Microglia-neuron contacts have been shown to regulate neural network activity through the formation and elimination of synapses. The pathogenesis of major depressive disorder is accompanied by a decline in brain-derived...Microglia-neuron contacts have been shown to regulate neural network activity through the formation and elimination of synapses. The pathogenesis of major depressive disorder is accompanied by a decline in brain-derived neurotrophic factor (BDNF) signaling, associated with increased microglia activity that disrupts cognitive function. The actions of both typical and rapid-acting antidepressant drugs, which have been shown to increase BDNF signaling through the tropomyosin receptor kinase B (TrkB) receptor, decrease microglia activation and the levels of pro-inflammatory cytokines. Examining the link between BDNF signaling and the microglial pro-inflammatory response, we demonstrate that TrkB signaling elicits the neuronal secretion of CD22 (Siglec-2), a sialic acid-binding immunoglobulin-type lectin, to inhibit microglial activation and alleviate depression-like symptoms. In a male chronic mild stress (CMS) mouse model of depression decreased expression of the postsynaptic scaffolding protein PSD-95 and Gαi1/3 were found to compromise TrkB signaling leading to reduced CD22 levels in hippocampal tissue. Restoration of TrkB-Gαi1/3-Akt signaling with dSyn3, a peptidomimetic compound targeting the PDZ3 domain of PSD-95, enhanced CD22 expression to inhibit microglial activation, promote dendritic spine formation and rapidly mitigate depression-like symptoms. Furthermore, hippocampal overexpression of CD22 in neurons was sufficient to reduce microglial activation and depressive-like behaviors in male CMS mice. S-ketamine, a rapid-acting antidepressant, increased CD22 expression to mitigate depression-like symptoms. While neuronal knockdown of CD22 in the hippocampus did not significantly impair the rapid (within 4 h) antidepressant effects typically observed with S-ketamine or dSyn3 administration, strikingly, knockdown of CD22 attenuated the long-acting (within 3 days) antidepressant effects of S-ketamine or dSyn3, as evidenced by sustained immobility in the TST (tail suspension test) and FST (forced swim test), and a lack of improvement in sucrose preference. In contrast, a single dose of fluoxetine failed to increase CD22 expression or inhibit microglia activity. These results suggest that rapidly-acting anti-depressant drugs enhance TrkB-induced neuronal expression and secretion of CD22 to promote the homeostatic state of microglia required for antidepressant actions. In male depression mice, dSyn3 facilitates BDNF-induced TrkB-PSD-95-Gαi1/3 complex formation to increase Akt-mTOR activation as well as synaptic and spine density in the hippocampus. TrkB signaling increases CD22 expression and secretion from neurons blocking microglial activation in the hippocampal region of male CMS mice.
Chronic stress induces neurobiological adaptations that manifest as altered behavioral patterns in both humans and animal models. To enhance the translational value of preclinical research, we systematically evaluated ch...Chronic stress induces neurobiological adaptations that manifest as altered behavioral patterns in both humans and animal models. To enhance the translational value of preclinical research, we systematically evaluated chronic restraint stress (CRS) protocols in mice through longitudinal tracking of behavioral outcomes across multiple validated assays. By comparing various CRS parameters, we identified specific protocols that elicited persistent behavioral adaptations across distinct measurements in male mice. Short-duration, high-intensity CRS (6 h/day for 3 days) induced persistent phenotypes of avoidance-related and repetitive behaviors in multiple assays of approach-avoidance conflict, whereas prolonged CRS exposure (2 h/day for 10-14 days) progressively disrupted reward-seeking and behavioral coping phenotypes. When prolonging CRS exposure, we observed a behavioral transition from the initial phenotypes of avoidance/repetitive behavior to the later deficits of reward seeking/behavioral coping, accompanied by a progressive dissociation between these behavioral domains. The 10-day CRS protocol represents a critical threshold for inducing reward-seeking deficit, as well as a comorbid model of avoidance-related response and reward-processing impairment. Rapid antidepressant ketamine reversed impairments of reward seeking and behavioral coping, and typical antidepressant/anxiolytic paroxetine alleviated both repetitive/avoidance-related behaviors and coping/reward-seeking deficits. These findings demonstrated the face, construct, and predictive validity of CRS as a male mouse model of stress-related neuropsychiatric disorders. Leveraging comprehensive behavioral characterization across diverse CRS protocols, our study provides standardized protocols for recapitulating clinically-relevant behavioral adaptations to chronic stress.
