Neuropsychopharmacology [JOURNAL]
Sun
200 papers
A phase 2 randomized controlled trial of luvadaxistat in treatment of adults with cognitive impairment associated with schizophrenia: results from the ERUDITE study.
Khin NA, Fan RH, Ge T … +10 more , Klein HS, Ballon JS, Brar S, Harvey PD, Kantrowitz JT, Keefe RSE, Asgharnejad M, Murthy V, Roberts E, Singh JB
Neuropsychopharmacology · 2026 Apr · PMID 42032293 · Publisher ↗
The phase 2 ERUDITE (NCT05182476) study evaluated the efficacy and safety of luvadaxistat, a selective ᴅ-amino acid oxidase inhibitor, for cognitive impairment associated with schizophrenia. ERUDITE was a randomized, dou...
The phase 2 ERUDITE (NCT05182476) study evaluated the efficacy and safety of luvadaxistat, a selective ᴅ-amino acid oxidase inhibitor, for cognitive impairment associated with schizophrenia. ERUDITE was a randomized, double-blind, placebo-controlled, parallel-group study in adults with schizophrenia receiving background antipsychotic therapy. Following a 2-week placebo run-in, participants were randomized 2:1:1 to receive placebo, luvadaxistat 20 mg, or luvadaxistat 50 mg once daily for a 12-week treatment period. The primary endpoint was change from baseline to Day 98 in the Brief Assessment of Cognition in Schizophrenia (BACS) composite score. Safety outcomes included the incidence of treatment-emergent adverse events (TEAEs). Overall, 203 participants were randomized (placebo, n = 101; luvadaxistat 20 mg, n = 50; luvadaxistat 50 mg, n = 52), and 178 (87.7%) completed the treatment period. Luvadaxistat did not significantly improve performance (change from baseline) in BACS composite score versus placebo at Day 98 (least-squares mean difference [95% confidence interval]: 20 mg, -0.7 [-2.8, 1.4], p = 0.75; 50 mg, -0.5 [-2.7, 1.6], p = 0.69). TEAEs were reported in approximately one-third of participants across groups, with comparable rates observed between the luvadaxistat and placebo groups. TEAEs were mostly mild or moderate, and no safety concerns were identified. Luvadaxistat 20 mg or 50 mg did not show statistically significant changes in cognitive performance or functioning within the ERUDITE study. Trial registration: ClinicalTrials.gov identifier NCT05182476.
Neural response to reward uncertainty in adolescents with mood and anxiety symptoms.
Liu Q, Nguyen TNB, Tobe RH … +3 more , Stern ER, Ely BA, Gabbay V
Neuropsychopharmacology · 2026 Apr · PMID 42026240 · Full text
Adolescence represents a critical neurodevelopmental period of high vulnerability to the onset of psychiatric conditions. Altered processing of uncertain reward outcomes likely contributes to this vulnerability, yet rema...
Adolescence represents a critical neurodevelopmental period of high vulnerability to the onset of psychiatric conditions. Altered processing of uncertain reward outcomes likely contributes to this vulnerability, yet remains poorly understood. Addressing this knowledge gap, we sought to use the fMRI Reward Flanker Task, originally developed by our group, to examine neural responses to uncertain rewards and their clinical associations. To fully capture clinical correlates, we recruited adolescents with mood and anxiety symptoms ranging from low to high severity, including healthy controls (HC). Participants were 84 psychotropic-medication-free adolescents (15.3 ± 2.1 years; 62% female; 17 HC); all completed diagnostic and dimensional symptom assessments. Neuroimaging data were preprocessed using Human Connectome Project pipelines. Analyses examined participant-level neural responses to uncertain reward expectancy and attainment, adjusted for age, sex, and multiple comparisons. Across the whole sample, uncertain versus certain cues activated the default network and suppressed the fronto-parietal control network. Neural responses during expectancy to uncertain reward were intermediate between responses to certain reward and non-reward stimuli. Outcome attainment following uncertain cues activated stronger neural responses in reward and salience regions compared to reward cues. Anhedonia severity correlated with default network activation during uncertain outcome attainment. Anxiety severity correlated with blunted striatal responses during uncertain vs. certain non-reward expectancy. Exploratory group comparisons revealed that adolescents with mood and anxiety symptoms versus HC showed blunted striatal responses during uncertain versus non-reward expectancy and hyperactivation in visual and default network areas during attainment following uncertain cues. Together, these findings support the role of uncertain reward processing in adolescent mood and anxiety psychopathology.
