Molecular Psychiatry最新文献

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.

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 × 10⁻⁶⁵–2.78 × 10⁻⁶) and long-term AD risk (HR:1.20-1.54; P:2.43 × 10⁻²¹–3.95 × 10⁻⁶). 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.

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.

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_Total =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^-6) 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.

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_V225A) with clinically featuring progressive dementia and typical AD pathologies in brain. In our present study, we further found that APP_V225A mutation alters the N-terminal structure of APP, which enhances its binding affinity to tau protein and significantly increases APP-mediated endocytosis. Consequently, APP_V225A promotes the uptake of extracellular tau into SH-SY5Y cells, further linking the structural change in APP to intracellular tau accumulation. In addition, APP_V225A also notably alters the liquid-liquid phase separation (LLPS) of intracellular tau and intensified tau phosphorylation and aggregation in SH-SY5Y cells. Moreover, APP_V225A 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_V225A-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^th 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.

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_A receptor subunit gene selectively from SST neurons, SSTCre:γ2^f/f 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^f/f mice to characterize the transcriptome changes underlying GABAergic control of stress resilience. We found that stress resilience of male but not female SSTCre:γ2^f/f mice is characterized by resilience to chronic stress-induced transcriptome changes in the mPFC. Interestingly, the transcriptome of non-stressed SSTCre:γ2^f/f (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^f/f mice showed no signs of physiological stress. Most strikingly, chronic stress exposure of SSTCre:γ2^f/f 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^f/f 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.

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_A receptor agonists, independent of sex and despite striking sex differences in the relevant brain substrates.

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.

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.