Neuroimaging-based subtyping is increasingly used to explain heterogeneity in psychiatric disorders. However, the clinical utility of these subtyping efforts remains unclear, and replication has been challenging. Here we examined how the choice of neuroimaging measures influences the derivation of neuro-subtypes and the consequences for clinical delineation. On a clinically heterogeneous dataset (total n = 566) that included controls (n = 268) and cases (n = 298) of psychiatric conditions, including individuals diagnosed with post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), and comorbidity of both (PTSD&TBI), we identified neuro-subtypes among the cases using either structural, resting-state, or task-based measures. The neuro-subtypes for each modality had high internal validity but did not significantly differ in their clinical and cognitive profiles. We further show that the choice of neuroimaging measures for subtyping substantially impacts the identification of neuro-subtypes, leading to low concordance across subtyping solutions. Similar variability in neuro-subtyping was found in an independent dataset (n = 1642) comprised of major depression disorder (MDD, n = 848) and controls (n = 794). Our results suggest that the highly anticipated relationships between neuro-subtypes and clinical features may be difficult to discover.

This study was conducted to clarify patterns of cortico-limbic volume abnormalities in late life depression (LLD) relative to non-depressed (ND) adults matched for amyloid β (Aβ) deposition and to evaluate the relationship of volume abnormalities with cognitive performance. Participants included 116 LLD and 226 ND. Classification accuracy of LLD status was estimated using area under the receiver operator characteristic curve. Twenty-one percent of LLD and ND participants were Aβ positive and the groups did not differ on white matter hyperintensity volume (WMH (logscale); β = 0.12, p = 0.28). Compared to ND, the LLD group exhibited significantly lower bilateral volume in the lateral orbitofrontal cortex, hippocampus, accumbens area, superior temporal lobe, temporal pole, and amygdala after multiple comparison correction (p < 0.009 for all). Cortico-limbic volumes significantly improved classification of LLD beyond demographic characteristics, Aβ status, and WMH (AUC = 0.71, AUC,  = 0.62, AUC difference, 0.09 [0.03 to 0.15]). LLD exhibited poorer performance on measures of global cognition, set shifting, and verbal learning and memory relative to ND. Cognitive function was positively associated with cortico-limbic volumes and these relationships did not differ by group. Secondary analyses with an ND sample additionally matched for Mild Cognitive Impairment (MCI) diagnosis showed a similar but attenuated pattern of volume abnormalities. Overall, our results support LLD as being associated with cortico-limbic volume abnormalities that are distinct from Aβ and white matter pathologies and that these volume abnormalities are important factors associated with cognitive dysfunction in LLD.

A novel radiotracer, [C]SL25.1188, targets monoamine oxidase-B (MAO-B) enzyme, found primarily in astrocytes, which metabolizes monoamines (including dopamine), particularly in subcortical regions. Altered astrocyte function in schizophrenia is supported by convergent evidence from post-mortem, genetic, transcriptomic, peripheral and preclinical findings. We aimed to test whether levels of MAO-B, an index of astrocyte function are low in the living brains of early psychosis and their high-risk states. Thirty-eight participants including antipsychotic-free/minimally exposed clinical participants with first-episode psychosis (FEP), clinical high-risk (CHR) individuals and healthy volunteers (HVs) underwent a 90-min positron emission tomography (PET) scan with [C]SL25.1188, to measure MAO-B V, an index of MAO-B concentration. Participants were excluded if tested positive on urine drug screen (except for cannabis). This study of 14 FEP (mean[SD] age, 25.7[5.7] years; 6 F), 7 CHR (mean[SD] age, 20.9[3.7] years; 4 F) and 17 HV (mean[SD] age, 31.2[13.9] years; 9 F) demonstrated significant group differences in regional MAO-B V (F = 4.56, p = 0.02, Cohen's f = 0.49), controlling for tobacco (F  = 5.37, p = 0.03) and cannabis use (F = 5.11, p = 0.03) with significantly lower MAO-B V in CHR compared to HV (Cohen's d = 0.99). We report a significant cannabis effect on MAO-B V (F = 12.57, p = 0.001, Cohen's f = 0.57), with a significant group-by-cannabis interaction (F = 3.82, p = 0.03, Cohen's f = 0.45), indicating lower MAO-B V in cannabis-using clinical groups. Lower MAO-B V levels were more robust in striatal than cortical regions, in both clinical groups (F = 2.08, p = 0.04, Cohen's f = 0.73) and in cannabis users (F = 6.42, p < 0.001, Cohen's f = 0.91). Lower MAO-B concentration supports astrocyte dysfunction in cannabis-using CHR and FEP clinical populations. Lower MAO-B is consistent with replicated striatal dopamine elevation in psychosis, as well as astrocyte dysfunction in schizophrenia.

