搜索结果：Molecular psychiatry

Schizophrenia is increasingly conceptualized as a disorder of large-scale brain network organization arising from atypical neurodevelopment. However, the relationship between early-emerging cortical folding patterns and the maturation of the structural connectome remains poorly understood. We introduced a sulcal morphology-centered framework that integrated normative modeling of sulcal width with diffusion-derived structural connectivity and cortical transcriptomics in a large multisite cohort (n=5,392; 377 schizophrenia). Deviations from normative folding patterns were mapped to the structural connectome and the Allen Human Brain Atlas. Individuals with schizophrenia exhibited widespread sulcal widening (30/40 sulci), primarily in frontal, temporal, and occipital regions. Nodal vulnerability followed a clear topological principle: sulci with higher degree centrality (sulcal network hubs) showed disproportionately greater widening (pspin=0.02). Transcriptomic integration identified a gene expression profile explaining 56.5% of the spatial variance in sulcal abnormalities (p ​=0.049). This profile was significantly enriched for synaptic signaling and energy metabolism genes, showed adult-onset expression bias, and was associated with common cross-disorder genetic risk. Conversely, genes with the opposite spatial weight showed significant prenatal expression bias and enrichment for rare disruptive variants associated with autism spectrum disorder. These findings demonstrate that aberrant cortical folding in schizophrenia is constrained by network topology and molecular architecture. By linking macroscopic folding to metabolic and synaptic pathways, this work establishes sulcal morphology as a mechanistically grounded biomarker that may help differentiate the neurodevelopmental trajectories of psychiatric disorders.

Evidence has accumulated that youth, the period between 12-25 years, may constitute a crucial period for the early detection and intervention of mental disorders. Thus, there is emerging evidence that targeted psycho-social and pharmacological interventions have potential to improve clinical outcomes in at-risk individuals as well as in youths with a first-episode of mental illness. However, while support for the early intervention paradigm has gained momentum, an explanatory framework for the emergence of mental disorders as well as for the mechanisms of preventive interventions is currently not available. Here, I will outline a neurobiology of early intervention that will highlight the importance of linking emerging psychopathology with developmental neuroscience and systems biology. Specifically, I will propose that critical periods during late brain development in combination with environmental exposures could account for the elevated occurrence of psychosis, affective disorders, substance abuse and personality disorders. In addition, the neurobiological mechanisms underlying critical periods could be important for understanding the potential of preventive interventions and the identification of biomarkers. Together, a neurobiological grounding of early intervention could provide a conceptual and empirical framework to advance early detection and prevention of mental disorders during youth.

Cellular homeostasis relies on regulation of processes, including protein post-translational modifications (PTMs) and biomolecular condensation. Aging disrupts the equilibrium of these processes, increasing susceptibility to disease and mortality. Here we used chemoproteomic techniques to generate an atlas of cysteine PTMs in the mouse brain and showed that age-related increases in thiol oxidation promoted the formation of biomolecular condensates. By contrast, protein persulfidation, regulated by hydrogen sulfide production, inhibited biomolecular condensation, preserving protein function. Age-induced alterations in cysteine PTMs influenced the phase separation properties of synapsin 1 and G3BP2, leading to impaired neurotransmitter release and defective stress granule formation and resolution, features associated with aging and neurodegenerative diseases. Mice deficient in cystathionine γ-lyase, the enzyme responsible for hydrogen sulfide production, exhibited reduced lifespans and spontaneously developed protein aggregates with age. Our results highlight the therapeutic potential of protein persulfidation in reversal of dysregulated biomolecular condensation and suggest that sulfide donors could be used to mitigate age-related diseases.

