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Abstract Slow waves are a distinguishing feature of non-rapid-eye-movement (NREM) sleep, an evolutionarily conserved process critical for brain function. Non-human studies suggest that the claustrum, a small subcortical nucleus, coordinates slow waves. We show that, in contrast to neurons from other brain regions, claustrum neurons in the human brain increase their spiking activity and track slow waves during NREM sleep, suggesting that the claustrum plays a role in coordinating human sleep architecture.

Abstract This study investigates the factors contributing to COVID vaccine hesitancy. Vaccine hesitancy has commonly been attributed to susceptibility to misinformation and linked to particular socio-demographic factors and personality traits. We present a new perspective, emphasizing the interplay between individual cognitive styles and perceptions of public health institutions. In January 2020, before the COVID-19 pandemic, 318 participants underwent a comprehensive assessment, including self-report measures of personality and clinical characteristics, as well as a behavioral task that assessed information processing styles. During 2021, attitudes towards vaccines, scientists, and the CDC were measured at three time points (February–October). Panel data analysis and structural equation modeling revealed nuanced relationships between these measures and information processing styles over time. Trust in public health institutions, authoritarian submission, and lower information processing capabilities together contribute to vaccine acceptance. Information processing capacities influenced vaccination decisions independently from the trust level, but their impact was partially mediated by authoritarian tendencies. These findings underscore the multifactorial nature of vaccine hesitancy, which emerges as a product of interactions between individual cognitive styles and perceptions of public health institutions. This novel perspective provides valuable insights into the underlying mechanisms that drive this complex phenomenon.

IntroductionDysfunction of the cortico-basal circuitry – including its primary input nucleus, the striatum – contributes to neuropsychiatric disorders, such as autism and Tourette Syndrome (TS). These conditions show marked sex differences, occurring more often in males than in females. Regulatory interneurons, such as cholinergic interneurons (CINs) and parvalbumin-expressing GABAergic fast spiking interneurons (FSIs), are implicated in human neuropsychiatric disorders such as TS, and ablation of these interneurons produces relevant behavioral pathology in male mice, but not in females. Here we investigate sex differences in the density and distribution of striatal interneurons.MethodsWe use stereological quantification of CINs, FSIs, and somatostatin-expressing (SOM) GABAergic interneurons in the dorsal striatum (caudate-putamen) and the ventral striatum (nucleus accumbens) in male and female mice.ResultsMales have a higher density of CINs than females, especially in the dorsal striatum; females have equal distribution between dorsal and ventral striatum. FSIs showed similar distributions, with a greater dorsal-ventral density gradient in males than in females. SOM interneurons were denser in the ventral than in the dorsal striatum, with no sex differences.DiscussionThese sex differences in the density and distribution of FSIs and CINs may contribute to sex differences in basal ganglia function, particularly in the context of psychopathology.

Abstract Recent studies have implicated the endogenous opioid system in the antidepressant actions of ketamine, but the underlying mechanisms remain unclear. We used a combination of pharmacological, behavioral, and molecular approaches in rats to test the contribution of the prefrontal endogenous opioid system to the antidepressant-like effects of a single dose of ketamine. Both the behavioral actions of ketamine and their molecular correlates in the medial prefrontal cortex (mPFC) are blocked by acute systemic administration of naltrexone, a competitive opioid receptor antagonist. Naltrexone delivered directly into the mPFC similarly disrupts the behavioral effects of ketamine. Ketamine treatment rapidly increases levels of β-endorphin and the expression of the μ-opioid receptor gene (Oprm1) in the mPFC, and the expression of gene that encodes proopiomelanocortin, the precursor of β-endorphin, in the hypothalamus, in vivo. Finally, neutralization of β-endorphin in the mPFC using a specific antibody prior to ketamine treatment abolishes both behavioral and molecular effects. Together, these findings indicate that presence of β-endorphin and activation of opioid receptors in the mPFC are required for the antidepressant-like actions of ketamine.