Adult neural stem and progenitor cells (NSPCs) reside in the dentate gyrus (DG) of the hippocampus throughout the lifespan of most mammalian species. In addition to generating new neurons, NSPCs may alter their niche via secretion of growth factors and cytokines. We recently showed that adult DG NSPCs secrete vascular endothelial growth factor (VEGF), which is critical for maintaining adult neurogenesis. Here, we asked whether NSPC-derived VEGF alters hippocampal function independent of adult neurogenesis. We found that loss of NSPC-derived VEGF acutely impaired hippocampal memory, caused neuronal hyperexcitability and exacerbated excitotoxic injury. Conversely, we observed that overexpression of VEGF reduced microglial response to excitotoxic injury. We also found that NSPCs generate substantial proportions of total DG VEGF and VEGF disperses widely throughout the DG, both of which help explain how this anatomically-restricted cell population could modulate function broadly. These findings suggest that NSPCs actively support and protect DG function via secreted VEGF, thereby providing a non-neurogenic functional dimension to endogenous NSPCs.

Maternal COVID-19 infection increases the incidence of neurodevelopmental disorders (NDDs) in offspring, although the underlying mechanisms have not been elucidated. This study demonstrated that COVID-19 infection during pregnancy disrupted the balance of maternal and fetal immune environments, driving alterations in astrocytes, endothelial cells, and excitatory neurons. A risk score was established using 47 unique genes in the single-cell transcriptome of gestational mothers. The high risk score in CD4 proliferating T cell level served as an indicator for increased risk of offspring NDDs. Summary-based Mendelian randomization and phenome-wide association study analyses were conducted to identify the causal association of the transcriptional changes with the increased risk of offspring NDDs. Additionally, 10 drugs were identified as potential therapeutic candidates. Our findings support a model where the maternal COVID-19 infection changed the levels of CD4 proliferating T cells, leading to the alterations of astrocytes, endothelial cells, and excitatory neurons in offspring, contributing to the increased risk of NDDs in these individuals.

This study explores the genetic and epidemiologic correlates of long-term photoplethysmography-derived pulse rate variability (PRV) measurements with anxiety disorders. Individuals with whole-genome sequencing, Fitbit, and electronic health record data (N = 920; 61,333 data points) were selected from the All of Us Research Program. Anxiety polygenic risk scores (PRS) were derived with PRS-CS after meta-analyzing anxiety genome-wide association studies from three major cohorts- UK Biobank, FinnGen, and the Million Veterans Program (N =364,550). PRV was estimated as the standard deviation of average five-minute pulse wave intervals over full 24-hour pulse rate measurements (SDANN). Antidepressant exposure was defined as an active antidepressant prescription at the time of the PRV measurement in the EHR. Anxiety PRS and antidepressant use were tested for association with daily SDANN. The potential causal effect of anxiety on PRV was assessed with one-sample Mendelian randomization (MR). Anxiety PRS was independently associated with reduced SDANN (beta = -0.08; p = 0.003). Of the eight antidepressant medications and four classes tested, venlafaxine (beta = -0.12, p = 0.002) and bupropion (beta = -0.071, p = 0.01), tricyclic antidepressants (beta = -0.177, p = 0.0008), selective serotonin reuptake inhibitors (beta = -0.069; p = 0.0008) and serotonin and norepinephrine reuptake inhibitors (beta = -0.16; p = 2×10) were associated with decreased SDANN. One-sample MR indicated an inverse effect of anxiety on SDANN (beta = -2.22, p = 0.03). Anxiety and antidepressants are independently associated with decreased PRV, and anxiety appears to exert a causal effect on reduced PRV. Those observational findings provide insights into the impact of anxiety on PRV.

Earlier research suggested that psychotic experiences (PEs), the extended-psychosis phenotype, are associated with cognitive impairment. Recent studies, however, revealed more mixed findings, and patterns and magnitude of cognitive deficits in PEs remain uncertain. We aimed to systematically review and quantitatively synthesize estimates of cognitive functioning covering a wide array of domains in individuals with versus without PEs. We systematically searched four databases from inception to 6 July 2023. We generated pooled effect size (Hedges'g) using random-effects models. Subgroup analyses and meta-regression examining the moderating effect of sex, age at PE assessment, study design, cognitive task, and PE assessment instrument on cognitive functioning were performed when applicable. The study was registered with PROSPERO (CRD42023442528). Twenty-seven and six studies were included for meta-analysis of cognitive functioning comparing individuals with versus without PEs (n = 82,561; 10,251 individuals with PEs) and individuals with high-level versus low-level PEs (n = 8062; 813 individuals with high-level PEs), respectively. Individuals with PEs exhibited worse cognitive performance in general cognition (Hedges'g = -0.10 [95%CI = -0.18 to -0.02]), verbal fluency (Hedges'g = -0.05 [95%CI = -0.10 to -0.00]), visual memory (Hedges'g = -0.21 [95%CI = -0.38 to -0.03]), and working memory (Hedges'g = -0.16 [95%CI = -0.28 to -0.04]). Meta-regression revealed that general cognition associated with PEs was related to younger age (z = 3.37, p = 0.001), male sex (z = -2.59, p = 0.010), and cognitive assessment before PE assessment (z = -2.15, p = 0.031), whereas working memory in individuals with PEs was associated with concurrent cognitive and PE assessment (z = 6.19, p < 0.001). We failed to find moderating effect of the choice of PE assessment instrument or cognitive task on cognitive functioning in PEs. Additional analysis showed no significant difference in the performance of any cognitive domains between individuals with high-level versus low-level PEs. Limitations included studies primarily derived from Western countries, no social-cognitive domains, and varied PE measurement. In sum, PEs are associated with milder and more circumscribed cognitive impairment relative to psychotic disorders. Future research is required to clarify differential cognitive trajectories between individuals with transient PEs and persistent/recurrent-PEs.