Animal models are important tools for investigating the neurobiological mechanisms underlying psychiatric disorders, particularly given the methodological limitations associated with human studies. In bipolar disorder (BD), the development of animal models with adequate translational relevance remains challenging due to the heterogeneous and multifactorial nature of the condition. Among the available models, intracerebroventricular (ICV) administration of ouabain (OUA), an endogenous cardiac steroid and Na+/K+-ATPase inhibitor, has been extensively used to investigate behavioral and molecular alterations in BD. This review summarizes recent evidence on the molecular alterations in the OUA-induced animal model of BD and discusses how these changes may contribute to the behavioral outcomes observed in this model. The available literature indicates that OUA administration induces both manic-like and depressive-like behaviors and, in some cases, mixed states. Also, the model shows a pharmacological response to established treatments, although the effects of antidepressants are more complex. At the molecular level, OUA inhibits Na+/K+-ATPase activity, which could disrupt ionic homeostasis and modulate intracellular signaling pathways. However, alterations in Na+/K+-ATPase activity appear to be region-dependent, with conflicting findings reported in some brain areas (e.g., the hippocampus). Other pathways impacted by OUA include glycogen synthase kinase-3 (GSK-3), protein kinase C (PKC), and extracellular signal-regulated kinase (ERK), although some heterogeneity has been reported, particularly regarding GSK-3 signaling. In addition, OUA administration is associated with alterations in neurotransmitter and neurotrophic signaling, inflammatory mediators, oxidative stress parameters, and cell death-related pathways. In contrast, current evidence does not indicate significant effects on epigenetic enzyme activity, with limited evidence. Taken together, these findings support the utility of the OUA model as an experimental approach to investigating biological mechanisms underlying the pathophysiology of BD.

The discovery of potentially many hundreds of risk genes for schizophrenia does not resolve the mystery of the illness at the level of an individual. The diversity of implicated gene functions has encouraged speculation that there are convergent biological pathways that mediate risk at the systems level, perhaps represented in gene coexpression patterns. The authors emphasize that gene coexpression varies across development, with some molecular elements related to schizophrenia risk losing importance or gaining momentum over time. The systems biology of risk and environmental exposures associated with risk are both time-dependent. The authors propose that the dynamic gene-environment interplay subtended by shifting coexpression patterns may explain variable expressivity of genetic risk during development. In particular, gene-environment correlations provide a mechanism for the individual-hence for their genes-to affect the environment and thus individual experience, promoting chains of life events. The authors envision the paired study of molecular and behavioral patterns over time as a way to identify novel treatments and preventive strategies to change the course of schizophrenia.

Major depressive disorder (MDD) remains a critical global health burden, and a substantial proportion of patients exhibit insufficient responses to conventional monoaminergic antidepressants. Selective inhibition of the two-pore domain potassium channel TREK1 has emerged as a promising antidepressant strategy; however, the regulatory mechanisms controlling TREK1 trafficking-particularly its functional coupling with G protein-coupled receptors (GPCRs)-remain poorly understood. Here, we established a cell-based screening platform using a biomolecular luminescence complementation (BiLC) assay to monitor agonist-induced changes in membrane-associated TREK1. Using this platform, we identified a TREK1-5-hydroxytryptamine receptor 4 (HTR4) complex in vitro and in native hippocampal tissues using biomolecular fluorescence complementation (BiFC), co-immunoprecipitation (Co-IP), and proximity ligation assays (PLA). Live-cell imaging demonstrated that treatment with the HTR4 agonist mosapride induces redistribution/internalization of a plasma membrane-associated TREK1-HTR4 pool into intracellular compartments. Electrophysiological recordings further confirmed that mosapride reduces TREK1 channel activity in an HTR4-dependent manner. In vivo, oral administration of mosapride for five days ameliorated lipopolysaccharide (LPS)-induced depressive-like behaviors in mice and preserved markers associated with hippocampal neurogenesis. Notably, viral expression of the TREK1 C-terminal interaction domain (C1), which competitively disrupts the TREK1-HTR4 complex, attenuated the neurogenic and behavioral effects of mosapride, supporting a causal role of TREK1 regulation in mediating these antidepressant-like actions. Collectively, our findings reveal a previously unrecognized mechanism in which HTR4 dynamically regulates TREK1 trafficking and function, and they highlight GPCR-based modulation of TREK1 as a potential therapeutic strategy for depressive disorders.

Methicillin-resistant Staphylococcus aureus (MRSA) remains a major clinical challenge, particularly intracellular MRSA infections are difficult to treat because antimicrobial agents must combine stability, host-cell access and bacterial target engagement. Cyclotides offer highly stable cyclic scaffolds for peptide engineering, but their use as intracellular antimicrobial protein inhibitors remains largely unexplored. Here, we engineered a cyclotide-grafted derivative of the antimicrobial peptide KTR by inserting it into the MCoTI-I scaffold, generating the cyclic construct MCo-KTR2. Molecular docking and molecular dynamics suggested potential interactions between MCo-KTR2 and the resistance-associated penicillin-binding protein PBP2a. Site-directed mutagenesis and fluorescence polarization assays indicated that specific residues contribute to binding in vitro. Although MCo-KTR2 displayed lower activity than linear KTR in standard MIC assays, cyclotide grafting increased serum stability by more than 30-fold and enhanced cellular uptake, colocalising with cytosolic S. aureus during infection. These properties were associated with improved activity against intracellular bacteria without detectable cytotoxicity or haemolytic activity. Furthermore, MCo-KTR2 showed higher antibacterial activity when combined with the membrane-active compound Visomitin as well as in combination with vancomycin and gentamicin. Together, these findings identify cyclotide grafting as a strategy to improve peptide stability and intracellular delivery, and support MCo-KTR2 as a scaffold for further optimization against intracellular MRSA infections.