Autoimmune anti-NMDA-receptor encephalitis is characterized by autoantibody-induced NMDA receptor hypofunction leading to severe neuropsychiatric symptoms including psychosis, hallucinations, memory dysfunction and seizu...Autoimmune anti-NMDA-receptor encephalitis is characterized by autoantibody-induced NMDA receptor hypofunction leading to severe neuropsychiatric symptoms including psychosis, hallucinations, memory dysfunction and seizures. However, it remains enigmatic what changes in intrinsic network organization at the multi-neuronal level, serving as the neural substrate of brain function, underlie disease symptomology. Using a mouse model with passive-transfer of patient's monoclonal anti-GluN1-autoantibodies, we performed two-photon in vivo recordings of spontaneous dynamics under light anesthesia in CA1 microcircuits, a key hippocampal area for memory processing. We find pronounced functional coupling and clustering between putative neurons (PNs), alongside an altered network architecture with pathological emergence of irregular neuronal ensembles. These alterations not only induce excessive hub-like properties but also contribute to the increased network's intrinsic synchrony, despite its reduced baseline activity; this hypersynchrony was further supported by pathologically faster intra-ripple oscillations and amplified population bursts during these coincident events in vivo. Next, using electrophysiological data ex vivo, we show that this profound functional rewiring is associated with a selective preservation of effectively strong excitatory synapses, despite overall reduced excitation and augmented long-term depression. Furthermore, we find abnormal PN firing characteristics, higher transmission fidelity, and increased similarity of spontaneous spatiotemporal activity patterns, all reflecting dysregulated intrinsic organization of CA1 dynamics. Collectively, the aberrant reorganization of hippocampal microcircuits and altered intrinsic network activity patterns provide new mechanistic insights into the consequences of NMDAR hypofunction and pathomechanisms of anti-NMDAR encephalitis.
Epigenetic mechanisms are thought to contribute to neurodevelopmental vulnerability for psychiatric disorders, yet longitudinal evidence linking DNA methylation (DNAm) to brain maturation and psychopathology is limited....Epigenetic mechanisms are thought to contribute to neurodevelopmental vulnerability for psychiatric disorders, yet longitudinal evidence linking DNA methylation (DNAm) to brain maturation and psychopathology is limited. Using epigenome-wide DNAm (372,582 CpGs) and whole-brain structural MRI data from the IMAGEN cohort (n = 506, ages 14-19), we identified 18 co-regulated DNAm clusters, ten enriched for brain-expressed genes involved in neuronal development and signalling. The clusters showed consistent longitudinal change and were reproducible in independent adult samples (PPMI, n = 513; ADNI, n = 606). Multivariate analyses revealed coordinated coupling between DNAm change and cortical-subcortical maturation, such that greater DNAm reductions in brain-related clusters associated with greater cortical thinning and subcortical volume changes in the fronto-limbic-striatal axis. Increases in depressive symptoms, and frequency of cannabis use and binge drinking were linked to DNAm changes, with mediation models supporting DNAm as a mechanistic bridge between behaviour and brain change. Two clusters (C1 and C7) were associated with depressive and negative psychotic symptoms across adolescence. Associations of these clusters with depressive symptoms replicated in the PPMI dataset. Their coupling with amygdala-striatal maturation suggests that these DNAm signatures index environmentally shaped affective-motivational neurodevelopment.
Papageorgiou G, Ibrahim EC, Gorgievski V
… +13 more, Maxson G, Lozano E, Gordon E, Lefrere A, Toupet MJ, Courtet P, Belzeaux R, Foster J, Carmody T, Perlis RH, Trivedi MH, Tzavara ET, Mellios N
Mennesson M, Abdelkaoui S, Roullot-Lacarrière V
… +12 more, Tronel S, Cathala A, Lalanne V, Raux PL, Makrini L, Valjent E, Duffaud AM, Claverie D, Vallée M, Desmedt A, Trousselard M, Revest JM
Post-traumatic stress disorder (PTSD) is a severe stress-related psychiatric condition triggered by traumatic life-threatening events, characterized notably by an altered memory profile. Although clinically well-document...Post-traumatic stress disorder (PTSD) is a severe stress-related psychiatric condition triggered by traumatic life-threatening events, characterized notably by an altered memory profile. Although clinically well-documented, no specific biomarker exists. This translational study identifies plasminogen activator inhibitor-1 (PAI-1) as a brain risk factor for PTSD, thereby supporting its potential as a blood-derived biomarker. Mice with genetically ablated PAI-1 were protected from developing a PTSD-like memory profile. Conversely, mice exhibiting PTSD-like cognitive impairment showed increased blood PAI-1 levels, correlating with their profile severity. In the brain, PAI-1 levels were specifically increased in the dorsal hippocampus, a key region for cognitive functions and in the etiology of PTSD. Finally, a longitudinal study of soldiers revealed that those developing PTSD symptoms exhibit rising blood PAI-1 levels over a 12-month period. Its significant association with various indicators of PTSD-related psychological distress attests to PAI-1's potential as a blood biomarker and brain therapeutic target for PTSD.