Amyloid precursor protein (APP) is predominantly located in synapses of neurons and its mutations have been well recognized as the most important genetic causal factor for the familial Alzheimer's disease (AD). While most disease-causal mutations of APP occur within the Aβ-coding region or immediately proximal, the pathological impacts of mutations in the N-terminus of APP protein, which remote from the Aβ sequence, on neuron and synapse are still largely unknown. It was recently reported a pathogenic APP N-terminal Val225Ala mutation (APP) with clinically featuring progressive dementia and typical AD pathologies in brain. In our present study, we further found that APP mutation alters the N-terminal structure of APP, which enhances its binding affinity to tau protein and significantly increases APP-mediated endocytosis. Consequently, APP promotes the uptake of extracellular tau into SH-SY5Y cells, further linking the structural change in APP to intracellular tau accumulation. In addition, APP also notably alters the liquid-liquid phase separation (LLPS) of intracellular tau and intensified tau phosphorylation and aggregation in SH-SY5Y cells. Moreover, APP promote AD-like tau pathology and synaptic damages in human induced pluripotent stem cells (hiPSCs)-derived neural progenitor cells and neurons, as well as in hiPSCs-derived human brain organoids and mouse brain, which can be ameliorated by tau knockdown. Proximity labeling identified several key APP-interacting proteins, including HS3ST3A1, which was shown to directly regulate tau LLPS and phosphorylation. These findings nicely build on our previous work on roles for APP in tau-related pathological phenotypes and further highlight the involvement of N-terminal APP as the key region for both amyloidopathy and tauopathy, two aspects of AD pathogenesis and progression. Our study may also provide a theoretical breakthrough for AD therapy and highlight the important hub roles of APP and making previously neglected N-terminal APP as a potential target for the discovery of novel disease-modifying therapeutic agents against AD, holding significant scientific values and clinical promise.

It had long been considered that no new neurons are generated in the primate brain beyond birth, but recent studies have indicated that neurogenesis persists in various locations throughout the lifespan. The dentate gyrus of the hippocampus is of particular interest due to the postulated role played by neurogenesis in memory. However, studies investigating the presence of adult hippocampal neurogenesis (AHN) have reported contradictory findings, and no systematic review of the evidence has been conducted to date. We searched MEDLINE, Embase and PsycINFO on 27 June 2023 for studies on hippocampal neurogenesis in adult primates, excluding review papers. Screening, quality assessment and data extraction was done by independent co-raters. We synthesised evidence from 112 relevant papers. We found robust evidence, primarily supported by immunohistochemical examination of tissue samples and neuroimaging, for newly generated neurons, first detected in the subgranular zone of the dentate gyrus, that mature over time and migrate to the granule cell layer, where they become functionally integrated with surrounding neuronal networks. AHN has been repeatedly observed in both humans and other primates and gradually diminishes with age. Transient increases in AHN are observed following acute insults such as stroke and epileptic seizures, and following electroconvulsive therapy, and AHN is diminished in neurodegenerative conditions. Markers of AHN correlate positively with measures of learning and short-term memory, but associations with antidepressant use and mood states are weaker. Heterogeneous outcome measures limited quantitative syntheses. Further research should better characterise the neuropsychological function of neurogenesis in healthy subjects.

Pathophysiological evolutions in early-stage Alzheimer's disease (AD) are not well understood. We used data of 2923 Olink plasma proteins from 51,296 non-demented middle-aged adults. During a follow-up of 15 years, 689 incident AD cases occurred. Cox-proportional hazard models were applied to identify AD-associated proteins in different time intervals. Through linking to protein categories, changing sequences of protein z-scores can reflect pathophysiological evolutions. Mendelian randomization using blood protein quantitative loci data provided causal evidence for potentially druggable proteins. We identified 48 AD-related proteins, with CEND1, GFAP, NEFL, and SYT1 being top hits in both near-term (HR:1.15-1.77; P:9.11 × 10-2.78 × 10) and long-term AD risk (HR:1.20-1.54; P:2.43 × 10-3.95 × 10). These four proteins increased 15 years before AD diagnosis and progressively escalated, indicating early and sustained dysfunction in synapse and neurons. Proteins related to extracellular matrix organization, apoptosis, innate immunity, coagulation, and lipid homeostasis showed early disturbances, followed by malfunctions in metabolism, adaptive immunity, and final synaptic and neuronal loss. Combining CEND1, GFAP, NEFL, and SYT1 with demographics generated desirable predictions for 10-year (AUC = 0.901) and over-10-year AD (AUC = 0.864), comparable to full model. Mendelian randomization supports potential genetic link between CEND1, SYT1, and AD as outcome. Our findings highlight the importance of exploring the pathophysiological evolutions in early stages of AD, which is essential for the development of early biomarkers and precision therapeutics.

