Sexual dimorphism in histamine regulation of striatal dopamine.

Background: Many neuropsychiatric disorders show sex differences in prevalence and presentation. For example, Tourette's Syndrome (TS) is diagnosed 3-5 times more often in males. Dopamine modulation of the basal ganglia is implicated in numerous neuropsychiatric conditions, including TS. Motivated by an unexpected genetic finding in a family with TS, we previously characterized the modulation of striatal dopamine by histamine. Methods: We used microdialysis to analyze striatal dopamine response to the targeted infusion of histamine and histamine agonists. siRNA knockdown of histamine receptors was used to identify the cellular mediators of observed effects. Results: Intracerebroventricular histamine reduced striatal dopamine in male mice, replicating previous work. Unexpectedly, histamine increased striatal dopamine in females. Targeted infusion of selected agonists revealed that the effect in males depends on H2R receptors in the substantia nigra pars compacta (SNc). Knockdown of H2R in SNc GABAergic neurons abrogated the effect, identifying these cells as a key locus of histamine's regulation of dopamine in males. In females, in contrast, H2R had no role; instead, H3R agonists in the striatum increased striatal dopamine. Strikingly, the effect of histamine on dopamine in females was modulated by the estrous cycle, appearing in estrus/proestrus but not in metestrus/diestrus. Conclusions: These findings confirm the regulation of striatal dopamine by histamine but identify marked sexual dimorphism in and estrous modulation of this effect. These findings may shed light on the mechanistic underpinnings of other sex differences in the striatal circuitry, perhaps including the marked sex differences seen in TS and related neuropsychiatric conditions.

Information processing style and institutional trust as factors of COVID vaccine hesitancy.

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.

Activation of M4 muscarinic receptors in the striatum reduces tic-like behaviours in two distinct murine models of Tourette syndrome.

BACKGROUND AND PURPOSE: Current pharmacotherapies for Tourette syndrome (TS) are often unsatisfactory and poorly tolerated, underscoring the need for novel treatments. Insufficient striatal acetylcholine has been suggested to contribute to tic ontogeny. Thus, we tested whether activating M1 and/or M4 receptors-the two most abundant muscarinic receptors in the striatum-reduced tic-related behaviours in mouse models of TS. EXPERIMENTAL APPROACH: Studies were conducted using CIN-d and D1CT-7 mice, two TS models characterized by early-life depletion of striatal cholinergic interneurons and cortical neuropotentiation, respectively. First, we tested the effects of systemic and intrastriatal xanomeline, a selective M1/M4 receptor agonist, on tic-like and other TS-related responses. Then, we examined whether xanomeline effects were reduced by either M1 or M4 antagonists or mimicked by the M1/M3 agonist cevimeline or the M4 positive allosteric modulator (PAM) VU0467154. Finally, we measured striatal levels of M1 and M4 receptors and assessed the impact of VU0461754 on the striatal expression of the neural marker activity c-Fos. KEY RESULTS: Systemic and intrastriatal xanomeline reduced TS-related behaviours in CIN-d and D1CT-7 mice. Most effects were blocked by M4, but not M1, receptor antagonists. VU0467154, but not cevimeline, elicited xanomeline-like ameliorative effects in both models. M4, but not M1, receptors were down-regulated in the striatum of CIN-d mice. Additionally, VU0467154 reduced striatal c-Fos levels in these animals. CONCLUSION AND IMPLICATIONS: Activation of striatal M4, but not M1, receptors reduced tic-like manifestations in mouse models, pointing to xanomeline and M4 PAMs as novel putative therapeutic strategies for TS.

Mechanisms of therapeutic change after psychedelic treatment in OCD.

Novel treatments are required for the 30-50% of individuals with obsessive-compulsive disorder (OCD) who remain resistant to first-line pharmacological and psychotherapeutic treatments. Recent pilot data suggest benefit from psilocybin-assisted psychotherapy (PAP) and from imagery rescripting (ImRs). We explore psychological mechanisms of change underpinning both interventions that appear to allow for reprocessing of negative emotions and core beliefs associated with past aversive events. A next critical step in PAP is the development of psychotherapeutic frameworks grounded in theory. We propose that basing PAP on an ImRs framework may provide synergistic benefits in symptom reduction, modification of core beliefs, and value-based living.

Sex differences in the distribution and density of regulatory interneurons in the striatum.

Dysfunction of the cortico-basal circuitry - including its primary input nucleus, the striatum - contributes to neuropsychiatric disorders, including autism and Tourette Syndrome (TS). These conditions show marked sex differences, occurring more often in males than in females. Regulatory interneurons, including 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, using 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. Males 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 effects, 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. These sex differences in the density and distribution of FSIs and CINs may contribute to sex differences in basal ganglia function, including in the context of psychopathology.

