Comparable roles for serotonin in rats and humans for computations underlying flexible decision-making

Biological Psychiatry Global Open Science

BackgroundThe nature of cognitive flexibility deficits in obsessive-compulsive disorder (OCD), which historically have been tested with probabilistic reversal learning tasks, remains elusive. Here, a novel deterministic reversal task and inclusion of unmedicated patients in the study sample illuminated the role of fixed versus uncertain rules/contingencies and of serotonergic medication. Additionally, our understanding of probabilistic reversal was enhanced through theoretical computational modeling of cognitive flexibility in OCD.MethodsWe recruited 49 patients with OCD, 21 of whom were unmedicated, and 43 healthy control participants matched for age, IQ, and gender. Participants were tested on 2 tasks: a novel visuomotor deterministic reversal learning task with 3 reversals (feedback rewarding/punishing/neutral) measuring accuracy/perseveration and a 2-choice visual probabilistic reversal learning task with …

medRxiv

One of the most complex human behaviours that defies singular explanatory models is suicidal behaviour, especially in the youth. A promising approach to make progress with this conundrum is to parse distinct subtypes of this behaviour. Utilizing 1,624 children with suicidal thoughts and behaviors (STBs) and 3,224 healthy controls from the ABCD Study, we clustered children with STB based on thirty-four cognitive and psychopathological measures which capture suicide-related risk-moderating traits. Environmental and genetic risk factors, as well as neuroanatomical characteristics of each subtype, were then compared with controls. We identified five distinct STB subtypes, each revealing unique neuroanatomy, environmental/genetic risks, and persistence patterns. Subtype 1 (Depressive, 9.6%) exhibited the most severe depressive symptoms. Subtype 2 (Externalizing, 20.1%) displayed anatomical and functional alterations in frontoparietal network and increased genetic risk for ADHD. Subtype 3 (Cognitive Deficit, 20.4%) demonstrated lower cognitive performance and widespread white-matter deficits. Subtype 4 (Mild Psychotic, 22.2%) presented higher prodromal psychotic symptoms, often unnoticed by parents. Subtype 5 (High Functioning, 27.6%) showed larger total brain volume, better cognition, and higher socio-economic status, contrasting subtypes 1-4. Only Subtypes 1 and 2 demonstrate persistent STB features at the 2-year follow-up. Our results suggested that youth suicidal behaviour may result from several distinct bio-behavioral pathways that are identifiable through co-occurring psychopathology, and provide insights into the …

2023-08-18 Assigned to SIRGARTAN HOLDINGS LTD reassignment SIRGARTAN HOLDINGS LTD ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GARZYA, VICENZO, ROBBINS, Trevor, SIREAU, Nicolas Thierry, TANCOCK, Jon

bioRxiv

Cognitive flexibility, the ability to adapt behavior in response to a changing environment, is disrupted in several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). Evidence suggests that flexibility, which can be operationalized using reversal learning tasks, is modulated by serotonergic transmission. However, how exactly flexible behavior and associated reinforcement learning (RL) processes are modulated by 5-HT action on specific receptors is unknown. We investigated the effects of 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) antagonism on cognitive flexibility and underlying RL mechanisms. Thirty-six male Lister-hooded rats were trained on the valence-probe visual discrimination (VPVD) task. We evaluated the effects of systemic treatments with the 5-HT2AR and 5-HT2CR antagonists M100907 and SB-242084, respectively, on reversal learning performance and performance on probe trials where correct and incorrect stimuli were presented with a third, probabilistically rewarded, stimulus. Computational models were fitted to VPVD choice data to extract RL parameters, including a novel model designed specifically for this task. 5-HT2AR antagonism impaired reversal learning during certain phases. 5-HT2CR antagonism, on the other hand, impaired learning from positive feedback. RL models further differentiated these effects. 5-HT2AR antagonism decreased punishment learning rate at high and low doses. The low dose also increased exploration (beta) and increased stimulus and side stickiness (kappa). 5-HT2CR antagonism also increased beta, but …