Schizophrenia (SCZ) is a severe mental disorder affecting around 1% of individuals worldwide. The variability in response to antipsychotic drugs (APDs) among SCZ patients presents a significant challenge for clinicians in determining the most effective medication. In this study, we investigated the biological markers and established a predictive model for APD response based on a large-scale genome-wide association study using 3269 Chinese schizophrenia patients. Each participant underwent an 8-week treatment regimen with one of five mono-APDs: olanzapine, risperidone, aripiprazole, quetiapine, or amisulpride. By dividing the response into ordinal groups of "high", "medium", and "low", we mitigated the bias of unclear treatment outcome and identified three novel significantly associated genetic loci in or near CDH12, WDR11, and ELAVL2. Additionally, we developed predictive models of response to each specific APDs, with accuracies ranging from 79.5% to 98.0%. In sum, we established an effective method to predict schizophrenia patients' response to APDs across three categories, integrating novel biomarkers to guide personalized medicine strategies.

With an increasing aging population and Alzheimer's disease tsunami, it is critical to identify early antecedents of brain aging to target for intervention and prevention. Women and men develop and age differently, thus using a sex differences lens can contribute to identification of early risk biomarkers and resilience. There is growing evidence for fetal antecedents to adult memory impairments, potentially through disruption of maternal prenatal immune pathways. Here, we hypothesized that in utero exposure to maternal pro-inflammatory cytokines will have sex-dependent effects on specific brain circuitry regulating offspring's memory and immune function that will be retained across the lifespan. Using a unique prenatal cohort, we tested this in 204 adult offspring, equally divided by sex, who were exposed/unexposed to an adverse in utero maternal immune environment and followed into early midlife (~age 50). Functional magnetic resonance imaging results showed exposure to pro-inflammatory cytokines in utero (i.e., higher maternal IL-6 and TNF-α levels) was significantly associated with sex differences in brain activity and connectivity underlying memory circuitry and performance and with a hyperimmune state, 50 years later. In contrast, the anti-inflammatory cytokine, IL-10 alone, was not significantly associated with memory circuitry in midlife. Predictive validity of prenatal exposure was underscored by significant associations with age 7 academic achievement, also associated with age 50 memory performance. Results uniquely demonstrated that adverse levels of maternal in utero pro-inflammatory cytokines during a critical period of the sexual differentiation of the brain produced long-lasting effects on immune function and memory circuitry/function from childhood to midlife that were sex-dependent, brain region-specific, and, within women, reproductive stage-dependent.

Preservation of dendritic spines is a putative mechanism of protection against cognitive impairment despite development of Alzheimer Disease (AD)-related pathologies. Aging, the chief late-onset AD risk factor, is associated with dendritic spine loss in select brain areas. However, no study to our knowledge has observed this effect in precuneus, an area selectively vulnerable to early accumulation of AD-related pathology. We therefore quantified dendritic spine density in precuneus from 98 subjects without evidence of neurocognitive decline, spanning ages 20-96, and found a significant negative correlation between age and large dendritic spine density. In these same subjects, we conducted liquid chromatography-tandem mass spectrometry of >5000 proteins and identified 203 proteins which statistically mediate the effect of age on large dendritic spine density. Using computational pharmacology, we identified ten drugs which are predicted to target these mediators, informing future studies designed to test their effects on age-related dendritic spine loss and cognitive decline.

Clinical and preclinical studies have identified somatostatin (SST)-positive interneurons as critical elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, disinhibition of SST neurons in mice results in resilience to the behavioral effects of chronic stress. Here, we established a low-dose chronic chemogenetic protocol to map these changes in positively and negatively motivated behaviors to specific brain regions. AAV-hM3Dq-mediated chronic activation of SST neurons in the prelimbic cortex (PLC) had antidepressant drug-like effects on anxiety- and anhedonia-like motivated behaviors in male but not female mice. Analogous manipulation of the ventral hippocampus (vHPC) had such effects in female but not male mice. Moreover, the activation of SST neurons in the PLC of male mice and the vHPC of female mice resulted in stress resilience. Activation of SST neurons in the PLC reversed prior chronic stress-induced defects in motivated behavior in males but was ineffective in females. Conversely, activation of SST neurons in the vHPC reversed chronic stress-induced behavioral alterations in females but not males. Quantitation of c-Fos and FosB neurons in chronic stress-exposed mice revealed that chronic activation of SST neurons leads to a paradoxical increase in pyramidal cell activity. Collectively, these data demonstrate that GABAergic microcircuits driven by dendrite targeting interneurons enable sex- and brain-region-specific neural plasticity that promotes stress resilience and reverses stress-induced anxiety- and anhedonia-like motivated behavior. The data provide a rationale for the lack of antidepressant efficacy of benzodiazepines and superior efficacy of dendrite-targeting, low-potency GABA receptor agonists, independent of sex and despite striking sex differences in the relevant brain substrates.