Adolescent obesity induces sex-specific alterations of action control.
Mukherjee D, Rougeux S, West RT … +3 more , Roumane A, Peters KZ, Naneix F
Neuropsychopharmacology · 2026 Apr · PMID 42026239 · Publisher ↗
The prevalence of obesity is rising worldwide in young people and is associated with poor long-term health outcomes. To counter obesity, weight loss strategies especially involve changes in feeding behaviors and food cho...
The prevalence of obesity is rising worldwide in young people and is associated with poor long-term health outcomes. To counter obesity, weight loss strategies especially involve changes in feeding behaviors and food choice. However, the high level of relapse to unhealthy dietary habits represents an important challenge, suggesting long-term alterations of decision-making and food-seeking processes. Previous studies showed that adolescence is critical for the development of decision-making functions. Thus, it is essential to understand the precise impact of the exposure to obesogenic diets during this life stage on the different processes underlying flexible control of food-seeking actions. To address this, we gave mice access to high-fat diets (HFDs) with different fat contents during adolescence and investigated the long-lasting impact on action control at adulthood after a switch to a healthy diet. We uncovered important sex differences. In both males and females, exposure to HFD with very high-fat content (60%) promoted habitual behavior, which is less flexible to adapt to changes in outcome value or action-outcome relationships. In contrast, exposure to HFD with lower fat content (45%) impaired action control based on the updating of outcome value in males only, while impairing action control based on the updating of action-outcome relationships in females only. These findings highlight how the consumption of obesogenic diets during adolescence has long-lasting, diet- and sex-dependent effects on decision-making processes, promoting habitual responses to food. These changes may support long-term vulnerability for mental and physiological health conditions.
Nucleus of the solitary tract regulation of cue-induced appetitive behaviors via midbrain dopamine neurons.
Yap JA, Gu YH, Vuong C … +2 more , Power JM, Ong ZY
Neuropsychopharmacology · 2026 Apr · PMID 42020765 · Publisher ↗
Internal states including stress and satiety, affect cue-induced feeding behaviors, yet the underlying neural mechanisms remain poorly understood. The nucleus of the solitary tract (NTS), a key hindbrain hub that integra...
Internal states including stress and satiety, affect cue-induced feeding behaviors, yet the underlying neural mechanisms remain poorly understood. The nucleus of the solitary tract (NTS), a key hindbrain hub that integrates interoceptive and viscerosensory signals and projects to reward processing nuclei, is anatomically well-positioned to modulate cue-induced feeding behaviors in response to internal state changes. Using behavioral paradigms combined with chemogenetics and fibre photometry, this study investigated the hypothesis that NTS mediates the effects of stress and satiety on cue-induced feeding behaviors via A2 neurons and modulation of ventral tegmental area (VTA) dopamine signaling. We first showed that both foot shock stress and outcome specific satiety (i.e., sucrose prefeed) reduced cue-induced appetitive behavior. Inhibition of NTS neurons only attenuated the suppressive effect of foot shock stress, but not that of outcome specific satiety, indicating that NTS is required for stress-induced suppression of cue-induced appetitive behavior. Further investigation into the contributing neural phenotype revealed that stimulation of NTS A2 neurons reduced conditioned approach and suppressed cue-evoked VTA dopamine neural activity, without any effects on lateral hypothalamus (LH) neuron activity. Together, these findings suggest that NTS neurons mediate the effects of foot shock stress, but not outcome specific satiety, on cue-induced appetitive behavior, in part through activation of NTS A2 neurons and modulation of cue-evoked VTA dopamine neural activity. These results provide an NTS-mediated mechanism through which stress suppresses cue-induced feeding behavior.
Model-based analysis of stop-signal data reveals robust neural and clinical correlates of evidence accumulation but not inhibition.