Journal of Clinical Medicine

(1) Background: Traumatic brain injury (TBI) often results in cognitive impairments, including in visuospatial planning and executive function. Methylphenidate (MPh) demonstrates potential improvements in several cognitive domains in patients with TBI. The Tower of London (TOL) is a visuospatial planning task used to assess executive function.(2) Methods: Volunteers with a history of TBI (n= 16) participated in a randomised, double-blinded, placebo-controlled, fMRI study to investigate the neurobiological correlates of visuospatial planning and executive function, on and off MPh.(3) Results: Healthy controls (HCs)(n= 18) and patients on placebo (TBI-placebo) differed significantly in reaction time (p< 0.0005) and accuracy (p< 0.0001) when considering all task loads, but especially for high cognitive loads for reaction time (p< 0.001) and accuracy (p< 0.005). Across all task loads, TBI-MPh were more accurate than TBI-placebo (p< 0.05) but remained less accurate than HCs (p< 0.005). TBI-placebo substantially improved in accuracy with MPh administration (TBI-MPh) to a level statistically comparable to HCs at low (p= 0.443) and high (p= 0.175) cognitive loads. Further, individual patients that performed slower on placebo at low cognitive loads were faster with MPh (p< 0.05), while individual patients that performed less accurately on placebo were more accurate with MPh at both high and low cognitive loads (p< 0.005). TBI-placebo showed reduced activity in the bilateral inferior frontal gyri (IFG) and insulae versus HCs. MPh normalised these regional differences. MPh enhanced within-network connectivity (between parietal, striatal, insula, and …

Psychological Medicine

BackgroundCOVID-19 lockdowns increased the risk of mental health problems, especially for children with autism spectrum disorder (ASD). However, despite its importance, little is known about the protective factors for ASD children during the lockdowns.MethodsBased on the Shanghai Autism Early Developmental Cohort, 188 ASD children with two visits before and after the strict Omicron lockdown were included; 85 children were lockdown-free, while 52 and 51 children were under the longer and the shorter durations of strict lockdown, respectively. We tested the association of the lockdown group with the clinical improvement and also the modulation effects of parent/family-related factors on this association by linear regression/mixed-effect models. Within the social brain structures, we examined the voxel-wise interaction between the grey matter volume and the identified modulation effects.ResultsCompared …

bioRxiv

Cognitive flexibility, the capacity to adapt behaviour to changes in the environment, is impaired in a range of brain disorders, including substance use disorder and Parkinson's disease. Putative neural substrates of cognitive flexibility include mesencephalic pathways to the ventral striatum (VS) and dorsomedial striatum (DMS), hypothesised to encode learning signals needed to maximize rewarded outcomes during decision-making. However, it is unclear whether mesencephalic projections to the ventral and dorsal striatum are distinct in their contribution to flexible reward-related learning. Here, rats acquired a two-choice spatial probabilistic reversal learning (PRL) task, reinforced on an 80%:20% basis, that assessed the flexibility of behaviour to repeated reversals of response-outcome contingencies. We report that optogenetic stimulation of projections from the ventral tegmental area (VTA) to the nucleus accumbens shell (NAcbS) in the VS significantly impaired reversal learning when optical stimulation was temporally aligned with negative feedback (i.e., reward omission). Moreover, the exploitation-exploration parameter, beta, was increased (indicating greater exploitation of information) when this pathway was optogenetically stimulated after a spurious loss (i.e. an incorrect (20%) response at the 80% reinforrced location) compared to after a spurious win (i.e. a correct (20%) response at the 20% reinforced location). VTA -> NAcbS stimulation during other phases of the behavioural task was without effect. Optogenetic stimulation of projection neurons from the substantia nigra (SN) to the DMS, aligned either with reward receipt or omission or …

Compulsive behaviour, an apparently irrational perseveration in often maladaptive acts, is a potential transdiagnostic symptom of several neuropsychiatric disorders, including obsessive-compulsive disorder and addiction, and may reflect the severe manifestation of a dimensional trait termed compulsivity. In this Review, we examine the psychological basis of compulsions and compulsivity and their underlying neural circuitry using evidence from human neuroimaging and animal models. Several main elements of this circuitry are identified, focused on fronto-striatal systems implicated in goal-directed behaviour and habits. These systems include the orbitofrontal, prefrontal, anterior cingulate and insular cortices and their connections with the basal ganglia as well as sensoriomotor and parietal cortices and cerebellum. We also consider the implications for future classification of impulsive–compulsive disorders and …