Taylor JJ, Li J, Lin C
… +19 more, Jones E, Frandsen S, Becker CR, Drew W, Haj-Darwish D, Jabbour S, Leach J, Palm S, Sanderson L, Santos E, Sterina L, Chiulli N, Miller J, Barantono S, Gonsalvez I, Lyndon S, Snider SB, Fox MD, Siddiqi SH
Mol Psychiatry
· 2026 Mar · PMID 41912790
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Full text
Transcranial magnetic stimulation (TMS) is effective for major depressive disorder (MDD) and anxious depression despite imprecise scalp-based targeting. Retrospective connectomics analyses suggest that targeting one brai...Transcranial magnetic stimulation (TMS) is effective for major depressive disorder (MDD) and anxious depression despite imprecise scalp-based targeting. Retrospective connectomics analyses suggest that targeting one brain circuit preferentially improves "dysphoric" symptoms, while targeting a different brain circuit preferentially improves "anxiosomatic" symptoms. Here, we tested this hypothesis prospectively by randomizing adults with MDD (n = 40, age 18-65) who had moderate-to-severe symptoms of depression (Beck Depression Inventory (BDI) ≥ 20) and anxiety (Beck Anxiety Inventory (BAI) ≥ 16) to a 30-treatment TMS course at the dysphoric circuit target (MNI coordinates [-32, 44, 34], close to the conventional left dorsolateral prefrontal cortex target for MDD), or at the anxiosomatic circuit target (MNI coordinates [0, 48, 46], a dorsomedial target not routinely used). As hypothesized, dysphoric circuit targeting (n = 16) improved BDI more than BAI (ratio 1.08, IQR 0.69-2.02), while anxiosomatic circuit targeting (n = 20) improved BAI more than BDI (ratio 0.70, IQR 0.01-1.01) (Wilcoxon rank-sum test p = 0.0195). Both targets improved BDI (55 vs 54%), but BAI improved significantly more with anxiosomatic circuit targeting (58 vs 36%, p = 0.0301), even when controlling for BDI (p < 0.001). Thus, TMS targeting different connectome-derived brain circuits differentially modulates anxiety that is comorbid with major depressive disorder. Future studies could target according to baseline symptom profile, a step toward precision psychiatry. Trial Registration Number NCT04604210.
Sleep disturbances and altered sensory processing are key features of neurodevelopmental and neuropsychiatric disorders (NDDs/NPDs). Clinical assessments of brain function in these conditions reveal increased connectivit...Sleep disturbances and altered sensory processing are key features of neurodevelopmental and neuropsychiatric disorders (NDDs/NPDs). Clinical assessments of brain function in these conditions reveal increased connectivity between the thalamus and cortical areas, alongside changes in restorative sleep patterns that rely on thalamic function, like decreased sleep spindle density and slow-wave oscillations. To assess the role of individual thalamic nuclei in such impairments, we activated thalamic nuclei within three different thalamocortical circuits in rats using the chemogenetic receptor hM3Dq. Activation of the mediodorsal thalamic (MDT) nuclei impaired restorative sleep by reducing spindle density and slow-wave oscillations, recapitulating phenotypes associated with NDDs/NPDs. Conversely, activating ventral posterior thalamic (VPT) and ventromedial thalamic (VMT) nuclei increased wakefulness, reducing sleep spindle density and alpha/beta band power during sleep. To examine downstream network effects, we used perfusion-based pharmacological MRI; MDT activation significantly modulated neural activity in MDT and interconnected regions, including prelimbic cortex and thalamic nuclei. Finally, we tested whether pharmacologically increasing inhibition in the thalamus using the GABAδ agonist gaboxadol and positive allosteric modulator DS-2, could counter phenotypes driven by thalamic hyperactivity. Gaboxadol partially normalized the balance between light and deep NREM sleep in the MDT-hM3Dq group, and in VPT- and VMT-hM3Dq animals, partially normalized resting-state oscillations but failed to rescue sleep physiology. DS-2 had minimal effects across groups. Collectively, our findings reveal that thalamic nuclei-specific activation impacts restorative sleep, and that this thalamocortical circuit model may provide valuable insights into the neural mechanisms underlying dysfunctions associated with NDDs/NPDs and neuropsychiatric conditions.