Weng Y, Boyle R, Lee CT … +30 more , Quinn D, Earley C, Splittgerber M, Zhang L, Franzen L, Banaschewski T, Bokde ALW, Desrivières S, Flor H, Grigis A, Garavan H, Gowland P, Heinz A, Brühl R, Martinot JL, Martinot MP, Artiges E, McGrath J, Nees F, Papadopoulos Orfanos D, Poustka L, Holz N, Hohmann S, Smolka MN, Vaidya N, Schumann G, Walter H, Weigard A, Whelan R, IMAGEN Consortium
Neuropsychopharmacology · 2026 Apr · PMID 42020764 · Publisher ↗
Poor inhibitory control and decision-making are often considered as risks for substance use and other adverse psychiatric outcomes. The Stop-Signal Task (SST) is a widely used protocol, from which inhibitory control is i...
Poor inhibitory control and decision-making are often considered as risks for substance use and other adverse psychiatric outcomes. The Stop-Signal Task (SST) is a widely used protocol, from which inhibitory control is indexed by stop signal reaction time (SSRT). However, heretofore models of SSRT may be too simplistic to capture complex processes underlying task performance. In contrast, the Racing Diffusion Ex-Gaussian ABCD (RDEX-ABCD) model provides a more mechanistic framework, capturing both inhibitory control and task-general decision-making processes during the SST. Here, we applied the RDEX-ABCD model to SST data from the IMAGEN cohort (n > 1000) at ages 19 and 23, and examined model parameters in relation to substance use via Elastic Net regression. Connectome-based predictive modeling was then performed to identify brain networks predicting parameters, and the association between these networks and substance use was examined. We found that parameters indexing inhibitory control had no associations with substance use and were only weakly associated with brain connectivity. In contrast, parameters reflecting general decision-making processes - such as efficiency of evidence accumulation, decision threshold (response caution), probability of go failure - and their associated brain activity were significant predictors of cannabis and cigarette use. These findings suggested that efficiency of evidence accumulation, a neurocognitive mechanism that facilitates adaptive decision making across many contexts, emerged as a robust predictor of substance use vulnerability. Overall, general decision-making mechanisms may act as more reliable indicators of vulnerability to substance use than the conventional inhibitory control measures.
Nucleus accumbens neuron subtype translatome signatures in socially stressed females.
Kumar G, Franco D, Basu M … +5 more , Olusakin J, Campbell R, Ament SA, Fox ME, Lobo MK
Neuropsychopharmacology · 2026 Apr · PMID 42020763 · Publisher ↗
Major depressive disorder (MDD) disproportionately affects women, yet the molecular mechanisms underlying female vulnerability remain poorly understood. The nucleus accumbens (NAc), a reward circuitry hub, is central to...
Major depressive disorder (MDD) disproportionately affects women, yet the molecular mechanisms underlying female vulnerability remain poorly understood. The nucleus accumbens (NAc), a reward circuitry hub, is central to stress- and depression-related pathology. While NAc medium spiny neuron (MSN) transcriptional adaptations have been characterized in stressed male rodents, much less is known about female adaptations. To address this, we exposed female D1-Cre-RiboTag and A2A-Cre-RiboTag mice to chronic witness defeat stress (CWDS) and classified them as high- or low-social interactors. Ribosome-associated mRNA was isolated from MSN subtypes and analyzed by RNA sequencing, differential gene expression analysis (DEG), and weighted gene co-expression network analysis (WGCNA). Cross-species consensus WGCNA with male mouse and human transcriptomic datasets was performed to identify conserved, sex-specific signatures. We detected 9 differentially expressed genes (DEGs) in D1-MSNs and 630 in A2A-MSNs (FDR < 0.05). In D1-MSNs, DEGs were primarily upregulated in low interactors and enriched for energy homeostasis and cell adhesion. A2A-MSN DEGs included upregulated structural genes and downregulated neurotransmission-related genes. WGCNA identified 9 significant D1- and 5 significant A2A-MSN modules, with the most impacted enriched for PI3K-Akt-mTOR signaling and regulated by Nf1. Consensus analysis revealed a stress-associated, sex- and subtype-specific module enriched for PI3K-Akt-mTOR signaling conserved across mice and humans. These findings reveal female-specific MSN transcriptional adaptations to chronic social stress and implicate PI3K-Akt-mTOR signaling as a convergent molecular pathway. By highlighting MSN subtype-specific vulnerabilities, this work suggests potential therapeutic targets for alleviating stress-induced pathology in women with MDD.
