Molecular Psychiatry最新文献

Autism Spectrum Disorders (ASD) are a set of neurodevelopmental disorders with complex biology. The identification of ASD risk genes from exome-wide association studies and de novo variation analyses has enabled mechanistic investigations into how ASD-risk genes alter development. Most functional genomics studies have focused on the role of these genes in neurons and neural progenitor cells. However, roles for ASD risk genes in other cell types are largely uncharacterized. There is evidence from postmortem tissue that microglia, the resident immune cells of the brain, appear activated in ASD. Here, we used CRISPRi-based functional genomics to systematically assess the impact of ASD risk gene knockdown on microglia activation and phagocytosis. We developed an iPSC-derived microglia-neuron coculture system and high-throughput flow cytometry readout for synaptic pruning to enable parallel CRISPRi-based screening of phagocytosis of beads, synaptosomes, and synaptic pruning. Our screen identified ADNP, a high-confidence ASD risk genes, as a modifier of microglial synaptic pruning. We found that microglia with ADNP loss have altered endocytic trafficking, remodeled proteomes, and increased motility in coculture.

The relationship between adiposity and dopamine type-2 receptor binding potential (D2BP) in the human brain has been repeatedly studied for >20 years with highly discrepant results, likely due to variable methodologies and differing study populations. We conducted a controlled inpatient feeding study to measure D2BP in the striatum using positron emission tomography with both [¹⁸F]fallypride and [¹¹C]raclopride in pseudo-random order in 54 young adults with a wide range of body mass index (BMI 20–44 kg/m²). Within-subject D2BP measurements using the two tracers were moderately correlated (r = 0.47, p < 0.001). D2BP was negatively correlated with BMI as measured by [¹¹C]raclopride (r = −0.51; p < 0.0001) but not [¹⁸F]fallypride (r = −0.01; p = 0.92) and these correlation coefficients were significantly different from each other (p < 0.001). Given that [¹⁸F]fallypride has greater binding affinity to dopamine type-2 receptors than [¹¹C]raclopride, which is more easily displaced by endogenous dopamine, our results suggest that adiposity is positively associated with increased striatal dopamine tone.ClinicalTrials.gov Identifier: NCT03648892

Deep Brain Stimulation (DBS) is a therapeutic option for treatment resistant (TR) obsessive-compulsive disorder (OCD). The OCD network comprises different sub-networks with homeostatic functions, altered under disease and modifiable with DBS. Connectomic analyses of DBS data sets have defined fiber selections explaining anti-OCD efficacy. This is a retrospective stimulation and outcome derived anatomical overlay analysis of 26 TR-OCD patients who received DBS at two academic centers. Grenoble, 14 anteromedial subthalamic nucleus (amSTN); Freiburg, 12 superolateral medial forebrain bundle (slMFB). Yale-Brown Obsessive Compulsive Scale improvement at 24 months served as outcome parameter. Structural proximity and outcomes were correlated using individual volumes of activated tissue for STN, slMFB, ORT (average OCD response tract) and further structures based on atlases or established connectomes. Connectomes (slMFB, ORT) were inspected for structural congruences. Normative connectomic data served to investigate cortical fiber penetration for the two target regions. Cortical sub-network conjugations were evaluated as peak levels. Our analyses revealed that ORT represents a fiber selection from the slMFB. DBS of amSTN and slMFB each address distinctive sub-networks while deep amSTN DBS can also address slMFB. Sub-network conjugations project amongst other regions onto the dorsomedial prefrontal cortex (dmPFC). The average ORT fiber selection is an integral part of the generic slMFB. Anti-OCD effects of amSTN DBS are not entirely explained by ORT overlay. The slMFB is dispersed and encompasses all OCD sub-networks and might qualify as a common DBS target when stimulated close to the ventral tegmental area. The dmPFC emerges as an interesting conjugation/hub between OCD sub-networks.