Infectious oral diseases represent the most prevalent categories of oral conditions, including dental caries, periodontitis, periapical lesions, and pericoronitis. Their bidirectional relationship with mental health has emerged as a critical interdisciplinary research frontier. This paper integrates epidemiological findings and molecular mechanism evidence to analyze the significant comorbidity and correlation characteristics between infectious oral diseases such as caries and periodontitis, and psychological disorders including depression and anxiety. Oral diseases not only directly impair mental well-being through pain, functional impairment, and social anxiety, but also induce systemic inflammatory responses that disrupt the blood-brain barrier, activate microglia, and alter neurotransmitter metabolism, thereby contributing to functional dysregulation within emotional regulatory centers. The dysbiosis of the oral microbiota caused by infectious oral diseases plays a central role in the vicious cycle of "oral infection-mental health disorders" through the"oral-gut-brain axis", inflammation-mediated neuroimmune cascades, and hypothalamic-pituitary-adrenal axis dysregulation. Meanwhile, mental disorders exacerbate oral microbial imbalance and tissue destruction through poor oral hygiene behaviors, xerostomia induced by psychotropic medications, and stress-related neuroendocrine alterations. This paper advocates for synergistically integrate oral clinical interventions with mental health improvement strategies, and for the development of microbiome-targeted precision modulation approaches. It further proposes an integrated health management paradigm that bridges dentistry and psychiatry, providing both theoretical foundations and practical pathways to transcend traditional disciplinary boundaries and achieve holistic oral-mental co-management. 口腔感染性疾病是发病率较高的一类口腔疾病，以龋病、牙周病、根尖周病、冠周炎为代表，其与心理疾病的双向关联已成为跨学科研究的重要前沿。本文整合了流行病学与分子机制研究证据，分析龋病、牙周炎等口腔感染性疾病与抑郁、焦虑障碍等心理健康问题之间存在的显著共病关系与相关性。口腔疾病不仅通过疼痛、功能障碍与社交焦虑直接损害心理健康，还可能诱发系统性炎症反应，通过破坏血脑屏障、激活小胶质细胞及改变神经递质代谢直接参与情绪调节中枢的功能紊乱。口腔感染性疾病所致的口腔菌群稳态失衡，可通过“口腔-肠-脑轴”、炎症介质驱动的神经免疫炎症级联反应以及下丘脑-垂体-肾上腺轴功能紊乱等在“口腔感染性疾病-心理健康障碍”恶性循环中起到核心作用。同时，心理疾病可通过口腔卫生行为退化、精神类药物所致口干症及应激相关神经内分泌改变，显著加剧口腔菌群失调与组织破坏。本文提出应推动口腔临床干预与心理健康改善的协同，发展以微生物组为靶点的精准调控策略，构建融合口腔医学与精神医学的综合健康管理范式，为突破传统单科诊疗局限、实现口-心共治提供理论依据与实践路径。.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Familial AD accounts for less than 1% of cases, while sporadic AD (SAD) accounts for over 95%. Mild cognitive impairment (MCI) is the critical transition phase from normal aging to AD dementia. Understanding the pathological progression from MCI to AD and the mechanisms underlying SAD is essential. Rodent models, including transgenic and non-transgenic models, are vital tools for developing effective AD therapies. However, transgenic models primarily mimic familial AD and poorly replicate MCI and the complex pathological features of SAD. Non-transgenic models address these limitations by incorporating genetic, environmental, and aging factors, thereby better simulating SAD complexity. In addition, non-transgenic models are valuable for studying the compensatory mechanisms within neural networks that preserve cognitive function despite early pathology during MCI. In this review, we provide a comprehensive summary of non-transgenic rodent models used in AD and MCI research. First, we detail modeling strategies, including agents, administration routes, and dosages. Next, we discuss evaluation methods, such as behavioral and molecular assessments. We emphasize the importance of electrophysiological data, such as long-term potentiation, for evaluating cognition. Finally, we discuss the advantages and limitations of these non-transgenic models. This review may serve as a reference for selecting models to study the progression from MCI to AD and to develop related therapeutics. Combining non-transgenic and transgenic models more accurately replicates the complex, multifactorial pathology of the disease.