Target engagement in a head-to-head clinical trial of dysphoric versus anxiosomatic transcranial magnetic stimulation targets.
Baldi S, Lin C, Li J … +7 more , Frandsen S, Jones E, Palm S, Greene AS, Taylor JJ, Fox MD, Siddiqi SH
Neuropsychopharmacology · 2026 Apr · PMID 42014856 · Publisher ↗
Resting-state functional connectivity is increasingly used to measure neural engagement following transcranial magnetic stimulation (TMS), but whether connectivity changes are specific to the stimulation target and clini...
Resting-state functional connectivity is increasingly used to measure neural engagement following transcranial magnetic stimulation (TMS), but whether connectivity changes are specific to the stimulation target and clinically meaningful remains unclear. In a head-to-head trial, thirty-six patients with depression and anxiety were randomized to 30 TMS sessions at one of two circuit-based targets: a dorsolateral prefrontal target hypothesized to improve "dysphoric" symptoms, and a dorsomedial prefrontal target hypothesized to improve "anxiosomatic" symptoms. We tested whether: (1) TMS selectively engaged the targeted circuit; (2) baseline TMS site connectivity to the targeted circuit predicted circuit engagement; (3) either metric correlated with improvement on the Beck Depression and Beck Anxiety Inventories. Twenty-nine participants with pre- and post-treatment MRI were included. Target engagement was defined as change in average connectivity within each circuit and compared between target groups; associations were measured using Spearman's partial correlation, controlling for relevant covariates. While connectivity decreased within both circuits, the effects were not clearly target-specific and did not predict symptom improvement. In contrast, stronger baseline TMS site connectivity to the targeted circuit predicted greater connectivity change (r = -0.61, p < 0.001) and anxiety improvement (r = 0.47, p = 0.004). These effects were driven by the anxiosomatic target group. Negative findings in the dysphoric target group may reflect greater inter-individual variability in dysphoric circuit topography, as suggested by post-hoc analyses. Within the constraints of a modest sample size, results suggest that baseline TMS site connectivity may represent a more informative biomarker than TMS-induced connectivity changes, and that circuit architecture should be considered when defining targeting protocols.
Lateral septal PACAP signaling regulates stress and anxiety reactions.
Fontebasso V, Ferro F, Basille-Dugay M … +4 more , Vaudry D, Hannibal J, Singewald N, Ebner K
Neuropsychopharmacology · 2026 Apr · PMID 42014855 · Publisher ↗
Severe and/or repeated stress exposure can lead to a number of maladaptive physiological and behavioral changes that contribute to psychiatric illnesses. Recent work indicates that the neuropeptide pituitary-adenylate-cy...
Severe and/or repeated stress exposure can lead to a number of maladaptive physiological and behavioral changes that contribute to psychiatric illnesses. Recent work indicates that the neuropeptide pituitary-adenylate-cyclase-activating-polypeptide (PACAP) plays an important role in stress-related psychopathologies relevant to depression and trauma-related disorders such as PTSD. However, the specific neural circuits that mediate PACAP effects on stress function are not fully understood. One candidate area is the lateral septum (LS), a limbic structure where PACAP and its cognate PAC1 receptors are abundantly expressed. Despite this neuroanatomical evidence, direct functional data supporting a role for septal PACAP/PAC1 receptor signaling in stress regulation are lacking. Using quantitative PCR, we show that forced swim stress increases PACAP mRNA expression in several limbic areas, including the LS, bed nucleus of the stria terminalis and basolateral amygdala, while chronic variable mild stress reduced PACAP expression in the LS only. Providing functional evidence of a PACAP/stress interaction, local administration of PACAP38 into the LS potentiated stress-induced ACTH release and altered stress-coping behavior by increasing passive (floating) and reducing active (struggling) coping during a forced swim challenge. Moreover, intraseptal PACAP38 administration significantly increased anxiety-like behavior in the elevated plus-maze and reduced grooming behavior in the sucrose splashtest, indicating anxiogenic and motivationally disruptive effects following enhanced PACAP signaling in the LS. Importantly, to assess the contribution of endogenous PACAP signaling, intra-LS administration of the PACAP receptor antagonist PACAP(6-38) produced a robust anxiolytic phenotype in the elevated plus-maze. Collectively, these findings provide the first direct evidence that PACAP/PAC1 receptor signaling in the LS modulates emotional and motivational processes in response to stress, identifying this system as a potential target for neuromodulatory interventions in stress-related psychiatric disorders.