BackgroundAs machine learning technology continues to advance and the need for standardized behavioral quantification grows, commercial and open-source automated behavioral analysis tools are gaining prominence in behavioral neuroscience. We present a comparative analysis of three behavioral analysis pipelines—DeepLabCut (DLC) and Simple Behavioral Analysis (SimBA), HomeCageScan (HCS), and manual scoring—in measuring repetitive self-grooming among mice.MethodsGrooming behavior of mice was recorded at baseline and after water spray or restraint treatments. Videos were processed and analyzed in parallel using 3 methods (DLC/SimBA, HCS, and manual scoring), quantifying both total number of grooming bouts and total grooming duration.ResultsBoth treatment conditions (water spray and restraint) resulted in significant elevation in both total grooming duration and number of grooming bouts. HCS measures of grooming duration were significantly elevated relative to those derived from manual scoring: specifically, HCS tended to overestimate duration at low levels of grooming. DLC/SimBA duration measurements were not significantly different than those derived from manual scoring. However, both SimBA and HCS measures of the number of grooming bouts were significantly different than those derived from manual scoring; the magnitude and direction of the difference depended on treatment condition.ConclusionDLC/SimBA provides a high-throughput pipeline for quantifying grooming duration that correlates well with manual scoring. However, grooming bout data derived from both DLC/SimBA and HCS did not reliably estimate measures obtained via manual scoring.

BackgroundTo date, few randomized controlled trials of psilocybin with non-directive support exist for obsessive-compulsive disorder (OCD). Results and participant feedback from an interim analysis of an ongoing single-dose trial (NCT03356483) converged on the possibility of administering a higher fixed dose and/or more doses of psilocybin in future trials for presumably greater benefits.ObjectivesThis trial aims to evaluate the safety, feasibility, tolerability, and clinical effects of two doses of psilocybin paired with non-directive support in the treatment of OCD. This trial also seeks to examine whether two doses of psilocybin lead to greater OCD symptom reduction than a single dose, and to elucidate psychological mechanisms underlying the effects of psilocybin on OCD.DesignA randomized (1:1), waitlist-controlled design with blinded ratings will be used to examine the effects of two doses of oral psilocybin paired with non-directive support vs. waitlist control on OCD symptoms. An adaptive dose selection strategy will be implemented (i.e., first dose: 25 mg; second dose: 25 or 30 mg).Methods and analysisThis single-site trial will enroll 30 adult participants with treatment-refractory OCD. Aside from safety, feasibility, and tolerability metrics, primary outcomes include OCD symptoms assessed on the Yale-Brown Obsessive-Compulsive Scale – Second Edition (Y-BOCS-II). A blinded independent rater will assess primary outcomes at baseline and the primary endpoint at the end of the second dosing week. Participants will be followed up to 12 months post-second dosing. Participants randomized to waitlist will be rescreened after 7 weeks post-randomization, and begin their delayed treatment phase thereafter if still eligible.EthicsWritten informed consent will be obtained from participants. The institutional review board has approved this trial (protocol v. 1.7; HIC #2000032623).DiscussionThis study seeks to advance our ability to treat refractory OCD, and catalyze future research seeking to optimize the process of psilocybin treatment for OCD through understanding relevant psychological mechanisms.Clinical trial registration: ClinicalTrials.gov, identifier NCT05370911.

Abstract Loss-of-function mutations of the gene Cul3 have been identified as a risk factor for autism-spectrum disorder (ASD), but the pathogenic mechanisms are not well understood. Conditional Cul3 ablation in cholinergic neurons of mice (ChatCRECul3F/+) recapitulated ASD-like social and sensory gating phenotypes and caused significant cognitive impairments, with diminished activity of cholinergic neurons in the basal forebrain (BF). Chemogenetic inhibition of BF cholinergic neurons in healthy mice induced similar social and cognitive deficits. Conversely, chemogenetic stimulation of BF cholinergic neurons in ChatCRECul3F/+ mice reversed abnormalities in sensory gating and cognition. Cortical hypofunction was also found after ChAT-specific Cul3 ablation and stimulation of cholinergic projections from the BF to the prefrontal cortex (PFC) mitigated cognitive deficits. Overall, we demonstrate that cholinergic dysfunction due to Cul3 deficiency is involved in ASD-like behavioral abnormalities, and that BF cholinergic neurons are particularly critical for cognitive component through their projections to the PFC.