Neuropsychopharmacology

Eugene Stern Paykel was born on 9 September 1934 in Auckland, New Zealand. His research work focused on affective disorders in which he made significant and far-reaching contributions to the study of both causes and treatments of depression, spanning the fields of epidemiology, community psychiatry, psychological therapy, and psychopharmacology. He was the sole editor of the influential ‘Handbook of Affective Disorders’(editions 1 and 2) which brought together these disparate areas of study as an early example of the biopsychosocial framework for understanding mental illness. Overall, he published approximately 400 papers, with over 32,000 citations, and authored, co-authored, or edited eight books. As a reflection of his research interest in psychopharmacology, he served as President of The British Association for Psychopharmacology (BAP) and The Collegium Internationale …

Biological Psychiatry

BACKGROUNDIrritable bowel syndrome (IBS) interacts with psychopathology in a complex way, yet little is known about the underlying brain, biochemical and genetic mechanisms.METHODSTo clarify the phenotypic and genetic associations between IBS and brain health, we performed a comprehensive retrospective cohort study on a large population. Our study included 171,104 participants from the UK Biobank who underwent a thorough assessment of the IBS syndrome, with the majority also providing neuroimaging, behavioral, biochemical, and genetic information. Multistage linked analyses were conducted, including phenome-wide association analysis, polygenic risk score calculation, and two-sample Mendelian Randomization (MR) analysis.RESULTSThe phenome-wide association analysis showed that IBS is linked to brain health problems, including anxiety and depression, and poor cognitive …

Subregions of the medial temporal lobe (MTL) undergo substantial changes during the female menopause. How the decline in MTL volumes during menopause affects cognitive function is still unknown. In this study, we aim to validate previous results of decreased MTL grey matter (GM) volumes in post-menopausal women and investigate how diffusion imaging measures are affected by it. We relate this to changes in cognition, specifically focussing on learning and memory changes. Furthermore, we investigate whether hormone replacement therapy can slow the progression of decline in cognition and MTL volumes. We use data from approximately 13,000 participants from the UK Biobank cohort that were either pre-or post-menopausal. We investigate the effect of spontaneous menopause, HRT, and duration of HRT use on GM volumes, fractional anisotropy (FA) and mean diffusivity (MD).

BJPsych Open

BackgroundIndividuals with cocaine use disorder or gambling disorder demonstrate impairments in cognitive flexibility: the ability to adapt to changes in the environment. Flexibility is commonly assessed in a laboratory setting using probabilistic reversal learning, which involves reinforcement learning, the process by which feedback from the environment is used to adjust behavior.AimsIt is poorly understood whether impairments in flexibility differ between individuals with cocaine use and gambling disorders, and how this is instantiated by the brain. We applied computational modelling methods to gain a deeper mechanistic explanation of the latent processes underlying cognitive flexibility across two disorders of compulsivity.MethodWe present a re-analysis of probabilistic reversal data from individuals with either gambling disorder (n = 18) or cocaine use disorder (n = 20) and control participants (n = 18), using a …

Biological Psychiatry

BACKGROUNDIrritable bowel syndrome (IBS) interacts with psychopathology in a complex way, yet little is known about the underlying brain, biochemical and genetic mechanisms.METHODSTo clarify the phenotypic and genetic associations between IBS and brain health, we performed a comprehensive retrospective cohort study on a large population. Our study included 171,104 participants from the UK Biobank who underwent a thorough assessment of the IBS syndrome, with the majority also providing neuroimaging, behavioral, biochemical, and genetic information. Multistage linked analyses were conducted, including phenome-wide association analysis, polygenic risk score calculation, and two-sample Mendelian Randomization (MR) analysis.RESULTSThe phenome-wide association analysis showed that IBS is linked to brain health problems, including anxiety and depression, and poor cognitive …