This study represents the first large-scale investigation of rare (<1% population frequency) copy number variants (CNVs) in anorexia nervosa (AN). Large, rare CNVs are reported to be causally associated with anthropometric traits, neurodevelopmental disorders, and schizophrenia, yet their role in the genetic basis of AN is unclear. Using genome-wide association study (GWAS) array data from the Anorexia Nervosa Genetics Initiative (ANGI), which included 7414 AN case and 5044 controls, we investigated the association of 67 well-established syndromic CNVs and 178 pleiotropic disease-risk dosage-sensitive CNVs with AN. To identify novel CNV regions (CNVRs) that increase the risk of AN, we conducted genome-wide association studies with a focus on rare CNV-breakpoints (CNV-GWAS). We found no net enrichment of rare CNVs, either deletions or duplications, in AN, and none of the well-established syndromic or pleiotropic CNVs had a significant association with AN status. However, the CNV-GWAS found 21 nominally associated CNVRs that contribute to AN risk, covering protein-coding genes implicated in synaptic function, metabolic/mitochondrial factors, and lipid characteristics, like the CD36 (7q21.11) gene, which transports long-chain fatty acids into cells. CNVRs intersecting genes previously related to neurodevelopmental traits include deletions of NRXN1 intron 5 (2p16.3), IMMP2L (7q31.1), and PTPRD (9p23). Overall, given that our study is well powered to detect the CNV burden level reported for schizophrenia, we can conclude that rare CNVs have a limited role in the etiology of AN, as reported for bipolar disorder. Our nominal associations for the 21 discovered CNVRs are consistent with AN being a metabo-psychiatric trait, as demonstrated by the common genetic architecture of AN, and we provide association results to allow for replication in future research.

Analyses of postmortem human brains and preclinical studies of rodents have identified somatostatin (SST)-positive, dendrite-targeting GABAergic interneurons as key elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, genetically induced disinhibition of SST neurons (induced by Cre-mediated deletion of the γ2 GABA receptor subunit gene selectively from SST neurons, SSTCre:γ2 mice) results in stress resilience. Similarly, chronic chemogenetic activation of SST neurons in the medial prefrontal cortex (mPFC) results in stress resilience but only in male and not in female mice. Here, we used RNA sequencing of the mPFC of SSTCre:γ2 mice to characterize the transcriptome changes underlying GABAergic control of stress resilience. We found that stress resilience of male but not female SSTCre:γ2 mice is characterized by resilience to chronic stress-induced transcriptome changes in the mPFC. Interestingly, the transcriptome of non-stressed SSTCre:γ2 (stress-resilient) male mice resembled that of chronic stress-exposed SSTCre (stress-vulnerable) mice. However, the behavior and the serum corticosterone levels of non-stressed SSTCre:γ2 mice showed no signs of physiological stress. Most strikingly, chronic stress exposure of SSTCre:γ2 mice was associated with an almost complete reversal of their chronic stress-like transcriptome signature, along with pathway changes suggesting stress-induced enhancement of mRNA translation. Behaviorally, the SSTCre:γ2 mice were not only resilient to chronic stress-induced anhedonia - they also showed an inversed, anxiolytic-like behavioral response to chronic stress exposure that mirrored the chronic stress-induced reversal of the chronic stress-like transcriptome signature. We conclude that GABAergic dendritic inhibition by SST neurons exerts bidirectional control over behavioral vulnerability and resilience to chronic stress exposure that is mirrored in bidirectional changes in the expression of putative stress resilience genes, through a sex-specific brain substrate.

Post-stroke depression (PSD) is a common but severe mental complication after stroke. However, the cellular and molecular understanding of PSD is still yet to be illustrated. In current study, we prepared PSD rat model (MD) via unilateral middle cerebral artery occlusion (MCAO) and chronic stress stimulation (DEPR), and isolated hippocampal tissues for single cell sequencing of 10x Genomics Chromium. First, we determined the presence of the increased cell population of endothelium and microglia and the compromised oligodendrocytes in MD compared to NC, MCAO and DEPR. The enriched functions of highly variable genes (HVGs) of endothelium and microglia suggested a reinforced blood-brain barrier in MD. Next, cell clusters of endothelium, microglia and oligodendrocytes were individually analyzed, and the subtypes with distinct functions were identified. The presence of expression profiles, intercellular communications and signaling pathways of these three cell populations of PSD displayed a similar but more aggressive appearance with DEPR compared to MCAO and NC. Taken together, this study characterized the specific gene profile of endothelium, microglia and oligodendrocytes of hippocampal PSD by single cell sequencing, emphasizing the crosstalk among them to provide theoretical basis for the in-depth mechanism research and drug therapy of PSD.