Over the past several decades, monoaminergic system dysfunction has been considered a key factor in the pathophysiology of some mental disorders. However, the therapeutic efficacy of drug therapy based on the monoamine hypothesis is unsatisfactory. In 2008, FDA approved the application of the repetitive transcranial magnetic stimulation (rTMS) for the treatment of patients with depression. Since then, TMS as a non-invasive neuromodulation technique, has been widely used to treat patients with mental disorders and assess their brain functions. This review article outlined the stimulation modes and parameter settings of TMS, summarized the therapeutic effects of TMS on main mental disorders such as depression, bipolar disorder (BD), schizophrenia, attention deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), and synthesized the cellular and molecular mechanisms of its therapeutic effects for the mental disorders mainly based on preclinical research. These mechanisms involve pathophysiological processes such as neurotransmitter expression, neuroinflammation, neurotrophic factor production, oxidative stress, and gene expression related to brain plasticity and apoptosis in the brain. Furthermore, it introduced the emerging applications that combine TMS with other non-invasive neuroimaging techniques to assess brain function, including mapping neural pathways, measuring cortical excitability, and evaluating brain neuroplasticity. These advances have facilitated real-time evaluation of the therapeutic efficacy of TMS and optimized its application in treating mental disorders.

Rare and undiagnosed genetic disorders affect millions of patients globally, and many patients endure years of inconclusive testing. Conventional genomic interpretation can be insufficiently sensitive and costly and is rarely repeated as knowledge evolves. We conducted a retrospective multicohort reanalysis using a large language model (LLM)-assisted workflow that ingests clinician notes, Human Phenotype Ontology (HPO) terms, and a filtered variant table to propose explanation-rich candidate hypotheses for expert adjudication under American College of Medical Genetics and Genomics and Association for Molecular Pathology criteria. A diagnosis was defined a priori as a variant classified as pathogenic or likely pathogenic, confirmed in a Clinical Laboratory Improvement Amendments-certified laboratory, and returned to families. Secondary outputs included "rediscoveries" of externally established diagnoses not yet available locally and hypothesis generation signals. Across four cohorts, new local diagnoses were made in 10 of 100 rare disease neurodevelopmental cases (10.0%, [exact binomial: 95% confidence interval (CI), 4.9 to 17.6]), 4 of 61 neuromuscular cases (6.6%, [CI, 1.8 to 16.0]), 2 of 200 cases of sudden unexpected death in pediatrics (1.0% [CI, 0.1 to 3.6]), and 2 of 15 early psychosis cases (13.3% [CI, 1.7 to 40.5]) for an overall diagnostic yield of 18 of 376 (4.8%, [CI, 2.9 to 7.5]). We identified seven rediscoveries in which pathogenic or likely pathogenic findings had been established externally but were not available in the local research record at the time of review. In one case, the model's synthesis of genotype-quality patterns and phenotype concordance triaged a putative 22q11.2 deletion that was subsequently confirmed by whole-genome sequencing. The workflow also generated testable biological hypotheses, including a candidate association between the sphingosine-1-phosphate receptor 1 gene (S1PR1) and vitiligo. In retrospective reanalysis, an explanation-first LLM applied to routine HPO terms and variant tables produced clinically relevant gains in diagnostic yield, surfaced overlooked pathogenic findings, and generated biologically grounded hypotheses. These results motivate prospective multicenter evaluation with predefined end points, calibration reporting, and comparator baselines. (Funded by the U.S. National Institute of Child Health and Human Development and others.).