Substantial asymmetries of motor dysfunction are evident in patients with Parkinson's disease (PD), the mechanisms of which remain largely unexplored. This study investigated how deep brain stimulation (DBS) targeting th...Substantial asymmetries of motor dysfunction are evident in patients with Parkinson's disease (PD), the mechanisms of which remain largely unexplored. This study investigated how deep brain stimulation (DBS) targeting the globus pallidus interna (GPi) and subthalamic nucleus (STN) modulates characteristics of hemispheric lateralization in PD patients, with particular emphasis on motor asymmetries and hemispheric integration (via homotopic functional connectivity) and segregation (via hemispheric asymmetry in connectivity). Resting-state functional magnetic resonance imaging (fMRI) and Unified Parkinson's Disease Rating Scale (UPDRS) III scores were analyzed from 55 PD patients who underwent either bilateral GPi- or STN-DBS. Both targets produced significant improvements in motor function. Notably, stimulation effects on motor asymmetry depend on patients' baseline asymmetry direction (DBS OFF): STN-DBS consistently reduced asymmetry in the leftward-asymmetry patients, whereas GPi-DBS has stronger effects in rightward patients. In both cases, stimulation led to a more symmetric pattern. Beyond motor outcomes, motor gains were associated with changes in homotopic connectivity in the lateral occipital region, overlapping the extrastriate body area, suggesting a compensatory role of visual networks. These findings highlight the contribution of the visual networks to motor improvement and reveal target-dependent effects of DBS on both motor asymmetry and non-motor cognitive domains.
Kuwabara H, Kojima M, Benner S
… +48 more, Otowa T, Watanabe T, Kuroda M, Owada K, Yassin W, Hamada J, Kano Y, Uno Y, Kushima I, Mori D, Arioka Y, Munesue T, Kasai K, Higashida H, Abe O, Takao H, Wakuda T, Kameno Y, Inoue J, Harada T, Yamauchi A, Ogawa N, Honda N, Kikuchi S, Seto M, Tomita H, Miyoshi N, Matsumoto M, Kawaguchi Y, Kanai K, Ikeda M, Nakamura I, Isomura S, Hirano Y, Onitsuka T, Takahashi N, Nakashima M, Saitsu H, Kondo K, Ikeda M, Iwata N, Shimada M, Sasaki T, Takei N, Ozaki N, Kosaka H, Okada T, Yamasue H
Previous studies suggest that oxytocin has therapeutic potential for modulating core symptoms of autism spectrum disorder (ASD), although findings have been inconsistent. The unknown mechanisms underlying oxytocin's effe...Previous studies suggest that oxytocin has therapeutic potential for modulating core symptoms of autism spectrum disorder (ASD), although findings have been inconsistent. The unknown mechanisms underlying oxytocin's effects and the substantial individual variability in treatment response impede the development of effective oxytocin-based therapies. In this study, we conducted a genome-wide association study (GWAS) using data from a randomized controlled trial (RCT) that examined the effects of a single dose oxytocin on behavioral and neural correlates of ASD. We further tested the association between the SNP identified in the GWAS and clinical efficacy in an independent, larger dataset comprising participants from three additional RCTs. In these trials, males with high-functioning ASD received repeated doses of oxytocin, and treatment response was assessed using the social reciprocity domain of the Autism Diagnostic Observation Schedule (ADOS), the common primary outcome across all three studies. The GWAS identified a significant association between oxytocin-induced improvements in medial prefrontal cortex activity during a social judgment task and the single nucleotide polymorphism (SNP) rs1871303 in the ryanodine receptor 2 (RYR2) gene (β = 2.37, t = 7.82, df = 72, P = 3.47 × 10⁻⁹). The validation analysis supported the association between this RYR2 SNP and individual variability in ADOS reciprocity improvement (β = 0.194, t = 2.30, df = 135, P = 0.023), with no significant association observed for placebo response (P > 0.1). To our knowledge, this is the first GWAS to investigate the pharmacogenomics of oxytocin efficacy in ASD. These findings highlight RYR2 as a key gene influencing oxytocin response, possibly through its role in calcium channel signaling and regulation of endogenous oxytocin release.