High post-menopausal levels of the pituitary gonadotropin follicle-stimulating hormone (FSH) are strongly associated with the onset of Alzheimer's disease (AD). We have shown recently that FSH directly activates the hippocampal FSH receptors (FSHRs) to drive AD-like pathology and memory loss in mice. To unequivocally establish a role for FSH in memory loss, we depleted the Fshr on a 3xTg background and utilized Morris Water Maze to study deficits in spatial memory. 3xTg;Fshr mice displayed impaired spatial memory at 5 months of age. The loss of memory acquisition and retrieval were both rescued in 3xTg;Fshr mice and, to a lesser extent, in 3xTg;Fshr mice-documenting clear gene-dose-dependent prevention of spatial memory loss. Furthermore, at 5 and 8 months, sham-operated 3xTg;Fshr mice showed better memory performance during the learning and/or retrieval phases, further suggesting that Fshr deletion prevents age-related progression of memory deficits. This prevention was not seen when mice were ovariectomized, except in the 8-month-old 3xTg;Fshr mice. There was also a gene-dose-dependent reduction mainly in the amyloid β40 isoform in whole brain extracts. Finally, serum FSH levels <8 ng/mL in 16-month-old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial memory deficits in mice and lay a firm foundation for the use of an FSH-blocking agent for the early prevention of memory loss in post-menopausal women.

Working memory (WM), a key component of cognitive functions, is often impaired in psychiatric disorders such as schizophrenia. Through a genome-guided drug repurposing approach, we identified fampridine, a potassium channel blocker used to improve walking in multiple sclerosis, as a candidate for modulating WM. In a subsequent double-blind, randomized, placebo-controlled, crossover trial in 43 healthy young adults (ClinicalTrials.gov, NCT04652557), we assessed fampridine's impact on WM (3-back d-prime, primary outcome) after 3.5 days of repeated administration (10 mg twice daily). Independently of baseline cognitive performance, no significant main effect was observed (Wilcoxon P = 0.87, r = 0.026). However, lower baseline performance was associated with higher working memory performance after repeated intake of fampridine compared to placebo (r = -0.37, P = 0.014, n = 43). Additionally, repeated intake of fampridine lowered resting motor threshold (F(1,37) = 5.31, P = 0.027, Rβ = 0.01), the non-behavioral secondary outcome, indicating increased cortical excitability linked to cognitive function. Fampridine's capacity to enhance WM in low-performing individuals and to increase brain excitability points to its potential value for treating WM deficits.

Neuronal activity in the hippocampus is critical for many types of memory acquisition and retrieval and influences an animal's response to stress. Moreover, the molecularly distinct principal neurons of hippocampal area CA2 are required for social recognition memory and aggression in mice. To interrogate the effects of stress on CA2-dependent behaviors, we chemogenetically manipulated neuronal activity in vivo during an acute, socially derived stressor and tested whether memory for the defeat was influenced. One day after an acute social defeat (aSD), defeated mice spent significantly less time investigating another mouse when compared to non-defeated control mice. We found that this avoidant phenotype persisted for up to one month following a single defeat encounter. When CA2 pyramidal neuron activity was inhibited with Gi-DREADD receptors during the defeat, subject mice exhibited a significantly higher amount of social avoidance one day later when compared to defeated littermates not expressing DREADDs. Moreover, CA2 inhibition during defeat caused a reduction in submissive defense behaviors in response to aggression. In vitro electrophysiology and tracing experiments revealed a circuit wherein CA2 neurons connect to caudal CA1 projection neurons that, in turn, project to corticolimbic regions including the anterior cingulate cortex. Finally, socially avoidant, defeated mice exhibited significant reductions in cFos expression in caudal hippocampal and limbic brain areas during a social investigation task 24 h after aSD. Taken together, these results indicate that CA2 neuronal activity is required to support behavioral resilience following an acute social stressor and that submissive defensive behavior during the defeat (vs. fleeing) is a predictor of future resilience to social stress. Furthermore, CA2 preferentially targets a population of caudal CA1 projection neurons that contact cortical brain regions where activity is modulated by an acute social stressor.