Abstract Obsessive-compulsive symptoms (OCS) are common in school-aged children and predict the development of obsessive compulsive disorder (OCD). White-matter abnormalities have been described in OCD, but the white matter correlates of OCS in the developing brain are unclear. Some correlates of OCS (or a diagnosis of OCD) may reflect correlates of a transdiagnostic or even general psychopathology factor. We examined these questions in a large sample of typically developing youth (N = 1208), using a hierarchical analysis of fixel-based white matter measures in relation to OCS and general psychopathology. General psychopathology was associated with abnormalities in the posterior corpus callosum and forceps major in an age-dependent manner, suggesting altered maturation (specifically, hypermaturation in younger subjects). A unidimensional measure of OCS did not associate with any white-matter abnormalities, but analysis of separate OCS dimensions (derived from factor analysis within this sample) revealed the ‘Bad Thoughts’ dimension to associate with white-matter abnormalities in dorsal parietal white-matter and descending corticospinal tracts, and the ‘Symmetry’ dimension to associate with abnormalities in the anterior corpus callosum. Repetition/checking and Symmetry OCS were additionally associated with posterior abnormalities overlapping with the correlates of general psychopathology. Contamination symptoms had no white-matter correlates. Secondary analysis of fractional anisotropy (FA) revealed distinct white-matter abnormalities, suggesting that fixel-based and FA analyses identify distinct features of white matter relevant to psychopathology. These findings suggest that OCS dimensions correlate with dissociable abnormalities in white matter, implicating separable networks. Future studies should examine these white-matter signatures in a longitudinal framework.

BackgroundPsilocybin may help treat obsessive–compulsive disorder (OCD). To date, only one open-label study of psilocybin for OCD exists, necessitating further investigation with a randomized controlled design. The neural correlates of psilocybin’s effects on OCD have also not been studied.ObjectivesThis first-of-its-kind trial aims to evaluate the feasibility, safety, and tolerability of psilocybin in the treatment of OCD, provide preliminary evidence on the effects of psilocybin on OCD symptoms, and elucidate neural mechanisms that may mediate psilocybin’s effects on OCD.DesignWe use a randomized (1:1), double-blind, placebo-controlled, non-crossover design to examine the clinical and neural effects of either a single dose of oral psilocybin (0.25 mg/kg) or active placebo-control agent (250 mg of niacin) on OCD symptoms.Methods and analysisWe are enrolling 30 adult participants at a single site in Connecticut, USA who have failed at least one trial of standard care treatment (medication/psychotherapy) for OCD. All participants will also receive unstructured, non-directive psychological support during visits. Aside from safety, primary outcomes include OCD symptoms over the past 24 h, assessed by the Acute Yale-Brown Obsessive–Compulsive Scale and Visual Analog Scale ratings. These are collected by blinded, independent raters at baseline and the primary endpoint of 48 h post-dosing. Total follow-up is 12 weeks post-dosing. Resting state neuroimaging data will be collected at baseline and primary endpoint. Participants randomized to placebo will be offered the chance to return for an open-label dose of 0.25 mg/kg.Ethics statementAll participants will be required to provide written informed consent. The trial (protocol v. 5.2) was approved by the institutional review board (HIC #2000020355) and registered with ClinicalTrials.gov (NCT03356483).DiscussionThis study may represent an advance in our ability to treat refractory OCD, and pave the way for future studies of neurobiological mechanisms of OCD that may respond to psilocybin.

Abstract Larger thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2649 OCD patients and 2774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were pre-registered ( https://osf.io/73dvy ) and adjusted for age, sex and intracranial volume. Unmedicated pediatric OCD patients (