BJPsych Open

BackgroundIndividuals with cocaine use disorder or gambling disorder demonstrate impairments in cognitive flexibility: the ability to adapt to changes in the environment. Flexibility is commonly assessed in a laboratory setting using probabilistic reversal learning, which involves reinforcement learning, the process by which feedback from the environment is used to adjust behavior.AimsIt is poorly understood whether impairments in flexibility differ between individuals with cocaine use and gambling disorders, and how this is instantiated by the brain. We applied computational modelling methods to gain a deeper mechanistic explanation of the latent processes underlying cognitive flexibility across two disorders of compulsivity.MethodWe present a re-analysis of probabilistic reversal data from individuals with either gambling disorder (n = 18) or cocaine use disorder (n = 20) and control participants (n = 18), using a …

International Clinical Psychopharmacology

Patients with obsessive compulsive disorder (OCD) randomised to sertraline, manualised cognitive behavioural therapy (CBT), or combination (sertraline+ CBT), underwent cognitive assessment. Cognitive testing was conducted at baseline and at week 16. The stop signal reaction time task (SSRT) was used to evaluate motor impulsivity and attentional flexibility was evaluated using the intra/extra-dimensional set shifting task. Paired-samples t-tests or nonparametric variants were used to compare baseline and posttreatment scores within each treatment group. Forty-five patients were tested at baseline (sertraline n= 14; CBT n= 14; sertraline+ CBT n= 17) and 23 patients at week 16 (sertraline n= 6; CBT n= 7; sertraline+ CBT n= 10). The mean dosage of sertraline was numerically higher in those taking sertraline as a monotherapy (166.67 mg) compared with those taking sertraline in combination with CBT (100 mg …

Biological Psychiatry Global Open Science

BackgroundThe nature of cognitive flexibility deficits in obsessive-compulsive disorder (OCD), which historically have been tested with probabilistic reversal learning tasks, remains elusive. Here, a novel deterministic reversal task and inclusion of unmedicated patients in the study sample illuminated the role of fixed versus uncertain rules/contingencies and of serotonergic medication. Additionally, our understanding of probabilistic reversal was enhanced through theoretical computational modeling of cognitive flexibility in OCD.MethodsWe recruited 49 patients with OCD, 21 of whom were unmedicated, and 43 healthy control participants matched for age, IQ, and gender. Participants were tested on 2 tasks: a novel visuomotor deterministic reversal learning task with 3 reversals (feedback rewarding/punishing/neutral) measuring accuracy/perseveration and a 2-choice visual probabilistic reversal learning task with …

The present project is part of a larger project aimed at examining cognitive flexibility, other executive functions, and learning in healthy adults (Melani et al., 2022; Sam et al., 2022; Tong et al., 2021) in Singapore. The current pre-registration form primarily aims to examining specific hypotheses related to the association between socio-cognitive variables and career development/transitional behaviours and outcomes, which might not be described in the main studies (https://osf. io/ay9gr; https://osf. io/n352u; https://osf. io/6rc9h) in detail. Changes in the workplace over the past decades have spawned an increase in research investigating contemporary career types, which are characterized by increased self-directedness, flexibility, and the aim of subjective career success. Living in a dynamic and complex environment necessitates that all living organisms be flexible and adaptive to survive (Powell & Ragozzino, 2017). Humans are required to proactively equip themselves with the ability to shift their strategies and update their beliefs and actions in response to changing environmental demands (Diamond, 2006; Garcia-Garcia et al., 2010; Geurts et al., 2009; Herrmann et al., 2015). For instance, the increasing volatility in the 21st-century workforce, particularly during the unprecedented COVID-19 pandemic, has served as a timely reminder of the urgency of cultivating the flexibility to respond to unforeseen changes and uncertainties more adaptively in order to stay competitive in turbulent job markets. The view of a linear career path (whereby workers are only trained to perform and master one job) that dominated the mainstream workplace system …