It is known that infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 2019 (COVID-19). It is widely reported that Alzheimer’s disease (AD) is associated with the highest risk of COVID-19 infection, hospitalization and mortality. However, it remains largely unclear about the link between AD and COVID-19. ACE2 is an entry receptor for SARS-CoV-2. We consider that there may be a link between AD and COVID-19 through the expression of ACE2. Here, we summarize recent findings about the ACE2 expression especially in AD and COVID-19, and shows that (1) ACE2 shows mRNA and protein expression in human brain tissues, especially in neurons and non-neuron cells; (2) low ACE2 mRNA and protein expression are sufficient for SARS-CoV-2 entry into the human brain through the neural route (olfactory and/or vagal) and the hematogenous route; (3) SARS-CoV-2 RNA and protein were detected in brains of COVID-19 patients; (4) SARS-CoV-2 infects and replicates in human brain dependent on ACE2; (5) SARS-CoV-2 viral RNA load shows a positive association with ACE2 mRNA levels and COVID-19 severity; (6) ACE2 shows increased expression in AD compared with controls in human brain; (7) ACE2 shows increased expression in COVID-19 compared with controls in human brain; (8) ACE2 expression levels affect COVID-19 outcomes. Together, ACE2 shows significantly increased mRNA and protein expression in AD compared with controls in human brain. Consequently, the increased expression of ACE2 would facilitate infection with SARS-CoV-2, and play a role in the context of COVID-19. These findings suggest that the expression of ACE2 may partly explain the link of AD with COVID-19 infection, hospitalization and mortality.

Maternal perceived prenatal stress (PPS) is a known risk factor for diverse developmental impairments in newborns, but the underlying molecular processes are incompletely understood. Here, we report that maternal PPS altered the birth profiles of blood transfer RNA fragments (tRFs), 16–50 nt long non-random cleavage products of tRNAs, in a sex-dependent manner. Importantly, comparing stressed versus control maternal and umbilical cord blood serum presented alterations that were not limited to individual tRFs, but rather reflected selective changes in particular tRF families grouped by their mitochondrial or nuclear genome origin, parental tRNA coded amino acid, and cleavage type. Specifically, tRF families that show stress- and sex-specific effects, revealed shared length and expression patterns which were strongest in the female newborns. Several of these tRFs carry complementary motifs to particular cholinergic mRNAs, suggesting possible translational regulation similar to microRNAs. Compatible with the cholinergic regulation of stress reactions, those “CholinotRFs” achieved an AUC of 95% when classifying female newborns according to maternal PPS. Moreover, we found altered catalytic activity of serum acetylcholinesterase, which was particularly elevated in male newborns, marking a second sex-specific effect. Our findings demonstrate an association of tRF families’ patterns with newborns’ sex-specific stress response to PPS and may lead to better diagnosis and therapeutic tools for these and other stressors.

Neuropsychiatric disorders that result from stress exposure are highly associated with central inflammation. Our previous work established that females selectively exhibit heightened proinflammatory cytokine production within the noradrenergic locus coeruleus (LC) along with a hypervigilant behavioral phenotype in response to witnessing social stress. Notably, ablation of microglia using pharmacological techniques prevents this behavioral response. These studies were designed to further investigate the impact of stress-induced neuroimmune signaling on the long-term behavioral and neuronal consequences of social stress exposure in females using chemogenetics. We first characterized the use of an AAV-CD68-G_i-DREADD virus targeted to microglia within the LC and confirmed viral transduction, selectivity, and efficacy. Clozapine-n-oxide (CNO) was used for the suppression of microglial reactivity during acute and chronic exposure to vicarious/witness social defeat in female rats. Chemogenetic-mediated inhibition of microglial reactivity during stress blunted the neuroimmune response to stress and prevented both acute and long-term hypervigilant behavioral responses. Further, a history of microglial suppression during stress prevented the heightened LC activity typically observed in response to stress cues. These studies are among the first to use a chemogenetic approach to inhibit central microglia in vivo and establish LC microglia as a key driver of the behavioral and neuronal responses to social stress in females.

Elevated anxiety and uncertainty avoidance are known to exacerbate maladaptive choice in individuals with affective disorders. However, the differential roles of state vs. trait anxiety remain unclear, and underlying computational mechanisms have not been thoroughly characterized. In the present study, we investigated how a somatic (interoceptive) state anxiety induction influences learning and decision-making under uncertainty in individuals with clinically significant levels of trait anxiety. A sample of 58 healthy comparisons (HCs) and 61 individuals with affective disorders displaying elevated anxiety symptoms (iADs; i.e., anxiety and/or depression) completed a previously validated explore-exploit decision task, with and without an added breathing resistance manipulation designed to induce state anxiety. Computational modeling revealed a significant group-by-condition interaction, such that information-seeking (i.e., directed exploration) in HCs was reduced by the anxiety induction (Cohen’s d = 0.47, p = 0.013), while no change was observed in iADs. The iADs also showed slower learning rates than HCs across conditions (Cohen’s d = 0.52, p = 0.003), suggesting their uncertainty decreased more slowly over time. These findings highlight a complex interplay between trait anxiety and state anxiety. Specifically, state anxiety may attenuate reflection on uncertainty in healthy individuals, while familiarity with anxious states in those with high trait anxiety may create an insensitivity to this effect.