Dopaminergic modulation of pancreatic beta-cell insulin secretion and implications for antipsychotic-induced glucose dysregulation: a systematic review and meta-analysis.
Al-Hasani W, Cheliotis-James T, Wierzbicki AS … +3 more , Freyberg Z, Howes O, Pillinger T
Neuropsychopharmacology · 2026 Jun · PMID 42010290 · Full text
Antipsychotic drugs exert their therapeutic effects through dopamine D-like receptor blockade but are also associated with clinically significant dysglycaemia. Whether these metabolic effects reflect consistent actions o...
Antipsychotic drugs exert their therapeutic effects through dopamine D-like receptor blockade but are also associated with clinically significant dysglycaemia. Whether these metabolic effects reflect consistent actions on peripheral dopaminergic targets, including pancreatic β-cell D-like receptors, remains uncertain. We conducted a systematic review and meta-analysis of preclinical in vitro and ex vivo studies examining the effects of dopamine, D-like receptor agonists and antagonists on insulin secretion in isolated pancreatic islets or β-cell lines. PubMed, Embase, and PsycINFO were searched from inception to Sept 22, 2025. Two reviewers independently screened studies, extracted data, and performed random-effects meta-analyses with subgroup and meta-regression analyses assessing glucose concentration, compound type, and dose. 39 studies met inclusion criteria, with 37 included in the metanalysis. Dopamine and D-like receptor agonists showed no significant effect under low-glucose conditions but robustly inhibited glucose-stimulated insulin secretion (GSIS) in rodent and rabbit models (g = -2.36; 95% CI: -2.77 to -1.96; P < 0.0001 & g = -1.98; 95% CI - 2.88 to -1.09; p < 0.0001 respectively), with greater GSIS suppression at higher glucose concentrations and dopamine doses. Though D-like receptor antagonists alone had no significant effect (g = -0.25, 95% CI -0.68 to 0.18, P = 0.25), these drugs blocked GSIS inhibiton by co-administered dopamine (g = 1.59 [0.76 to 2.42]; p = 0.0002). These findings demonstrate that D-like receptor activation inhibits pancreatic β-cell insulin secretion in a glucose- and dose-dependent manner, whereas receptor blockade reverses this effect, identifying a peripheral dopaminergic mechanism that may contribute to antipsychotic drug-associated dysglycaemia independent of weight gain. Together, these findings highlight the need for metabolic monitoring beyond weight alone in response to treatment with antipsychotic medications.
Longitudinal neurocognitive trajectories in a large cohort of youth who use cannabis: combining self-report and toxicology.
Wade NE, Sullivan RM, Wallace AL … +9 more , Visontay R, Szpak V, Lisdahl KM, Huestis MA, Gonçalves PD, Byrne H, Mewton L, Jacobus J, Tapert SF
Neuropsychopharmacology · 2026 Apr · PMID 42002627 · Full text
Adolescents experience extensive neurocognitive development, with cannabis use potentially impacting developmental trajectories. Here, we comprehensively assess the influence of adolescent cannabis use onset on neurocogn...