Etyemez S, Sivananthan R, Faria AV
… +23 more, Iasevoli F, Pontillo G, Di Giorgio A, Chung YC, Kim WS, Odkhuu S, Kwon JS, Kim M, Ha M, Georgiadis F, Milano BA, Kirschner M, Kaiser S, Tordesillas-Gutiérrez D, Sim K, Tan Y, Chan SKW, Turner JA, van Erp TGM, Lee J, Calhoun VD, Sawa A, Yang K
Treatment-resistant schizophrenia (TRS) poses a considerable challenge in psychiatric care, with approximately 10-60% of patients exhibiting non-responsiveness to antipsychotic medication. While early treatment could imp...Treatment-resistant schizophrenia (TRS) poses a considerable challenge in psychiatric care, with approximately 10-60% of patients exhibiting non-responsiveness to antipsychotic medication. While early treatment could improve clinical outcomes, the absence of objective biomarkers hinders timely intervention. General structural changes have been suggestively associated with TRS. However, there is a lack of clear and robust conclusions due to challenges in obtaining data from TRS cases with large sample sizes. To address this knowledge gap, we collaborated with Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium to investigate brain structural changes associated with TRS. Leveraging data from multiple institutions spanning various continents and ethnic groups, our meta- and mega-analysis revealed a significant reduction in the volume of bilateral putamen and bilateral hippocampus, as well as the left superior frontal gyrus (SFG) surface area in TRS patients compared with non-TRS patients with sufficient statistical power. Further analysis, incorporating data from healthy controls (HCs), unveiled a decreasing trend in bilateral hippocampal volumes and left SFG surface area from HCs to non-TRS patients and further to TRS patients. There were no significant effects of either clozapine dose or cumulative antipsychotic exposure on bilateral hippocampal volumes or left SFG surface area. In contrast, the putamen volume exhibited an increase in non-TRS patients compared with HCs, with no significant difference between TRS patients and HCs. Antipsychotic exposure was significantly correlated with the putamen volume with small effect size. In conclusion, this study underscores the volume of the hippocampus and SFG as potential biomarkers for TRS.
Individual differences in fear extinction learning are centrally involved in anxiety vulnerability. We here investigate individual extinction differences using a model-free, data-driven approach, by applying Latent Class...Individual differences in fear extinction learning are centrally involved in anxiety vulnerability. We here investigate individual extinction differences using a model-free, data-driven approach, by applying Latent Class Growth Modeling (LCGM) to four in-house data sets from altogether N = 234 healthy male participants. This revealed two distinct trajectory classes: fast extinguishers and slow extinguishers. This pattern was replicated in two independent public data sets (total N = 275, female and male). In a subset of the in-house samples with functional magnetic resonance imaging (fMRI) data (n = 122 males), we investigated the neural correlates of class membership, focusing on the ventral striatum (VS), a key area previously implicated in encoding extinction prediction errors (EPE). We found that fast extinguishers exhibited VS activity at the time of unconditioned stimulus omission early in extinction, consistent with an EPE signal, whereas this signal only appeared late in extinction in slow extinguishers. These findings suggest that extinction success is shaped by how the VS learns safety.
Extracellular adenosine triphosphate (ATP) dysregulation has been implicated in the pathogenesis of major depressive disorder. However, the mechanisms underlying ATP deficiency in the medial prefrontal cortex (mPFC) unde...Extracellular adenosine triphosphate (ATP) dysregulation has been implicated in the pathogenesis of major depressive disorder. However, the mechanisms underlying ATP deficiency in the medial prefrontal cortex (mPFC) under stress conditions remain unclear. Here, we found that only stress-susceptible mice exhibited deficiencies in both the basal ATP levels and reward task-evoked ATP release, and these deficits could be reversed by treatment with fluoxetine. We also observed specific downregulation of Slc17a9, a gene encoding the vesicular nucleotide transporter (VNUT), in the mPFC of stress-susceptible mice. Conditional knockout of Slc17a9 in neurons (n-cKO), but not in astrocytes was sufficient to induce depressive-like behaviors following subthreshold social defeat stress (SSDS), accompanied by decreased basal extracellular ATP levels and impaired reward-evoked ATP release in the mPFC. Similar deficits were reproduced by specific knockdown of Slc17a9 in BLA neurons. Notably, these behavioral deficits were reversed by microinjection of the nonhydrolyzable ATP analogs (ATPγS) into the mPFC. Furthermore, we demonstrated that the BLA-mPFC pathway bidirectionally regulated depressive-like behaviors via ATP release following SSDS. Overall, our study provides evidence that ATP release modulates susceptibility to social stress in a circuit-specific manner and highlights the essential role of stress-induced ATP deficiency in the pathogenesis of depression.