Neuropsychopharmacology

Individuals with cocaine addiction can experience many craving episodes and subsequent relapses, which represents the main obstacle to recovery. Craving is often favored when abstinent individuals ingest a small dose of cocaine, encounter cues associated with drug use or are exposed to stressors. Using a cocaine-primed reinstatement model in rat, we recently showed that cocaine-conditioned interoceptive cues can be extinguished with repeated cocaine priming in the absence of drug reinforcement, a phenomenon we called extinction of cocaine priming. Here, we applied a large-scale c-Fos brain mapping approach following extinction of cocaine priming in male rats to identify brain regions implicated in processing the conditioned interoceptive stimuli of cocaine priming. We found that cocaine-primed reinstatement is associated with increased c-Fos expression in key brain regions (e.g., dorsal and ventral …

Neuropsychopharmacology

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with …

Neuropsychopharmacology

Trauma and chronic stress exposure are the strongest predictors of lifetime neuropsychiatric disease presentation. These disorders often have significant sex biases, with females having higher incidences of affective disorders such as major depression, anxiety, and PTSD. Understanding the mechanisms by which stress exposure heightens disease vulnerability is essential for developing novel interventions. Current rodent stress models consist of a battery of sensory, homeostatic, and psychological stressors that are ultimately integrated by corticotropin-releasing factor (CRF) neurons to trigger corticosteroid release. These stress paradigms, however, often differ between research groups in the type, timing, and duration of stressors utilized. These inconsistencies, along with the variability of individual animals’ perception and response to each stressor, present challenges for reproducibility and translational …

Neuropsychopharmacology

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with …

Neuropsychopharmacology

Correction: Psychosocial moderators of polygenic risk scores of inflammatory biomarkers in relation to GrimAge - PMC Back to Top Skip to main content NIH NLM Logo Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search PMC Full-Text Archive Search in PMC Advanced Search User Guide Journal List Neuropsychopharmacology v.49(4); 2024 Mar PMC10876612 Other Formats PDF (405K) Actions Cite Collections Share Permalink Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Journal List Neuropsychopharmacology v.49(4); 2024 Mar PMC10876612 As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Logo of nppharm Neuropsychopharmacology. …

Neuropsychopharmacology

Previous studies of brain structure in anorexia nervosa (AN) have reported reduced gray matter in underweight patients, which largely normalizes upon weight gain. One underlying biological mechanism may be glial cell alterations related to low-grade inflammation. Here, we investigated relationships between brain structure as measured by magnetic resonance imaging and serum concentrations of two pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor alpha) cross-sectionally in 82 underweight adolescent and young adult female patients (mean age 16.8 years; 59 of whom were observed longitudinally after short-term weight restoration; mean duration 2.8 months), 20 individuals long-term weight-recovered from AN (mean age 22.7 years) and 105 healthy control (HC) participants (mean age 17.2 years). We measured cortical thickness, subcortical volumes and local gyrification index, a measure …

Neuropsychopharmacology

The majority of lifetime smokers begin using nicotine during adolescence, a critical period of brain development wherein neural circuits critical for mood, affect and cognition are vulnerable to drug-related insults. Specifically, brain regions such as the medial prefrontal cortex (mPFC), the ventral tegmental area (VTA), nucleus accumbens (NAc) and hippocampus, are implicated in both nicotine dependence and pathological phenotypes linked to mood and anxiety disorders. Clinical studies report that females experience higher rates of mood/anxiety disorders and are more resistant to smoking cessation therapies, suggesting potential sex-specific responses to nicotine exposure and later-life neuropsychiatric risk. However, the potential neural and molecular mechanisms underlying such sex differences are not clear. In the present study, we compared the impacts of adolescent nicotine exposure in male vs. female rat …

Neuropsychopharmacology

Creating long-lasting memories requires learning-induced changes in gene expression, which are impacted by epigenetic modifications of DNA and associated histone proteins. Post-translational modifications (PTMs) of histones are key regulators of transcription, with different PTMs producing unique effects on gene activity and behavior. Although recent studies implicate histone variants as novel regulators of memory, effects of PTMs on the function of histone variants are rarely considered. We previously showed that the histone variant H2A.Z suppresses memory, but it is unclear if this role is impacted by H2A.Z acetylation, a PTM that is typically associated with positive effects on transcription and memory. To answer this question, we used a mutation approach to manipulate acetylation on H2A.Z without impacting acetylation of other histone types. Specifically, we used adeno-associated virus (AAV) constructs to …