Retrosplenial cortex (RSC) is a brain region involved in neuropsychiatric and neurodegenerative disorders. It has reciprocal connections with a diverse set of cortical and subcortical brain regions, but the afferent structure and behavioral function of circuits defined by its projection-specific sub-populations have yet to be determined. The corticocortical connections between RSC and secondary motor cortex (M2), as well as corticothalamic connections between RSC and anterodorsal thalamus (AD) have been hypothesized to function as semi-independent, but parallel pathways that impact spatial information processing in distinct ways. We used retrograde and anterograde viral tracers and monosynaptic retrograde rabies virus to quantitatively characterize and compare the afferent and efferent distributions of retrosplenial neuron sub-populations projecting to M2 and AD. AD-projecting and M2-projecting RSC neurons overlap in their collateral projections to other brain regions, but not in their projections to M2 and AD, respectively. Compared with AD-projecting RSC neurons, M2-projecting RSC neurons received much greater afferent input from the dorsal subiculum, AD, lateral dorsal and lateral posterior thalamus, and somatosensory cortex. AD-projecting RSC neurons received greater input from the anterior cingulate cortex and medial septum. We performed chemogenetic inhibition of M2- and AD-projecting RSC neurons and examined its impact on object-location memory, object-recognition, open-field exploration, and place-action association. Our findings indicate that inhibition of M2-projecting RSC neurons impairs object location memory as well as place-action association, while the RSC to AD pathway impacts only object-location memory. The findings indicate that RSC is composed of semi-independent circuits distinguishable by their afferent/efferent distributions and differing in the cognitive functions to which they contribute.

Repetitive stereotyped behaviors are core symptoms of autism spectrum disorders (ASD) and fragile X syndrome (FXS), the prevalent genetic cause of intellectual disability and autism. The nigrostriatal dopamine (DA) circuit rules movement and creation of habits and sequential behaviors; therefore, its dysregulation could promote autistic repetitive behaviors. Nevertheless, inspection of substantia nigra pars compacta (SNpc) DA neurons in ASD models has been overlooked and specific evidence of their altered activity in ASD and FXS is absent. Here, we show that hyperactivity of SNpc DA neurons is an early feature of FXS. The underlying mechanism relies on an interplay between metabotropic glutamate receptor 1 (mGluR1) and ErbB tyrosine kinases, receptors for the neurotrophic and differentiation factors known as neuregulins. Up-regulation of ErbB4 and ErbB2 in nigral DA neurons drives neuronal hyperactivity and repetitive behaviors of the FXS mouse, concurrently rescued by ErbB inhibition. In conclusion, beyond providing the first evidence that nigral DA neuron hyperactivity is a signature of FXS and nigral mGluR1 and ErbB4/2 play a relevant role in FXS etiology, we demonstrate that inhibiting ErbB is a valuable pharmacological approach to attenuate stereotyped repetitive behaviors, thus opening an avenue toward innovative therapies for ASD and FXS treatment.

The C-terminal binding protein 2 (CTBP2) gene (translational isoforms: CTBP2-L/S, RIBEYE) had been identified by a cross-trait analysis of genome-wide association studies for anorexia nervosa (AN) and body mass index (BMI). Here, we did a mutation analysis in CTBP2 by performing polymerase chain reactions with subsequent Sanger-sequencing to identify variants relevant for AN and body weight regulation and ensued functional studies. Analysis of the coding regions of CTBP2 in 462 female patients with AN (acute or recovered), 490 children and adolescents with severe obesity, 445 healthy-lean adult individuals and 168 healthy adult individuals with normal body weight detected 24 variants located in the specific exon of RIBEYE. In the initial analysis, three of these were rare non-synonymous variants (NSVs) detected heterozygously in patients with AN (p.Arg72Trp - rs146900874; p.Val289Met -rs375685611 and p.Gly362Arg - rs202010294). Four NSVs and one heterozygous frameshift variant were exclusively detected in children and adolescents with severe obesity (p.Pro53Ser - rs150867595; p.Gln175ArgfsTer45 - rs141864737; p.Leu310Val - rs769811964; p.Pro397Ala - rs76134089 and p.Pro402Ser - rs113477585). Ribeye mRNA was detected in mouse hypothalamus. No effect of fasting or overfeeding on murine hypothalamic Ribeye expression was determined. Yet, increased Ribeye expression was detected in hypothalami of leptin-treated Lep mice. This increase was not related to reduced food intake and leptin-induced weight loss. We detected rare and frequent variants in the RIBEYE specific exon in both patients with AN and in children and adolescents with severe obesity. Our data suggest RIBEYE as a relevant gene for weight regulation.

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic associations of EDs with ADHD and ASD. The nationwide population-based cohort study included all individuals born in Denmark, 1981-2008, linked to their siblings and cousins. Cox regression was used to estimate associations between EDs and ADHD or ASD, and mediation analysis was used to assess the effects of intermediate mood or anxiety disorders. Polygenic scores (PGSs) were used to investigate the genetic association between anorexia nervosa (AN) and ADHD or ASD. Significantly increased risk for any ED was observed following an ADHD or ASD diagnosis. Mediation analysis suggested that intermediate mood or anxiety disorders could account for 44%-100% of the association between ADHD or ASD and ED. Individuals with a full sibling or maternal half sibling with ASD had increased risk of AN compared to those with siblings without ASD. A positive association was found between ASD-PGS and AN risk whereas a negative association was found between AN-PGS and ADHD. In this study, positive phenotypic associations between EDs and ADHD or ASD, mediation by mood or anxiety disorder, and genetic associations between ASD-PGS and AN and between AN-PGS and ADHD were observed. These findings could guide future research in the development of new treatments that can mitigate the development of EDs among individuals with ADHD or ASD.