IntroductionSelective serotonin reuptake inhibitor (SSRI) antidepressants represent first-line pharmacological treatment for a variety of neuropsychiatric illnesses, including major depressive disorder (MDD), anxiety, and post-traumatic stress disorder (PTSD), which show high rates of comorbidity. SSRIs have a delayed onset of action. Most patients do not show significant effects until 4–8 weeks of continuous treatment, have impairing side effects and as many as 40% of patients do not respond. Methylone (3,4-methylenedioxy-N-methylcathinone; MDMC, βk-MDMA, M1) is a rapid-acting entactogen that showed significant benefit in a clinical case series of PTSD patients and was well-tolerated in two Phase 1 studies of healthy volunteers. Based on these early observations in humans, in the current study we tested the hypothesis that methylone has antidepressant-like and anxiolytic effects in preclinical tests.MethodsFor all studies, 6–8-week-old male Sprague Dawley rats (N = 6–16) were used. We employed the Forced Swim Test (FST), a classic and widely used screen for antidepressants, to explore the effects of methylone and to probe dose-response relationships, durability of effect, and potential interactions with combined SSRI treatment. We compared the effect of methylone with the prototypical SSRI fluoxetine.ResultsThree doses of fluoxetine (10 mg/kg) given within 24 h before FST testing caused a 50% reduction in immobility compared with controls that lasted less than 24 h. In contrast, a single dose of methylone (5–30 mg/kg) administered 30 min prior to testing produced a rapid, robust, and durable antidepressant-like response in the FST, greater in magnitude than fluoxetine. Immobility was reduced by nearly 95% vs. controls and effects persisted for at least 72 h after a single dose (15 mg/kg). Effects on swimming and climbing behavior in the FST, which reflect serotonergic and noradrenergic activity, respectively, were consistent with studies showing that methylone is less serotoninergic than MDMA. Fluoxetine pretreatment did not change methylone’s antidepressant-like effect in the FST, suggesting the possibility that the two may be co-administered. In addition, methylone (5–30 mg/kg) exhibited anxiolytic effects measured as increased time spent in the center of an open field.DiscussionTaken together, and consistent with initial clinical findings, our study suggests that methylone may have potential for treating depression and anxiety.

Classic psychedelics, such as psilocybin, act on the brain's serotonin system and produce striking psychological effects. Early work in the 1950s and 1960s and more recent controlled studies suggest benefit from psychedelic treatment in a number of conditions. A few case reports in recreational users and a single experimental study suggest benefit in patients with obsessive-compulsive disorder (OCD), but careful clinical data and long-term follow-up have been lacking. Here we describe a case of a patient with refractory OCD treated with psilocybin and followed prospectively for a year, with marked symptomatic improvement. We provide qualitative and quantitative detail of his experience during and after treatment. Improvement in OCD symptoms (YBOCS declined from 24 to 0–2) was accompanied by broader changes in his relationship to his emotions, social and work function, and quality of life. This individual was an early participant in an ongoing controlled study of psilocybin in the treatment of OCD (NCT03356483). These results are preliminary but promising, motivating ongoing investigations of the therapeutic potential of appropriately monitored and supported psychedelic treatment in the treatment of patients with obsessions and compulsions.

IntroductionAn inactivating mutation in the histidine decarboxylase gene (Hdc) has been identified as a rare but high-penetrance genetic cause of Tourette syndrome (TS). TS is a neurodevelopmental syndrome characterized by recurrent motor and vocal tics; it is accompanied by structural and functional abnormalities in the cortico-basal ganglia circuitry. Hdc, which is expressed both in the posterior hypothalamus and peripherally, encodes an enzyme required for the biosynthesis of histamine. Hdc knockout mice (Hdc-KO) functionally recapitulate this mutation and exhibit behavioral and neurochemical abnormalities that parallel those seen in patients with TS.Materials and methodsWe performed exploratory RNA-seq to identify pathological alterations in several brain regions in Hdc-KO mice. Findings were corroborated with RNA and protein quantification, immunohistochemistry, and ex vivo brain imaging using MRI.ResultsExploratory RNA-Seq analysis revealed, unexpectedly, that genes associated with oligodendrocytes and with myelin production are upregulated in the dorsal striatum of these mice. This was confirmed by qPCR, immunostaining, and immunoblotting. These results suggest an abnormality in myelination in the striatum. To test this in an intact mouse brain, we performed whole-brain ex vivo diffusion tensor imaging (DTI), which revealed reduced fractional anisotropy (FA) in the dorsal striatum.DiscussionWhile the DTI literature in individuals with TS is sparse, these results are consistent with findings of disrupted descending cortical projections in patients with tics. The Hdc-KO model may represent a powerful system in which to examine the developmental mechanisms underlying this abnormality.

The authors show that a subanesthetic dose of ketamine markedly elevate calcium signals in apical dendritic spines in the mouse prefrontal cortex. This effect is driven by a local-circuit mechanism that involves the suppression of somatostatin interneurons leading to dendritic disinhibition.