Neuropsychopharmacology

Although many genetic risk factors for psychiatric and neurodevelopmental disorders have been identified, the neurobiological route from genetic risk to neuropsychiatric outcome remains unclear. 22q11.2 deletion syndrome (22q11.2DS) is a copy number variant (CNV) syndrome associated with high rates of neurodevelopmental and psychiatric disorders including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia. Alterations in neural integration and cortical connectivity have been linked to the spectrum of neuropsychiatric disorders seen in 22q11.2DS and may be a mechanism by which the CNV acts to increase risk. In this study, magnetoencephalography (MEG) was used to investigate electrophysiological markers of local and global network function in 34 children with 22q11.2DS and 25 controls aged 10–17 years old. Resting-state oscillatory activity and …

Neuropsychopharmacology

The central nucleus of the amygdala is known to play key roles in alcohol use and affect. Neurotensin neurons in the central nucleus of the amygdala have been shown to regulate alcohol drinking in male mice. However, little is known about which neurotransmitters released by these cells drive alcohol consumption or whether these cells drive alcohol consumption in female mice. Here we show that knockdown of GABA release from central amygdala neurotensin neurons using a Nts-cre-dependent vGAT-shRNA-based AAV strategy reduces alcohol drinking in male, but not female, mice. This manipulation did not impact avoidance behavior, except in a fasted novelty-suppressed feeding test, in which vGAT shRNA mice demonstrated increased latency to feed on a familiar high-value food reward, an effect driven by male mice. In contrast, vGAT shRNA female mice showed heightened sensitivity to thermal …

Neuropsychopharmacology

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with …

Neuropsychopharmacology

GrimAge acceleration has previously predicted age-related morbidities and mortality. In the current study, we sought to examine how GrimAge is associated with genetic predisposition for systemic inflammation and whether psychosocial factors moderate this association. Military veterans from the National Health and Resilience in Veterans study, which surveyed a nationally representative sample of European American male veterans, provided saliva samples for genotyping (N = 1135). We derived polygenic risk scores (PRS) from the UK Biobank as markers of genetic predisposition to inflammation. Results revealed that PRS for three inflammatory PRS markers—HDL (lower), apolipoprotein B (lower), and gamma-glutamyl transferase (higher)—were associated with accelerated GrimAge. Additionally, these PRS interacted with a range of potentially modifiable psychosocial variables, such as exercise and …

Neuropsychopharmacology

Creating long-lasting memories requires learning-induced changes in gene expression, which are impacted by epigenetic modifications of DNA and associated histone proteins. Post-translational modifications (PTMs) of histones are key regulators of transcription, with different PTMs producing unique effects on gene activity and behavior. Although recent studies implicate histone variants as novel regulators of memory, effects of PTMs on the function of histone variants are rarely considered. We previously showed that the histone variant H2A.Z suppresses memory, but it is unclear if this role is impacted by H2A.Z acetylation, a PTM that is typically associated with positive effects on transcription and memory. To answer this question, we used a mutation approach to manipulate acetylation on H2A.Z without impacting acetylation of other histone types. Specifically, we used adeno-associated virus (AAV) constructs to …

Neuropsychopharmacology

Psychiatric illnesses are major public health problems and leading causes of disability and death worldwide. These illnesses often have their origins in childhood and adolescence, and account for over a third of disabilities across the human lifespan. Psychiatric disorders also contribute to premature aging and risk of dementias. Individuals with severe and persistent mental illnesses die years earlier than expected for their birth cohorts. Contributors to premature death include smoking, obesity, sedentary lifestyle, drug and alcohol use, cardiovascular illnesses, violence, and suicide. In 2021,“deaths of despair”—including suicide, drug overdoses, and drug and alcohol-related deaths—claimed the lives of over 185,000 individuals in the United States. The devastation wreaked by psychiatric illnesses strongly underlies the need for novel, rapid, and more effective treatments. The latest treatments—including …