Since cannabis use (CU) has increased substantially worldwide, understanding the neurobiological mechanisms differentiating CU from cannabis use disorder (CUD) has important public health implications. Leveraging genome-wide data available from UK Biobank, International Cannabis Consortium, the Psychiatric Genomics Consortium, and the Million Veteran Program, we characterized the pleiotropy differentially linking brain structural and functional variation to CU and CUD. Specifically, we conducted linkage disequilibrium score regression, local analysis of [co]variant association, and latent causal variable analysis. Distinct patterns of global genetic correlations were observed, where CU was specifically related to default mode network-related functional activity and the functional connectivity between default mode and central executive networks, while CUD was related to functional connectivity linking default mode and salience networks and with white matter microstructure. Latent causal variable analyses suggested partial genetic causality differentially linking the functional connectivity among salience, default mode, and central executive networks to CU and CUD. Local genetic correlation analyses further identified CU and CUD-specific shared genetic architecture with brain variation related to genes involved in neurodevelopment, chromatin regulation, synaptic signaling, and white matter biology. Through gene-set enrichment analyses, we identified pathways related to brain variation converging on inflammatory response and cell activation for CU, and on cellular stress-response and immune regulation for CUD. Applying gene2drug framework, our drug-repurposing analyses identified nine molecular compounds, also including raloxifene (a cannabinoid-receptor 2 inverse agonist) and albendazole (reported to interact with cannabis smoking). Overall, these findings provide new insights into the neurobiological pathways underlying CU and its progression to CUD.

Metabolic pathways are increasingly recognized as tractable targets in aging and disease. Building on prior work demonstrating that supplementation with low-molecular weight metabolites (amino acids, vitamins, and their intermediates) can extend lifespan in Caenorhabditis elegans, we focused on pantothenate (vitamin B5), which is dysregulated in sarcopenic muscle and in several neurodegenerative and metabolic disorders. Pantothenate is the obligate precursor of coenzyme A through a short, highly conserved biosynthetic pathway in which loss-of-function mutations can cause neurodegeneration with brain iron accumulation. In C. elegans, the longevity curtailing transcription factor DAF-16/FOXO has a conserved binding element in the promoter region of pnk-1, encoding the first enzyme (PNK-1) in the coenzyme A pathway, and pnk-1 is markedly upregulated in long-lived daf-2 (insulin/-like receptor) mutants, implicating coenzyme A metabolism in longevity. Here, we demonstrate that CoA levels naturally increase during early life and decrease towards older age in C. elegans. Dietary pantothenate supplementation increases coenzyme A levels with minimal effects on lifespan but systemic effects on lipid metabolism, mitochondrial dynamics, and muscle structure under basal conditions. Under DAF-16-associated stress conditions, including heat and oxidative stress, pnk-1 expression is upregulated and pantothenate supplementation robustly extends lifespan and improves mobility. Finally, we demonstrate dysregulation of daf-16 and pnk-1 expression in amyotrophic lateral sclerosis (ALS) models, in which pantothenate supplementation confers both lifespan extension and cholinergic neuroprotection.

Electroacupuncture (EA) has emerged as a promising alternative therapy for ischemic brain injury, yet its underlying molecular mechanisms remain incompletely understood. This study investigated the neuroprotective effects and epigenetic mechanisms of EA in a mouse model of ischemic stroke. Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in mice. EA was applied at Baihui (GV20) and left Zusanli (ST36) acupoints following surgery. Neurological deficits were assessed, infarct volume was measured by TTC staining, and neuronal damage was evaluated by Nissl staining. RhoGDIα protein expression was determined by Western blot. Global DNA methylation was quantified by ELISA, and promoter-specific methylation of RhoGDIα was examined by quantitative methylation-specific PCR (MSP), and mRNA expression of candidate DNA methyltransferases (DNMTs) and demethylases (TETs) was measured by qPCR. EA alleviated MCAO-induced brain injury, as reflected by improved neurological scores, reduced infarct volume, and attenuated neuronal loss. RhoGDIα expression was downregulated after MCAO and restored by EA treatment. Pharmacological inhibition of RhoGDIα abolished the neuroprotective effects of EA, underscoring its essential role in EA-mediated protection. Mechanistically, MCAO induced hypermethylation of the RhoGDIα promoter, which was reversed by EA, leading to restoration of RhoGDIα expression. Furthermore, co-administration of the DNA methylation inhibitor 5-Azacytidine synergistically enhanced the neuroprotective efficacy of EA. Our findings demonstrate that EA ameliorates ischemic brain injury in association with epigenetic regulation of RhoGDIα via promoter demethylation. This study identifies RhoGDIα as a key mediator of EA-induced neuroprotection and suggests that the DNA methylation-RhoGDIα axis may represent a promising therapeutic target for ischemic stroke.