Electroencephalography (EEG) measures the brain's electrical activity with high temporal resolution. In comparison to neuroimaging modalities such as MRI or PET, EEG is relatively cheap, non-invasive, portable, and simple to administer, making it an attractive tool for clinical deployment. Despite this, studies utilizing EEG to investigate obsessive-compulsive disorder (OCD) are relatively sparse. This contrasts with a robust literature using other brain imaging methodologies. The present review examines studies that have used EEG to examine predictors and correlates of response in OCD and draws tentative conclusions that may guide much needed future work. Key findings include a limited literature base; few studies have attempted to predict clinical change from EEG signals, and they are confounded by the effects of both pharmacotherapy and psychotherapy. The most robust literature, consisting of several studies, has examined event-related potentials, including the P300, which several studies have reported to be abnormal at baseline in OCD and to normalize with treatment; but even here the literature is quite heterogeneous, and more work is needed. With more robust research, we suggest that the relatively low cost and convenience of EEG, especially in comparison to fMRI and PET, make it well-suited to the development of feasible personalized treatment algorithms.

Individuals with obsessive-compulsive disorder (OCD) often have difficulty making decisions. Valuation and value-based judgements are particularly difficult. The mechanisms underlying these impairments are still poorly understood. Previous work has suggested that individuals with OCD require more information prior to making a choice during perceptual discrimination tasks. Little previous work has examined value-guided choice in OCD. Here we examined perceptual and value-based decision making in adults with OCD, using a novel task in which the two types of decision are tested in parallel using the same individually calibrated sets of visual stimuli (Perceptual and Value-based decision-making task, PVDM). Twenty-seven unmedicated participants with OCD (16 female) and thirty-one healthy controls (15 female) were tested. Data were analyzed using hierarchical drift-diffusion modeling (HDDM). Decision formation was altered in OCD, but differentially between genders: males with OCD, but not females, accumulated more information (i.e., were more cautious) and were less effective in evidence accumulation than age- and IQ-matched healthy males. Furthermore, males with OCD, but not females, were less likely than controls to adjust the process of evidence accumulation across decision contexts. These unexpectedly gender-dimorphic effects suggest that more attention should be paid to gender differences in studies of OCD, and of pathophysiology more broadly.

Difficulties in advancing effective patient-specific therapies for psychiatric disorders highlight a need to develop a stable neurobiologically grounded mapping between neural and symptom variation. This gap is particularly acute for psychosis-spectrum disorders (PSD). Here, in a sample of 436 PSD patients spanning several diagnoses, we derived and replicated a dimensionality-reduced symptom space across hallmark psychopathology symptoms and cognitive deficits. In turn, these symptom axes mapped onto distinct, reproducible brain maps. Critically, we found that multivariate brain-behavior mapping techniques (e.g. canonical correlation analysis) do not produce stable results with current sample sizes. However, we show that a univariate brain-behavioral space (BBS) can resolve stable individualized prediction. Finally, we show a proof-of-principle framework for relating personalized BBS metrics with molecular targets via serotonin and glutamate receptor manipulations and neural gene expression maps derived from the Allen Human Brain Atlas. Collectively, these results highlight a stable and data-driven BBS mapping across PSD, which offers an actionable path that can be iteratively optimized for personalized clinical biomarker endpoints.

Summary: Heterozygous coding mutations in TRIO are associated with neurodevelopmental disorders, including autism, schizophrenia, bipolar disorder, and epilepsy, and impair TRIO’s biochemical activities. To model mutant alleles, we ablated one or both Trio alleles from excitatory neurons in the cortex and hippocampus of mice. Trio haploinsufficiency increases anxiety and impairs social preference and motor coordination. Trio loss reduces forebrain size and dendritic arborization but increases dendritic spine densities. Cortical synapses in Trio haploinsufficient mice are small, exhibit pre- and postsynaptic deficits, and cannot undergo long-term potentiation. Similar phenotypes are observed in Trio knockout mice. Overall, Trio haploinsufficiency causes severe disease-relevant deficits in behavior and neuronal structure and function. Interestingly, phosphodiesterase 4A5 (PDE4A5) levels are reduced and protein kinase A (PKA) signaling is increased when TRIO levels are reduced. Elevation of PDE4A5 and drug-based attenuation of PKA signaling rescue Trio haploinsufficiency-related dendritic spine defects, suggesting an avenue for therapeutic intervention for TRIO-related neurodevelopmental disorders. : Heterozygous TRIO mutations are associated with neurodevelopmental disorders. Katrancha et al. reveal that mouse Trio haploinsufficiency impairs sociability and motor coordination; decreases brain and neuron size; and impairs synaptic anatomy, function, and plasticity. Altering PDE4A5 levels and PKA signaling rescues some synaptic defects, suggesting an avenue to treat TRIO-related neurodevelopmental disorders. Keywords: TRIO, triple functional domain protein, neurodevelopmental disorder, haploinsufficiency, dendritic spine, anxiety, social preference, motor cortex, long-term potentiation, phosphodiesterase 4A5