Substance use disorders (SUDs) induce widespread molecular dysregulation in nucleus accumbens (NAc), a brain region pivotal for coordinating motivation and reward, which is linked to neural and behavioral disturbances promoting addiction. Despite the overlapping symptomatology of SUDs, different drug classes exert partly unique influences on neural circuits, cell types, physiology, and gene expression. To better understand common and divergent molecular mechanisms governing SUD pathology, we characterized the cell-type-specific restructuring of the NAc transcriptional landscape after psychostimulant or opioid exposure. We combined fluorescence-activated nuclei sorting and deep RNA sequencing to profile NAc D1 and D2 medium spiny neurons (MSNs) across cocaine and morphine exposure paradigms, including initial exposure, prolonged withdrawal after repeated exposure, and re-exposure post-withdrawal. Our analyses reveal that D1 MSNs display many convergent transcriptional responses between the two drug classes, whereas D2 MSNs manifest highly divergent responses, with morphine causing more adaptations in this cell type. Utilizing multiscale embedded gene co-expression network analysis (MEGENA), we discerned transcriptional regulatory networks subserving biological functions altered by cocaine vs. morphine. We observed largely integrative engagement of overlapping gene networks across drug classes in D1 MSNs, but opposite regulation of key D2 networks, highlighting potential therapeutic gene network targets within MSNs. Analysis of gene regulatory systems at the level of enhancers revealed that morphine engages a unique enhancer landscape in D2 MSNs compared to cocaine. Our findings, and future work leveraging this dataset, will open avenues for the development of targeted therapeutic interventions, addressing the urgent need for more effective treatments for SUDs.

Autism Spectrum Disorder (ASD) is characterized by impairments in social interaction and repetitive behaviors. A key characteristic of ASD is a decreased interest in social interactions, which affects individuals’ ability to engage with their social environment. This study explores the neurobiological basis of these social deficits, focusing on the pathway between the Superior Colliculus (SC) and the Ventral Tegmental Area (VTA). Adopting a translational approach, our research used Shank3 knockout mice (Shank3^−/−), which parallel a clinical cohort of young children with ASD, to investigate these mechanisms. We observed consistent deficits in social orienting across species. In children with ASD, fMRI analyses revealed a significant decrease in connectivity between the SC and VTA. Additionally, using miniscopes in mice, we identified a reduction in the frequency of calcium transients in SC neurons projecting to the VTA, accompanied by changes in neuronal correlation and intrinsic cellular properties. Notably, the interneuronal correlation in Shank3^−/− mice and the functional connectivity of the SC to VTA pathway in children with ASD correlated with the severity of social deficits. Our findings underscore the potential of the SC-VTA pathway as a biomarker for ASD and open new avenues for therapeutic interventions, highlighting the importance of early detection and targeted treatment strategies.

Psychiatric disorders pose substantial global burdens on public health, yet therapeutic options remain limited. Recently, gut microbiota is in the spotlight of new research on psychiatric disorders, as emerging discoveries have highlighted the importance of gut microbiome in the regulation of central nervous system via mediating the gut-brain-axis bidirectional communication. While metagenomics studies have accumulated for psychiatric disorders, few systematic efforts were dedicated to integrating these high-throughput data across diverse phenotypes, interventions, geographical regions, and biological species. To present a panoramic view of global data and provide a comprehensive resource for investigating the gut microbiota dysbiosis in psychiatric disorders, we developed the PsycGM, a manually curated and well-annotated database that provides the literature-supported associations between gut microbiota and psychiatric disorders or intervention measures. In total, PsycGM incorporated 559 studies from 31 countries worldwide, encompassing research involving humans, rats, mice, and non-human primates. PsycGM documented 8907 curated associations between 1514 gut microbial taxa and 11 psychiatric disorders, as well as 4050 associations between 869 taxa and 232 microbiota-based and non-microbiota-based interventions. Moreover, PsycGM provided a user-friendly web interface with comprehensive information, enabling browsing, retrieving and downloading of all entries. In the application of PsycGM, we panoramically depicted the intestinal microecological imbalance in depression. Additionally, we identified 9 microbial taxa consistently altered in patients with depression, with the most common dysregulations observed for Parabacteroides, Alistipes, and Faecalibacterium; in animal models of depression, consistent changes were observed in 21 microbial taxa, most frequently reported as Helicobacter, Lactobacillus, Roseburia, and the ratio of Firmicutes/Bacteroidetes. PsycGM is a comprehensive resource for future investigations on the role of gut microbiota in mental and brain health, and for therapeutic target innovations based on modifications of gut microbiota. PsycGM is freely accessed at http://psycgmomics.info.