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by sudden onset obsessive-compulsive disorder (OCD) symptoms in conjunction with other neuropsychiatric manifestations including disturbances in sleep, cognition, and behavior. Studies have revealed high rates of autoimmune and inflammatory markers-as well as comorbid rheumatologic disease-in patients with PANS. While published studies have suggested autoantibodies are common in PANS patients, the molecular targets of these autoantibodies (AAbs) remain poorly characterized. Here, we profile the AAbs in 224 plasma samples taken from 166 PANS patients during periods of active disease, or flares, compared to 83 pediatric healthy controls using custom Luminex microbead panels conjugated with highly curated antigens from common autoimmune diseases as well as cytokines and chemokines. We find that PANS patients exhibit increased prevalence of AAbs against autoantigens known to be targeted in scleroderma and GI/endocrine autoimmune conditions. Furthermore, a subset of PANS patients exhibited AAbs against IFN-λ, an important line of defense against infections at anatomic barriers. Among the 11 tested PANS plasma samples with IFN-λ-binding AAbs, 9 showed detectable inhibition of IFN-λ signaling, and 4 met our predefined stringent threshold for IFN-λ-neutralizing activity, while no tested HC samples met this neutralization threshold. These findings support a link between autoimmunity and PANS, and may provide insight into a potential disease mechanism mediated by immune deficits at barrier surfaces in a subset of patients.

Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive neuronal damage. Incidence rises with age, and early diagnosis is difficult. This study examined DLX6-AS1 clinical relevance and regulatory mechanism in AD, and its interaction with miR-204-5p in AD pathology. It offers new insights into early diagnosis and treatment. A total of 133 AD patients and 105 healthy controls were selected. Their serum levels of DLX6-AS1 and miR-204-5p were analyzed using quantitative polymerase chain reaction. β-amyloid (Aβ)1-42-induced SH-SY5Y neuronal injury and okadaic acid (OA)-induced Neuro-2a tau abnormal phosphorylation models were constructed. The role/function of DLX6-AS1/miR-204-5p axis was then investigated using cell counting kit-8, flow cytometry, western blotting, enzyme-linked immunosorbent assay and a dual-luciferase reporter gene assay. AD patients had higher serum DLX6-AS1 and lower miR-204-5p levels. DLX6-AS1 showed an AUC of 0.838 for AD diagnosis. DLX6-AS1 levels were negatively associated with cognitive function, brain structural integrity, and benign pathology-and positively associated with disease severity, functional impairment, and pathological markers. In AD cell models, DLX6-AS1 was upregulated. Silencing it promoted cell proliferation, reduced apoptosis and oxidative stress, improved mitochondrial and synaptic function, decreased tau phosphorylation, and enhanced microtubule stability and axonal transport. Dual-luciferase assays confirmed direct binding between DLX6-AS1 and miR-204-5p. Co-inhibition reversed the protective effects of DLX6-AS1 silencing. Serum DLX6-AS1 is a potential biomarker for early diagnosis and assessment of AD. It regulates Aβ-induced neuronal damage and tau phosphorylation by targeting miR-204-5p, offering a new mechanism target for AD molecular therapy.

Despite distinct receptor targets, both ketamine and serotonergic psychedelics produce a rapid clinical response and share biological signatures that suggest convergence on common downstream molecular mediators. To identify shared biomarkers of rapid antidepressant response, this study integrated CSF proteomics from healthy volunteers (HVs) who received intravenous ketamine with transcriptomic analyses from induced pluripotent stem cells (iPSCs) derived from participants with treatment-resistant depression (TRD) and HVs; iPSCs were treated with ketamine, its metabolite (2&#x2009;R,6&#x2009;R)-hydroxynorketamine, lysergic acid diethylamide (LSD), or psilocybin. Multimodal clinical characterization (transcriptomics (n&#x2009;=&#x2009;16 TRD; 11 HV), magnetoencephalography (MEG) (n&#x2009;=&#x2009;30 TRD; 25 HV), and plasma cytokines (n&#x2009;=&#x2009;39 TRD; 25 HV) were also performed on TRD and HV participants who received a single dose of intravenous ketamine (0.5&#x2009;mg/kg) or placebo. Conserved immune pathways were identified across CSF and iPSC neurons with interleukin-15 (IL)-15 and monocyte chemoattractant protein-1 (MCP-1) emerging as key regulatory hubs. Transcriptomically, in whole blood, ketamine responders exhibited decreased IL-15 and elevated B-cell signaling pathways at baseline that were reversed post-treatment. At the protein level, plasma IL-7 levels (primary B-cell driver) correlated with baseline MEG gamma power, reaching brain-wide significance across all participants (main effect pFDR&#x2009;<&#x2009;0.05). The association was most pronounced in the TRD participants across subcortical regions (diagnosis x IL-7 pFDR&#x2009;<&#x2009;10-14). Post-ketamine, the TRD IL-7-gamma relationship inverted, paralleling widespread gamma power reductions throughout default-mode network regions (session x IL-7 pclc&#x2009;<&#x2009;0.05). In mixed-effects models, cytokine ratios linked to IL-7/IL-15 signaling predicted antidepressant response (IL-4/interferon gamma (IFN-&#x3b3;) pFDR&#x2009;<&#x2009;0.041) and non-response (MCP-1/IL-7 pFDR&#x2009;<&#x2009;0.009), suggesting that rebalancing within the IL-7/IL-15 axis may contribute to therapeutic efficacy. Clinicaltrials.gov identifier: NCT00088699; NCT02484456.