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20634-x

Individuals with obsessive-compulsive disorder often identify psychosocial stress as a factor that exacerbates their symptoms, and many trace the onset of symptoms to a stressful period of life or a discrete traumatic incident. However, the pathophysiological relationship between stress and obsessive-compulsive disorder remains poorly characterized: it is unclear whether trauma or stress is an independent cause of obsessive-compulsive disorder symptoms, a triggering factor that interacts with a preexisting diathesis, or simply a nonspecific factor that can exacerbate obsessive-compulsive disorder along with other aspects of psychiatric symptomatology. Nonetheless, preclinical research has demonstrated that stress has conspicuous effects on corticostriatal and limbic circuitry. Specifically, stress can lead to neuronal atrophy in frontal cortices (particularly the medial prefrontal cortex), the dorsomedial striatum (caudate), and the hippocampus. Stress can also result in neuronal hypertrophy in the dorsolateral striatum (putamen) and amygdala. These neurobiological effects mirror reported neural abnormalities in obsessive-compulsive disorder and may contribute to an imbalance between goal-directed and habitual behavior, an imbalance that is implicated in the pathogenesis and expression of obsessive-compulsive disorder symptomatology. The modulation of corticostriatal and limbic circuits by stress and the resultant imbalance between habit and goal-directed learning and behavior offers a framework for investigating how stress may exacerbate or trigger obsessive-compulsive disorder symptomatology.

There is accumulating evidence that immune dysregulation contributes to the pathophysiology of obsessive-compulsive disorder (OCD), Tourette syndrome, and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). The mechanistic details of this pathophysiology, however, remain unclear. Here we focus on one particular component of the immune system: microglia, the brain’s resident immune cells. The role of microglia in neurodegenerative diseases has been understood in terms of classic, inflammatory activation, which may be both a consequence and a cause of neuronal damage. In OCD and Tourette syndrome, which are not characterized by frank neural degeneration, the potential role of microglial dysregulation is much less clear. Here we review the evidence for a neuroinflammatory etiology and microglial dysregulation in OCD, Tourette syndrome, and PANDAS. We also explore new hypotheses as to the potential contributions of microglial abnormalities to pathophysiology, beyond neuroinflammation, including failures in neuroprotection, lack of support for neuronal survival, and abnormalities in synaptic pruning. Recent advances in neuroimaging and animal model work are creating new opportunities to elucidate these issues.

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.

Microglia, the brain's resident immune cells, are phagocytes of the macrophage lineage that have a key role in responding to inflammation and immune challenge in the brain. More recently, they have been shown to have a number of important roles beyond immune surveillance and response, including synaptic pruning during development and the support of adult neurogenesis. Microglial abnormalities have been found in several neuropsychiatric conditions, though in most cases it remains unclear whether these are causative or are a reaction to some other underlying pathophysiology. Here we summarize postmortem, animal, neuroimaging, and other evidence for microglial pathology in major depression, schizophrenia, autism, obsessive-compulsive disorder, and Tourette syndrome. We identify gaps in the existing literature and important areas for future research. If microglial pathology proves to be an important causative factor in these or other neuropsychiatric diseases, modulators of microglial function may represent a novel therapeutic strategy.

The striatum participates in multiple forms of behavioral adaptation, including habit formation, other forms of procedural memory, and short and long-term responses to drugs of abuse. The CREB family of transcription factors has been implicated in various forms of behavioral plasticity, but its role in the dorsal portion of the striatum-has been little explored. We previously showed that in transgenic mice in which CREB function is inhibited in the dorsal striatum, bidirectional synaptic plasticity and certain forms of long-term procedural memory are impaired. Here we show, in startling contrast, that inhibition of striatal CREB facilitates cocaine- and morphine-place conditoning and enhances locomotor sensitization to cocaine. These findings propose CREB as a positive regulator of dorsal striatum-dependent procedural learning but a negative regulator of drug-related learning.