Recent research suggests that brain anatomy may help identify the most effective pharmacological treatment for each individual with bipolar disorder and reduce trial-and-error prescribing. We aimed to investigate whether...Recent research suggests that brain anatomy may help identify the most effective pharmacological treatment for each individual with bipolar disorder and reduce trial-and-error prescribing. We aimed to investigate whether brain anatomy predicts whether a medication is currently prescribed or has been discontinued, as a proxy for treatment effectiveness. The rationale is that medications that provide clinical benefit without unacceptable side effects are likely to be continued, whereas those with limited benefit or poor tolerability are typically discontinued. We used T1-weighted MRI from twelve ENIGMA-BD cohorts (n = 2462; 473 individuals with BD [61% female, age 18-73] and 1989 controls) to derive regional cortical thickness and surface area and subcortical volumes. Site differences were harmonized using ComBat models fitted on controls' data. Within cross-validation, models were trained to first adjust for cumulative dose and other covariates and then predict medication status. On test sets, current prescription (vs. discontinuation) of lithium was predicted by greater cortical thickness and reduced surface area, whereas current prescription (vs. discontinuation) of antidepressants and atypical antipsychotics was predicted by greater cortical thickness. Predictive regions for atypical antipsychotics were generally consistent across subgroups of age, gender, illness duration, and history of psychosis, and in the largest site, and differed from those associated with cumulative effects of medication on the cortex. Predictions were poor for subcortical volumes and for antiepileptic mood stabilizers and typical antipsychotics. These findings provide preliminary support that cortical anatomy may help inform future development of biomarkers for treatment selection, pending validation in longitudinal studies.
Brain-derived neurotrophic factor (BDNF) has been firmly implicated in the synaptic plasticity of neurons in the central nervous system (CNS), which make BDNF as an important regulator of memory and emotion. In this revi...Brain-derived neurotrophic factor (BDNF) has been firmly implicated in the synaptic plasticity of neurons in the central nervous system (CNS), which make BDNF as an important regulator of memory and emotion. In this review we will discuss our knowledge about the multiple intracellular signaling pathways activated by BDNF, and the regulation of intracellular trafficking of BDNF/TrkB in synaptic plasticity, memory and emotion. Alternations in BDNF/TrkB trafficking has been shown to be involved in memory deficits and mood disorders. Future studies could explore targeting the regulation of BDNF/TrkB trafficking to devise BDNF-based therapeutics for human memory and mood disorders.
Wu J, Zhou X, Luo T
… +18 more, Wang X, Zuo H, Yang R, Tian R, Wu Y, Wu Y, Jiang W, Wang Y, Yang J, Huang Y, Zhang J, Li Y, Liu P, Tan X, Yuan M, Wong ML, Licinio J, Zheng P
Major depressive disorder (MDD) is a major psychiatric condition associated with neuroimmune dysregulation. Microglia, the principal innate immune cells of the central nervous system, have been implicated in MDD. Neverth...Major depressive disorder (MDD) is a major psychiatric condition associated with neuroimmune dysregulation. Microglia, the principal innate immune cells of the central nervous system, have been implicated in MDD. Nevertheless, the specific subpopulations involved and the mechanisms that govern their responses are still elusive. Here, we found that gut microbiota intervention using bedding from control non-stressed mice reverses chronic unpredictable mild stress (CUMS)-induced alterations in behavior. Using CD45 immune cell sorting and single-cell RNA sequencing (scRNA-seq), we built an atlas of brain-resident microglia and non-microglial immune cells in the central and peripheral compartments. CUMS primarily induced transcriptional alterations in microglia and monocytes, while the reversed changes induced by bedding exchange mainly detected in microglia (85%). Among the microglial subtypes, homeostatic microglia 2 (HM2) primarily responded to CUMS. HM2 shaped microglial states through activation trajectory: the HM2→chemokine-related microglia 3→inflame microglia 1, which could be reversed by bedding exchange. Brain Mdcs served as the mainly immune cells interact with microglia. Furthermore, we systematically characterized alterations in the myeloid-derived cells across the brain, skull, and peripheral blood mononuclear cells (PBMC). Meanwhile, CUMS disrupted immune cell differentiation by suppressing chromatin openness in global accessibility sequencing analyses, and Krüppel-like factors Klf2 emerged as a master regulator expressed in monocytes and HM2 microglial subtype. Remarkably, microbiota remodeling partially reversed this epigenetic dysregulation, restoring immune cell migration and activation processes. In summary, this study revealed that gut microbiota intervention ameliorates depressive phenotypes by dynamically reprogramming microglia via the "periphery-CNS immune" axis, providing a novel entry for antidepressant strategies targeting neuro-immune interactions.