Perimenopausal women typically face a heightened risk of emotional disturbances, including anxiety and depression. The estrogen decline increases vulnerability to mood disorders, but the molecular mechanisms underlying stress resilience remain unclear. Here, we identify hippocampal neuronal progranulin (PGRN), a secreted neuroprotective glycoprotein, as a key regulator of affective resilience under estrogen-deficient conditions. Ovariectomy (OVX) reduces hippocampal neuronal PGRN expression and induces anxiety- and depression-like behaviors, whereas estradiol supplementation restores both PGRN levels and behavior. Adeno-associated virus (AAV)-mediated overexpression of PGRN alleviates affective deficits across OVX, 4&#x2011;vinylcyclohexene diepoxide (4-VCD)-induced ovarian failure, and natural aging models, while neuronal, but not microglial, Grn deletion exacerbates stress susceptibility. Mechanistically, PGRN restores lysosomal protease activity, normalizes autophagic flux, activates AMP-activated protein kinase (AMPK) phosphorylation, and rescues mushroom spine loss, thereby restoring cellular and synaptic homeostasis. Intracerebral recombinant PGRN rescues OVX&#x2011;induced behavioral deficits, and the blood-brain barrier (BBB)-permeable fragment granulin-E (GRN&#x2011;E) confers similar protection after systemic administration. Collectively, these findings demonstrate that hippocampal neuronal PGRN links estrogen signaling to lysosomal-autophagy pathways and synaptic plasticity, and highlight PGRN or its active fragments as promising therapeutic targets for perimenopausal depression and anxiety.

Alzheimer's disease (AD) is increasingly characterized as a disorder of large-scale brain networks driven by synaptic dysfunction, excitation-inhibition imbalance, and progressive breakdown of hippocampal-cortical communication. While recently developed disease-modifying therapies target molecular pathology, their clinical benefits remain modest, underscoring the need for interventions that target dysfunctional circuits. Neuromodulatory techniques such as transcranial magnetic stimulation, transcranial electrical stimulation, and deep brain stimulation demonstrate safety and act at network/system levels to engage target sites yet are limited by their ability to modulate deep anatomic structures and/or their invasiveness. Focused ultrasound (FUS) offers the distinct capability of modulating cortical and deep subcortical networks noninvasively and with anatomic precision. Preclinical studies demonstrate that FUS neuromodulation can influence mechanosensitive ion channels, synaptic plasticity, neurotrophic signaling, and oscillatory dynamics, with downstream effects on distributed memory networks. Early human investigations similarly suggest FUS neuromodulation can alter functional connectivity within default mode, frontoparietal, and limbic networks. Together, these findings support a framework in which FUS may help reshape pathological network states that emerge prior to irreversible neurodegeneration. Here, we present a narrative review of evidence across neuromodulation approaches to define principles of circuit engagement in AD and discuss a network-based rationale for ultrasound interventions. As an illustration of this framework, we also report preliminary findings from a Phase I pilot study of FUS neuromodulation in amyloid-positive mild cognitive impairment demonstrating safety, tolerability, and measurable modulation of hippocampal connectivity. We conclude mechanistic biomarkers of network response may accelerate translational development and guide future controlled trials.