- and depression-like behaviors, separately. These findings deepen our understanding of the neuroinflammatory mechanisms underlying trauma-related psychiatric disorders and identify novel targets for immunomodulation-based targets for transdiagnostic interventions .