Adolescents experience extensive neurocognitive development, with cannabis use potentially impacting developmental trajectories. Here, we comprehensively assess the influence of adolescent cannabis use onset on neurocognitive trajectories and consider how recent delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) may influence neurocognition. We use the large, diverse longitudinal Adolescent Brain Cognitive Development (ABCD) Study dataset, combining self-reported substance use with objective toxicological tests (hair, urine, breath, oral fluid). Longitudinal mixed methods of the full cohort (n = 11,036, ages 9-17; 47% Female/53% Male) investigate time-varying cannabis onset on neurocognitive performance. Primary model covariates include sociodemographics, family history of substance use disorder, prenatal substance exposure, early psychopathology, other substance use, and nesting for participant ID, study site, and family ID. Secondarily, in participants with repeat toxicological hair testing (n = 645; 38% Female/62% Male) at ages 12-16, we consider the influence of THC v. CBD v. Controls. Primary models included false discovery rate corrections (FDR-p < .05) while secondary models were interpreted at p < .01. Cannabis group interacted with age to show altered neurocognitive trajectories across domains (immediate recall and delayed memory, processing speed, inhibitory control, visuospatial processing, language, and working memory; βs = -0.11- -0.52). Secondary models indicated hair-identified THC exposure*age predicted worse episodic memory than in Controls (β = -0.60, p = .007), with no difference between CBD exposed and Controls. Data suggest those who use cannabis show likely pre-existing better cognitive performance during late childhood, with reduced improvement or flattened trajectories over time. These neurocognitive trajectories in youth (ages 9-17) who initiate cannabis use were demonstrated after accounting for within-person change and numerous known confounds and improving accuracy in identifying cannabis use through incorporating toxicological measures. Continued monitoring of this cohort will clarify cannabinoid-cognition relationships into young adulthood, including the impact of timing of cannabis use initiation.
Cannabidiol at the crossroads: panacea, placebo, or problem?
Bidwell LC, Vandrey R
Neuropsychopharmacology · 2026 Jul · PMID 42000963 · Full text
Cannabidiol (CBD) is widely perceived as a safe and effective treatment for a growing list of health indications and use for general wellness. Evidence for its safety and efficacy comes from a variety of sources, includi...
Cannabidiol (CBD) is widely perceived as a safe and effective treatment for a growing list of health indications and use for general wellness. Evidence for its safety and efficacy comes from a variety of sources, including preclinical studies, clinical trials, and observational studies of real-world evidence. The challenge in interpreting these data is that CBD products are diverse with respect to format, formulation, intended route of administration, dose, and regulatory oversight with regard to quality assurance and labeling. This Circumspectives article presents two perspectives: one emphasizing CBD's potential as a pharmacologically diverse therapeutic agent with tremendous potential to treat debilitating health conditions for which there are limited alternative therapies and another highlighting concerns with the quality of existing evidence, misapplications of use, and risks related to both direct effects of CBD as well as quality control issues with retail products that lack proper regulatory oversight. Finally, these perspectives are integrated to provide guidance for reducing variability and improving clinical translation in CBD research.
Dopaminergic hypersensitivity of the opioid-responsive striatal-entopeduncular pathway in a rodent model of restless legs syndrome.
Valle-León M, Rea W, Quiroz C … +7 more , Sánchez WN, Albornoz S, Rule AM, Cai NS, Ciruela F, Earley CJ, Ferré S
Neuropsychopharmacology · 2026 Apr · PMID 41998146 · Publisher ↗
We hypothesized that Restless Legs Syndrome (RLS) and the restlessness of opioid withdrawal share common neurobiological mechanisms based on the efficacy of μ-opioid receptor (MOR) agonists in RLS and the common RLS-like...
We hypothesized that Restless Legs Syndrome (RLS) and the restlessness of opioid withdrawal share common neurobiological mechanisms based on the efficacy of μ-opioid receptor (MOR) agonists in RLS and the common RLS-like phenotype of patients with opioid withdrawal. We also hypothesized this involves an increased sensitivity of the striatal striosomal neurons that co-express MORs and dopamine D receptors (DRs) and release GABA in the internal segment of the globus pallidus (GPi). This hypothesis was tested in mice with diet-induced brain iron deficiency (BID), a rodent model of RLS. Fiber-photometry experiments were performed in mice with BID using a viral GABA biosensor injected in the entopeduncular nucleus (EPN), the GPi equivalent in rodents. EPN GABA release was measured after the systemic administration of the DR agonist SKF81297 and the MOR agonist methadone. Locomotor activation and striatal mRNA expression of DRs, MORs and adenosine A receptors (ARs) were also analyzed. A minimal locomotor-activating dose of SKF81297 induced a significant EPN GABA release in mice with BID but not controls, while a maximal locomotor-activating dose of the MOR agonist methadone significantly reduced EPN GABA release in mice with BID after saline or SKF81297 administration. BID was associated with a significant reduction in the striatal expression of MORs and ARs. The results indicate that BID induces an increased dopaminergic sensitivity of the opioid-responsive striatal-EPN pathway, which might represent a pivotal pathogenetic mechanism of the restlessness of RLS and opioid withdrawal.