Hakimi N, Chou KP, Stewart JL
… +2 more, Paulus MP, Smith R
Mol Psychiatry
· 2026 Mar · PMID 41882257
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Full text
Depression and anxiety are common, highly co-morbid conditions associated with maladaptive learning and decision-making processes. While the computational mechanisms underlying these deficits have received growing attent...Depression and anxiety are common, highly co-morbid conditions associated with maladaptive learning and decision-making processes. While the computational mechanisms underlying these deficits have received growing attention, the transdiagnostic vs. diagnosis-specific nature of these mechanisms remains insufficiently characterized. In this discovery-focused study, we aim to better characterize these mechanisms and generate novel hypotheses. To do so, we employed a commonly used, domain-general decision-making task, combined with computational models of learning, to assess differences in patterns of choice and reaction times in individuals with affective disorders (iADs; i.e., depression with or without co-morbid anxiety; N = 168 and 74, respectively). To establish diagnostic specificity, we further incorporated data from individuals with substance use disorders (iSUDs; N = 147) and healthy comparisons (HCs; N = 54). Computational modeling afforded separate measures of learning and forgetting rates, among other parameters. Bayesian analyses indicated that forgetting rates (reflecting recency bias) were elevated in both iADs and iSUDs compared to HCs (posterior probabilities [pp] = 0.99 and 1, respectively). In contrast, iADs showed faster learning rates for negative outcomes than iSUDs (pp = 0.98), but they did not differ from HCs. Reaction times in iSUDs also showed less sensitivity to uncertainty than both iADs and HCs using model-based metrics. Finally, exploratory dimensional analyses suggested possible links between learning rates for negative outcomes and early adversity. These findings demonstrate two model-based metrics that differentiate iADs from iSUDs (learning from negative outcomes and sensitivity to uncertainty) as well as a third metric (forgetting rate) that appears transdiagnostic, differentiating both disorders from HCs. This pattern of results points to distinct cognitive mechanisms that could inform disease models for each disorder and paves the way for future work investigating their potential clinical utility.
Behavioral regression occurs in approximately 40% of individuals with SHANK3-associated autism spectrum disorder (ASD). We previously reported that significant behavioral regression in a small cohort of patients with SHA...Behavioral regression occurs in approximately 40% of individuals with SHANK3-associated autism spectrum disorder (ASD). We previously reported that significant behavioral regression in a small cohort of patients with SHANK3 haploinsufficiency, triggered by subclinical infections, responded to immunomodulator treatments. We hypothesize that behavioral regression results from the interplay between SHANK3 deficiency and neuroinflammation. Using Shank3 exon 4-22 deletion heterozygous mutant (Sh3) mouse, which shows no significant behavior impairments, we established a preclinical model - Shank3 haploinsufficiency mouse undergoing a systemic inflammation challenge via intraperitoneal injection of lipopolysaccharides (LPS). We found that, two weeks after LPS challenge, wild-type mice (WT) recovered but Sh3 mice exhibited motor impairment, anxiety-like behaviors, and excessive grooming, similar to Shank3 exon 4-22 deletion homozygous mutants. Anti-inflammatory treatment partially reversed LPS-induced behavioral changes. Transcriptomic analysis revealed upregulation of neuroinflammation-related genes and downregulation of synaptic function-related genes in LPS challenged Sh3 mice. Especially, pro-inflammatory genes and microglia markers were overly activated that may result from the increased toll-like receptor 4 (TLR4) in Sh3 mice. Microglia overactivation elevated synapse engulfment and disrupted synaptic protein may underlie LPS-triggered worsen behavior phenotypes in Sh3 mice. Together, our findings indicate that neuroinflammation increases the penetrance of behavioral impairment in Shank3 haploinsufficiency mice and support a potential mechanism for the behavioral regression in human SHANK3 related disorders for future investigations.