Neuroactive steroids including allopregnanolone are implicated in the pathophysiology of peripartum depressive symptoms (PDS). We performed a systematic review searching PubMed/Embase/PsychInfo/Cinhail through 08/2023 (updated in 07/2024), and conducted a random-effects meta-analysis of studies comparing allopregnanolone blood concentrations in women with versus without PDS at various timepoints during the 2 and 3 trimester and the postpartum period, calculating standardized mean differences (SMDs) and 95% confidence intervals (CIs). Meta-regression and subgroup analyses included age, diagnoses of affective disorders before pregnancy, antidepressant treatment, analytical methods, and sample type. Study quality was assessed using the Newcastle-Ottawa-scale. The study protocol was registered on PROSPERO (registration number CRD42022354495). We retrieved 13 studies with 2509 women (n = 849 with PDS). Allopregnanolone concentrations did not differ between women with versus without PDS at any timepoint (p > 0.05). Allopregnanolone concentrations assessed during pregnancy did not differ for women with versus without PDS at postpartum follow-up (p > 0.05). Subgroup analyses indicated higher allopregnanolone concentrations in women with versus without PDS at gestational weeks 21-24 and 25-28 (SMD = 1.07, 95% CI = 0.04, 2.11 and SMD = 0.92, 95% CI = 0.26, 1.59 respectively). Moreover, we reported differences between studies using mass-spectrometry combined with chromatography versus immunoassays at gestational weeks 25-28 (p = 0.01) and plasma versus serum samples at gestational weeks 21-24 (p = 0.005). Study quality was rated as poor, good, and fair for two, one and ten studies respectively. PDS were not associated with differences for allopregnanolone concentrations. The use of heterogenous peripartum time points, study cohorts, depression symptom measures and analytical methods has hampered progress in elucidating neuroactive steroid signaling linked to PDS.

People with bipolar disorder (BD) have an increased risk of premature mortality and the respiratory mortality rate is higher than those of the general population. To date, however, the evidence on respiratory disease in this population has not been meta-analyzed. We systematically review and meta-analyze the frequency of respiratory diseases in patients with BD and to compare prevalence and odds ratio (OR) with the general population. The systematic literature search was conducted in Pubmed, PsycINFO, Scielo and Scopus, with snowball search of reference and citation lists. Inclusion criteria were studies reporting diagnoses of respiratory diseases (asthma, chronic obstructive pulmonary disease (COPD), pneumonia, lung cancer and tuberculosis) in people with BD according to operationalized criteria and where possible, control group. Of the 2158 articles screened, 20 including 962,352 people with BD and 37,340,405 control group, met the inclusion criteria. In people with BD, the prevalence of COPD was 9.14% (95%CI: 6.61-12.5%), asthma 6.4% (95%CI: 4.56-8.91%), pneumonia 2.78% (95%CI: 2.51-3.08%) and lung cancer 0.44% (95%CI:0.23-0.84%). Compared to the general population, people with BD had significantly higher rates of COPD (OR: 1.73; 95% CI: 1.40-2.14), showing an increased rate in younger and female patients; asthma (OR: 1.91, 95% CI: 1.25-2.94), with a greater rate in younger patients; and pneumonia (OR: 2.82, 95% CI: 1.33-5.99). In the first meta-analysis on the topic, BD was associated with an increased risk of respiratory illness versus the general population. In COPD and asthma, young people and women are at particular risk. Prevention programs are urgently needed.

Although specific risk factors for brain alterations in bipolar disorders (BD) are currently unknown, obesity impacts the brain and is highly prevalent in BD. Gray matter correlates of obesity in BD have been well documented, but we know much less about brain white matter abnormalities in people who have both obesity and BD. We obtained body mass index (BMI) and diffusion tensor imaging derived fractional anisotropy (FA) from 22 white matter tracts in 899 individuals with BD, and 1287 control individuals from 20 cohorts in the ENIGMA-BD working group. In a mega-analysis, we investigated the associations between BMI, diagnosis or medication and FA. Lower FA was associated with both BD and BMI in six white matter tracts, including the corpus callosum and thalamic radiation. Higher BMI or BD were uniquely associated with lower FA in three and six white matter tracts, respectively. People not receiving lithium treatment had a greater negative association between FA and BMI than people treated with lithium in the posterior thalamic radiation and sagittal stratum. In three tracts BMI accounted for 10.5 to 17% of the negative association between the number of medication classes other than lithium and FA. Both overweight/obesity and BD demonstrated lower FA in some of the same regions. People prescribed lithium had a weaker association between BMI and FA than people not on lithium. In contrast, greater weight contributed to the negative associations between medications and FA. Obesity may add to brain alterations in BD and may play a role in effects of medications on the brain.