Correction: Psychedelic therapeutics in psychiatric conditions.
Harvey PD, Nemeroff CB
Neuropsychopharmacology · 2026 Jun · PMID 41992034 · Full text
Abstract loading — click title to view on PubMed.
Sex-dependent role of the ventral hippocampus, but not its projection to the medial prefrontal cortex, in a novel operant conflict-driven ethanol choice task.
McNamara TA, Chen Y, Manoon J … +3 more , Wang M, Lee AC, Ito R
Neuropsychopharmacology · 2026 Apr · PMID 41992033 · Publisher ↗
Sex differences in approach-avoidance decision making with sucrose rewards are well documented, with males exhibiting greater conflict approach behavior and females exhibiting greater conflict avoidance. Consistent with...
Sex differences in approach-avoidance decision making with sucrose rewards are well documented, with males exhibiting greater conflict approach behavior and females exhibiting greater conflict avoidance. Consistent with this, previous work has shown that approach bias under conflict in males reliably predicts persistent operant ethanol self-administration under punishment. In females, however, heightened vulnerability to ethanol reward-seeking in the face of aversive consequences is observed, despite their tendency to avoid sucrose reward paired with punishment. We sought to further investigate this seeming paradox by designing an ethanol-based choice decision-making task wherein rats could lever press for a large ethanol reward accompanied by shock (of increasing intensity) or for a small ethanol reward on discrete trials. We further probed the role of the ventral hippocampus (vHPC), a known hub in approach-avoidance conflict resolution and its projections to the medial prefrontal cortex (mPFC) in the ethanol choice task, using a chemogenetics approach. We found that vHPC CA1 inactivation caused a relative shift towards choosing the large ethanol plus shock lever in males, and a relative shift towards choosing the safe small ethanol option in females at high levels of conflict. The pathway manipulation, however, had no influence on choice behavior. These findings implicate the vHPC CA1 in modulating ethanol choice during high conflict situations, with opposing effects in males and females.
Functional genomic profiling of schizophrenia-associated genes reveals key microglial regulators.
Horng JE, McCrea LT, Batorsky RE … +5 more , Bowen JJ, Boschian C, Song Y, Perlis RH, Sheridan SD
Neuropsychopharmacology · 2026 Apr · PMID 41992032 · Publisher ↗
Microglia are increasingly recognized as key regulators of neural circuit development and putative contributors to the pathophysiology of neuropsychiatric disorders such as schizophrenia (SCZ). However, the functional im...
Microglia are increasingly recognized as key regulators of neural circuit development and putative contributors to the pathophysiology of neuropsychiatric disorders such as schizophrenia (SCZ). However, the functional impact of SCZ-associated genes in microglia remains largely unexplored. Here, we performed an arrayed CRISPR targeting screen of 30 SCZ-associated genes predicted to be differentially expressed in human microglia-like cells. Target genes were prioritized based on post-mortem transcriptomic relevance and predicted ontology-based roles in phagocytosis pathways. We quantified phagocytic activity and morphological changes following gene targeting using high-content confocal imaging. Key targets, including CYFIP1, MSR1, TREM2, SYK, ITGB2, ITGAM, and IRF8, modulated phagocytosis and altered morphological properties consistent with activation states, validating their functional roles in microglia. To elucidate transcriptional impact, we further applied a multiplexed RNA sequencing platform across gene targets. These analyses revealed gene-specific transcriptional signatures, implicating divergent pathways related to phagocytic, activation, cytoskeletal, and lysosomal function. Together, these findings demonstrate the utility of CRISPR-based functional genomics in characterizing microglia function and identifying new target genes and mechanisms that may underlie their contributions to SCZ pathophysiology.
Repeated semaglutide treatment attenuates cocaine-vs-food choice in male and female rats.
Heslep N, Marsh SA, Banks ML
Neuropsychopharmacology · 2026 Jun · PMID 41986468 · Full text
The present study determined the effectiveness of the glucagon-like peptide 1 agonist semaglutide to attenuate cocaine-vs-food choice in male and female rats. Repeated 5-day semaglutide treatment decreased cocaine choice...