Externally orienting cues improve cognitive control in OCD.

BACKGROUND AND OBJECTIVES: An executive overload model of obsessive-compulsive disorder (OCD) posits that broad difficulties with executive functioning in OCD result from an overload on the executive system by obsessive thoughts. It implies that, if individuals with OCD "snap out" of their obsessive thoughts, their performance on neurocognitive tasks will improve. METHODS: We test this prediction using the revised Attention Network Test, ANT-R, and distinct subsamples of data from unmedicated OCD and healthy controls (HC). ANT-R includes Simon and Flanker tasks; in both, incongruent trials take longer to resolve ('conflict costs'). On some trials, a warning cue helps participants to respond faster ('alerting benefits'). In OCD (N = 34) and HC (N = 46), matched on age, IQ, and sex, we tested (1) the effect of OCD on alerting benefits, and (2) the effect of OCD on warning cue related reductions in conflict costs. In a distinct subsample of OCD (N = 32) and HC (N = 51), we assessed whether alerting benefits and cue-related reductions in conflict costs are associated differently with different OCD symptoms. RESULTS: A warning cue can help individuals with OCD more than HC to improve performance on Simon and Flanker tasks. This effect is positively associated with severity of contamination symptoms. LIMITATIONS: This study did not directly assess how distracted participants are by obsessive thoughts. It relied on the ANT-R subtraction measures. Symptom severity was assessed using self-report measures. CONCLUSIONS: Difficulties in resolving conflict during decision-making in OCD can be modulated by a warning cue presented immediately before an attentional task.

Corrigendum: Safety, feasibility, tolerability, and clinical effects of repeated psilocybin dosing combined with non-directive support in the treatment of obsessive-compulsive disorder: protocol for a randomized, waitlist-controlled trial with blinded ratings.

[This corrects the article DOI: 10.3389/fpsyt.2023.1278823.].

The human claustrum tracks slow waves during sleep.

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

The endogenous opioid system in the medial prefrontal cortex mediates ketamine's antidepressant-like actions.

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 ß-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 ß-endorphin, in the hypothalamus, in vivo. Finally, neutralization of ß-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 ß-endorphin and activation of opioid receptors in the mPFC are required for the antidepressant-like actions of ketamine.

A comparison of machine learning methods for quantifying self-grooming behavior in mice.

Background: As 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. Methods: Grooming 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. Results: Both 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. Conclusion: DLC/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.

A novel naïve Bayes approach to identifying grooming behaviors in the force-plate actometric platform.

BACKGROUND: Self-grooming behavior in rodents serves as a valuable behavioral index for investigating stereotyped and perseverative responses. Most current grooming analyses rely on video observation, which lacks standardization, efficiency, and quantitative information about force. To address these limitations, we developed an automated paradigm to analyze grooming using a force-plate actometer. NEW METHOD: Grooming behavior is quantified by calculating ratios of relevant movement power spectral bands. These ratios are input into a naïve Bayes classifier, trained with manual video observations. The effectiveness of this method was tested using CIN-d mice, an animal model developed through early-life depletion of striatal cholinergic interneurons (CIN-d) and featuring prolonged grooming responses to acute stressors. Behavioral monitoring was simultaneously conducted on the force-place actometer and by video recording. RESULTS: The naïve Bayes approach achieved 93.7% accurate classification and an area under the receiver operating characteristic curve of 0.894. We confirmed that male CIN-d mice displayed significantly longer grooming durations than controls. However, this elevation was not correlated with increases in grooming force. Notably, the dopaminergic antagonist haloperidol reduced grooming force and duration. COMPARISON WITH EXISTING METHODS: In contrast to observation-based approaches, our method affords rapid, unbiased, and automated assessment of grooming duration, frequency, and force. CONCLUSIONS: Our novel approach enables fast and accurate automated detection of grooming behaviors. This method holds promise for high-throughput assessments of grooming stereotypies in animal models of neuropsychiatric disorders.

The endogenous opioid system in the medial prefrontal cortex mediates ketamine's antidepressant-like actions.

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) were blocked by acute systemic administration of naltrexone, a competitive opioid receptor antagonist. Naltrexone delivered directly into the mPFC similarly disrupted the behavioral effects of ketamine. Ketamine treatment rapidly increased levels of ß-endorphin and the expression of the µ-opioid receptor gene (Oprm1) in the mPFC, and the expression of the gene that encodes proopiomelanocortin, the precursor of ß-endorphin, in the hypothalamus, in vivo. Finally, neutralization of ß-endorphin in the mPFC using a specific antibody prior to ketamine treatment abolished both behavioral and molecular effects. Together, these findings indicate that presence of ß-endorphin and activation of opioid receptors in the mPFC are required for the antidepressant-like actions of ketamine.