Yan Y, Song D, Li G
… +18 more, Li J, Tang Y, Li D, Mao J, Li H, Liu X, Yu D, Ma F, Pang Y, Jin Y, Deng Y, Qiu Y, Quan Z, Ni J, Cheng Y, Wang Z, Dong Z, Hong Q
Olfactory dysfunction has emerged as a promising target for the early diagnosis and treatment of Alzheimer's disease (AD). However, the mechanisms underlying neural circuit disruption associated with olfactory dysfunctio...Olfactory dysfunction has emerged as a promising target for the early diagnosis and treatment of Alzheimer's disease (AD). However, the mechanisms underlying neural circuit disruption associated with olfactory dysfunction in AD remain poorly understood. We conducted single-cell RNA sequencing (RNA-seq) and ex vivo electrophysiological studies to determine the link between olfactory memory in AD and dynamic synaptic transmission disorders in PCx-IL engram cell circuits. Clinical functional magnetic resonance imaging (fMRI) data revealed that connectivity between the piriform cortex (PCx) and the infralimbic cortex (IL) was impaired during the early mild cognitive impairment (MCI) stage of AD. Optogenetic stimulation of IL-projecting PCx engram neurons successfully improved olfactory memory retrieval in 5xFAD mice. In addition, single-cell RNA sequencing was employed to investigate the mechanisms of damage in IL engram cells, which revealed increased glutamate expression and impaired synaptic function as key alterations. Guided by single-cell sequencing data, we analyzed glutamatergic synaptic transmission in the PCx-IL engram cell circuit in 5xFAD mice. These results indicated dynamic impairments in AMPA receptor-associated synaptic transmission within this circuit. Optical long-term potentiation (LTP) of synaptic transmission restored directional engram synaptic transmission and prevented olfactory memory decline. Therefore, dynamic impairment of synaptic transmission in the PCx-IL engram cell circuit underlies the early decline in olfactory memory in AD. Impairment of PCx-IL functional connectivity may represent a new target for the diagnosis and treatment of early-stage AD.
Depression is associated with increased self-harm risk, particularly in the early illness course, yet individualised predictions models remain underexplored. We aimed to develop and externally validate a prediction model...Depression is associated with increased self-harm risk, particularly in the early illness course, yet individualised predictions models remain underexplored. We aimed to develop and externally validate a prediction model for self-harm risk in people with newly-diagnosed-depression. Utilizing a territory-wide electronic health-record (EHR) database spanning Hong-Kong public healthcare services (including all public hospitals, specialists, and general outpatient clinics), we identified individuals aged ≥12 years with first-diagnosed depression between 1-January-2002 and 31-December-2021. The primary outcome was non-fatal self-harm and/or completed suicide. We developed 1-year and 3-year self-harm risk prediction models using the least absolute shrinkage and selection operator (LASSO) method and backward regression model. This population-based cohort comprised 102,863 individuals with newly-diagnosed-depression (mean age 48.22 [SD 17.78] years; 71.5% female), 2678 self-harm incidents occurred over 98,807.5 person-years (rate: 27.09 [95%CI 26.1-28.1] per 1000 person-years). Key predictors included history of self-poisoning/self-inflicted injury, past psychiatric hospitalisation, comorbid somatoform and conversion disorders, and substance use disorders, while use of lithium and antidepressants represented protective factors. In external validation cohort (n = 14,843), our model achieved good discrimination (C-statistics = 0.83 [95%CI 0.80-0.85], D = 2.35 [2.17-2.53]), near-perfect calibration (calibration slope =1.00 [0.94-1.06], O/E ratio = 1.00 [0.90-1.10]), and high accuracy (brier score = 0.02 [0.02-0.02]). Performance remained robust in age, sex-stratified subgroups and 1-year vs. 3-year self-harm prediction windows. This validated model leverages EHR data to accurately identified individuals at elevated self-harm risk post-depression diagnosis, may tailor individual-level risk estimates and facilitate timely interventions, thereby potentially averting risk escalation, in the critical window of heightened self-harm risk.