Neuropsychopharmacology

Psychiatric and obstetric diseases are growing threats to public health and share high rates of co-morbidity. G protein-coupled receptor signaling (e.g., vasopressin, serotonin) may be a convergent psycho-obstetric risk mechanism. Regulator of G Protein Signaling 2 (RGS2) mutations increase risk for both the gestational disease preeclampsia and for depression. We previously found preeclampsia-like, anti-angiogenic obstetric phenotypes with reduced placental Rgs2 expression in mice. Here, we extend this to test whether conserved cerebrovascular and serotonergic mechanisms are also associated with risk for neurobiological phenotypes in the Rgs2 KO mouse. Rgs2 KO exhibited anxiety-, depression-, and hedonic-like behaviors. Cortical vascular density and vessel length decreased in Rgs2 KO; cortical and white matter thickness and cell densities were unchanged. In Rgs2 KO, serotonergic gene expression …

Neuropsychopharmacology

Neural complexity correlates with one’s level of consciousness. During coma, anesthesia, and sleep, complexity is reduced. During altered states, including after lysergic acid diethylamide (LSD), complexity is increased. In the present analysis, we examined whether low doses of LSD (13 and 26 µg) were sufficient to increase neural complexity in the absence of altered states of consciousness. In addition, neural complexity was assessed after doses of two other drugs that significantly altered consciousness and mood: delta-9-tetrahydrocannabinol (THC; 7.5 and 15 mg) and methamphetamine (MA; 10 and 20 mg). In three separate studies (N = 73; 21, LSD; 23, THC; 29, MA), healthy volunteers received placebo or drug in a within-subjects design over three laboratory visits. During anticipated peak drug effects, resting state electroencephalography (EEG) recorded Limpel-Ziv complexity and spectral power …

Neuropsychopharmacology

Genomic prediction of antipsychotic dose and polypharmacy has been difficult, mainly due to limited access to large cohorts with genetic and drug prescription data. In this proof of principle study, we investigated if genetic liability for schizophrenia is associated with high dose requirements of antipsychotics and antipsychotic polypharmacy, using real-world registry and biobank data from five independent Nordic cohorts of a total of N = 21,572 individuals with psychotic disorders (schizophrenia, bipolar disorder, and other psychosis). Within regression models, a polygenic risk score (PRS) for schizophrenia was studied in relation to standardized antipsychotic dose as well as antipsychotic polypharmacy, defined based on longitudinal prescription registry data as well as health records and self-reported data. Meta-analyses across the five cohorts showed that PRS for schizophrenia was significantly positively …

Neuropsychopharmacology

Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome, in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, male Sprague-Dawley rats received either untreated water or antibiotics to …

Neuropsychopharmacology

REPLYING TO Martz J et al. Neuropsychopharmacology https://doi. org/10.1038/s41386-024-01838-x (2024) Karadag et al.[1] were concerned that the corticosterone inhibitor, metyrapone, reversed the effect of lipopolysaccharide (LPS) on sickness behavior. While not the focus of our paper, we also find it interesting that maternal sickness responses were decreased in rat dams that received metyrapone and LPS. Classically, corticosteroids are thought to be anti-inflammatory and can be used to treat endotoxemia, yet here its inhibition was associated with reductions in sickness behaviors and their associated plasma cytokines following LPS. As mentioned in our article, the differential LPS-induced cytokine profiles (inhibition/activation) across studies likely depend on the reproductive status of the animal, as well as on methodological aspects of the LPS dose and timing of plasma cytokine sampling. It is important to …

Neuropsychopharmacology

Prototypic antidepressants, such as tricyclic/tetracyclic antidepressants (TCAs), have multiple pharmacological properties and have been considered to be more effective than newer antidepressants, such as selective serotonin reuptake inhibitors, in treating severe depression. However, the clinical contribution of non-monoaminergic effects of TCAs remains elusive. In this study, we discovered that amitriptyline, a typical TCA, directly binds to the lysophosphatidic acid receptor 1 (LPAR1), a G protein-coupled receptor, and activates downstream G protein signaling, while exerting a little effect on β-arrestin recruitment. This suggests that amitriptyline acts as a G protein-biased agonist of LPAR1. This biased agonism was specific to TCAs and was not observed with other antidepressants. LPAR1 was found to be involved in the behavioral effects of amitriptyline. Notably, long-term infusion of mouse hippocampus with the …