Frontopolar multifocal transcranial direct current stimulation reduces conditioned fear reactivity during extinction training: A pilot randomized controlled trial.

Exposure-based therapies for anxiety and related disorders are believed to depend on fear extinction learning and corresponding changes in extinction circuitry. Frontopolar multifocal transcranial direct current stimulation (tDCS) has been shown to improve therapeutic safety learning during in vivo exposure and may modulate functional connectivity of networks implicated in fear processing and inhibition. A pilot randomized controlled trial was completed to determine the effects of frontopolar tDCS on extinction learning and memory. Community volunteers (n = 35) completed a 3-day fear extinction paradigm with measurement of electrodermal activity. Participants were randomized (single-blind) to 20-min of sham (n = 17, 30 s. ramp in/out) or active (n = 18) frontopolar (anode over Fpz, 10-10 EEG) multifocal tDCS (20-min, 1.5 mA) prior to extinction training. Mixed ANOVAs revealed a significant group*trial effect on skin conductance response (SCR) to the conditioned stimulus (CS + ) during extinction training (p = 0.007, Cohen's d = 0.55). The effects of frontopolar tDCS were greatest during the first two extinction trials, suggesting that tDCS may have promoted fear inhibition prior to safety learning. Return of fear to the CS + during tests were comparable across conditions (ps > 0.50). These findings suggest that frontopolar tDCS may modulate the processing of threat cues and associated circuitry or promote the inhibition of fear. This has clear implications for the treatment of anxiety and related disorders with therapeutic exposure.

Postinfectious Inflammation, Autoimmunity, and Obsessive-Compulsive Disorder: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection, and Pediatric Acute-Onset Neuropsychiatric Disorder.

Postinfectious neuroinflammation has been implicated in multiple models of acute-onset obsessive-compulsive disorder including Sydenham chorea (SC), pediatric acute-onset neuropsychiatric syndrome (PANS), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). These conditions are associated with a range of autoantibodies which are thought to be triggered by infections, most notably group A streptococci (GAS). Based on animal models using huma sera, these autoantibodies are thought to cross-react with neural antigens in the basal ganglia and modulate neuronal activity and behavior. As is true for many childhood neuroinflammatory diseases and rheumatological diseases, SC, PANS, and PANDAS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. In this review article, we outline the accumulating evidence supporting the role neuroinflammation plays in these disorders. We describe work with animal models including patient-derived anti-neuronal autoantibodies, and we outline imaging studies that show alterations in the basal ganglia. In addition, we present research on metabolites, which are helpful in deciphering functional phenotypes, and on the implication of sleep in these disorders. Finally, we encourage future researchers to collaborate across medical specialties (e.g., pediatrics, psychiatry, rheumatology, immunology, and infectious disease) in order to further research on clinical syndromes presenting with neuropsychiatric manifestations.

Neurofeedback for obsessive compulsive disorder: A randomized, double-blind trial.

We aim to develop fMRI neurofeedback as a treatment for obsessive compulsive disorder (OCD). In prior work, we found that providing neurofeedback of activity in the anterior prefrontal cortex (aPFC) improved control over contamination anxiety in a subclinical population. Here, we present the results of a randomized, double-blind clinical trial (NCT02206945) testing this intervention in patients with OCD. We recruited patients with primary symptoms in the fear-of-harm/checking or contamination/washing domains. During neurofeedback, they viewed symptom provocative images and attempted to up- and down-regulate the aPFC during different blocks of time. The active group received two sessions of neurofeedback and the control group received yoked sham feedback. The primary outcome measure was the Yale-Brown Obsessive-Compulsive Symptom scale. The secondary outcome was control over aPFC. Thirty-six participants completed feedback training (18 active, 18 control). The active group had a slightly but significantly greater reduction of obsessive-compulsive symptoms after neurofeedback compared to the control group (p<.05) but no significant differences in control over the aPFC. These data demonstrate that neurofeedback targeting the aPFC can reduce symptoms in OCD. Future investigations should seek to optimize the training protocol to yield larger effects and to clarify the mechanism of action.

A novel naïve Bayes approach to identifying grooming behaviors in the force-plate actometric platform.

Background: Self-grooming behavior in rodents serves as a valuable model for investigating stereotyped and perseverative responses. Most current grooming analyses primarily rely on video observation, which lacks standardization, efficiency, and quantitative information about force. To address these limitations, we developed an automated paradigm to analyze grooming using a force-plate actometer. New Method: Grooming behavior is quantified by calculating ratios of relevant movement power spectral bands. These ratios are then input into a naïve Bayes classifier, trained with manual video observations. To validate the effectiveness of this method, we applied it to the behavioral analysis of the early-life striatal cholinergic interneuron depletion (CIN-d) mouse, a model of tic pathophysiology recently developed in our laboratory, which exhibits prolonged grooming responses to acute stressors. Behavioral monitoring was simultaneously conducted on the force-place actometer and by video recording. Results: The naïve Bayes approach achieved 93.7% accurate classification and an area under the receiver operating characteristic curve of 0.894. We confirmed that male CIN-d mice displayed significantly longer grooming durations compared to controls. However, this elevation was not correlated with increases in grooming force. Notably, haloperidol, a benchmark therapy for tic disorders, reduced both grooming force and duration. Comparison with Existing Methods: In contrast to observation-based approaches, our method affords rapid, unbiased, and automated assessment of grooming duration, frequency, and force. Conclusions: Our novel approach enables fast and accurate automated detection of grooming behaviors. This method holds promise for high-throughput assessments of grooming stereotypies in animal models of tic disorders and other psychiatric conditions.

Pleiotropic Association of CACNA1C Variants With Neuropsychiatric Disorders.

BACKGROUND: Neuropsychiatric disorders are highly heritable and have overlapping genetic underpinnings. Single nucleotide polymorphisms (SNPs) in the gene CACNA1C have been associated with several neuropsychiatric disorders, across multiple genome-wide association studies. METHOD: A total of 70,711 subjects from 37 independent cohorts with 13 different neuropsychiatric disorders were meta-analyzed to identify overlap of disorder-associated SNPs within CACNA1C. The differential expression of CACNA1C mRNA in five independent postmortem brain cohorts was examined. Finally, the associations of disease-sharing risk alleles with total intracranial volume (ICV), gray matter volumes (GMVs) of subcortical structures, cortical surface area (SA), and average cortical thickness (TH) were tested. RESULTS: Eighteen SNPs within CACNA1C were nominally associated with more than one neuropsychiatric disorder (P < .05); the associations shared among schizophrenia, bipolar disorder, and alcohol use disorder survived false discovery rate correction (five SNPs with P < 7.3 × 10-4 and q < 0.05). CACNA1C mRNA was differentially expressed in brains from individuals with schizophrenia, bipolar disorder, and Parkinson's disease, relative to controls (three SNPs with P < .01). Risk alleles shared by schizophrenia, bipolar disorder, substance dependence, and Parkinson's disease were significantly associated with ICV, GMVs, SA, or TH (one SNP with P ≤ 7.1 × 10-3 and q < 0.05). CONCLUSION: Integrating multiple levels of analyses, we identified CACNA1C variants associated with multiple psychiatric disorders, and schizophrenia and bipolar disorder were most strongly implicated. CACNA1C variants may contribute to shared risk and pathophysiology in these conditions.

The functional connectome in obsessive-compulsive disorder: resting-state mega-analysis and machine learning classification for the ENIGMA-OCD consortium.

Current knowledge about functional connectivity in obsessive-compulsive disorder (OCD) is based on small-scale studies, limiting the generalizability of results. Moreover, the majority of studies have focused only on predefined regions or functional networks rather than connectivity throughout the entire brain. Here, we investigated differences in resting-state functional connectivity between OCD patients and healthy controls (HC) using mega-analysis of data from 1024 OCD patients and 1028 HC from 28 independent samples of the ENIGMA-OCD consortium. We assessed group differences in whole-brain functional connectivity at both the regional and network level, and investigated whether functional connectivity could serve as biomarker to identify patient status at the individual level using machine learning analysis. The mega-analyses revealed widespread abnormalities in functional connectivity in OCD, with global hypo-connectivity (Cohen's d: -0.27 to -0.13) and few hyper-connections, mainly with the thalamus (Cohen's d: 0.19 to 0.22). Most hypo-connections were located within the sensorimotor network and no fronto-striatal abnormalities were found. Overall, classification performances were poor, with area-under-the-receiver-operating-characteristic curve (AUC) scores ranging between 0.567 and 0.673, with better classification for medicated (AUC = 0.702) than unmedicated (AUC = 0.608) patients versus healthy controls. These findings provide partial support for existing pathophysiological models of OCD and highlight the important role of the sensorimotor network in OCD. However, resting-state connectivity does not so far provide an accurate biomarker for identifying patients at the individual level.

Safety, tolerability, and clinical and neural effects of single-dose psilocybin in obsessive-compulsive disorder: protocol for a randomized, double-blind, placebo-controlled, non-crossover trial.

Background: Psilocybin 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. Objectives: This 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. Design: We 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 analysis: We 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 statement: All 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). Discussion: This 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.