The present study determined the effectiveness of the glucagon-like peptide 1 agonist semaglutide to attenuate cocaine-vs-food choice in male and female rats. Repeated 5-day semaglutide treatment decreased cocaine choice and significantly reduced body weight. These preclinical results support the clinical evaluation of semaglutide as a candidate cocaine use disorder medication.
Causal links among gut microbiota, immune-inflammatory and compensatory immune-regulatory systems, and schizophrenia.
Yang BZ, He L, Liu TQ … +4 more , Ma S, Wu YF, Wen L, Emu B
Neuropsychopharmacology · 2026 Apr · PMID 41986467 · Full text
Schizophrenia (SCZ) has been increasingly linked to disruptions in gut microbiota (GM) and immune system dysregulation, including the immune-inflammatory response system (IRS) and compensatory immune-regulatory system (C...
Schizophrenia (SCZ) has been increasingly linked to disruptions in gut microbiota (GM) and immune system dysregulation, including the immune-inflammatory response system (IRS) and compensatory immune-regulatory system (CIRS). To investigate their causal roles and potential confounding effects, we applied genetically informed Mendelian randomization (MR) using genome-wide association study (GWAS) data from a large SCZ meta-analysis (52,017 cases and 75,889 controls), 72 GM genera, and 22 traits of IRS, CIRS, and immune cell indices of European ancestry cohorts. We followed the STROBE-MR guidelines for the MR approach. We found complex causality involving both protective and risk effects. Our analysis revealed protective causal effects of GM genera Barnesiella, Desulfovibrio, Gordonibacter, and Romboutsia (OR = 0.85-0.93, p = 0.005-0.00018), and a risk effect from Clostridium innocuum (OR = 1.09, p = 0.007). Notably, Barnesiella and Gordonibacter represent novel findings. Among immune traits, tumor necrosis factor receptor 1 (sTNF-R1) showed a protective effect (OR = 0.83, p = 0.047), whereas regulatory T cell (Treg) counts increased the risk of SCZ (OR = 1.05, p = 0.006). Multivariate MR confirmed the independent effects of Desulfovibrio, Gordonibacter, and sTNF-R1 after adjusting for other traits. The identified bacterial genera and immune measures exhibit biological relevance to the pathogenesis of SCZ. These findings suggest that specific GM and immune traits contribute independently to SCZ pathogenesis. Particularly, cumulating evidence supporting Tregs as a therapeutic target for psychosis underscores the significance of our results. Further research on their function is needed to validate the causal role of the identified gut microbes and immune mechanisms in SCZ.
Semantic encoding of trauma memories in the hippocampus among individuals with PTSD.
Cisler JM, Malloy LT, Jaeb M … +2 more , Dunsmoor JE, Stowe ZN
Neuropsychopharmacology · 2026 Apr · PMID 41981270 · Publisher ↗
The recall of traumatic memories is central to clinical and neurobiological models of PTSD, yet neurocircuitry mechanisms underlying traumatic memory recall remain elusive. Recent advances in natural language processing...
The recall of traumatic memories is central to clinical and neurobiological models of PTSD, yet neurocircuitry mechanisms underlying traumatic memory recall remain elusive. Recent advances in natural language processing and large language models enable complex semantic quantification of autobiographical memories. Here, we leveraged these analytic approaches to define the neurocircuitry encoding the semantic content of traumatic autobiographical narratives among individuals with PTSD. 79 women with PTSD related to interpersonal violence listened to traumatic and neutral autobiographical narratives during fMRI. Sentence-level brain activity and semantic embeddings were quantified for each script and participant. Neurocircuitry encoding semantic content of the narratives was defined through cross-validation across participants. A priori regions of interest included the hippocampus, superior temporal gyrus (STG), and posterior cingulate cortex (PCC). Our approach detected significant hippocampal sensitivity for semantic content of both trauma and neutral narratives; however, spatial encoding patterns of semantic content within the hippocampus differed between trauma and neutral narratives. Specifically, spatial encoding patterns in CA1 and dentate gyrus differentiated narrative type. Regardless of narrative type, PTSD symptom severity was positively associated with semantic encoding across the hippocampus and its subfields, except for the subiculum. For trauma narratives, semantic sensitivity was greater within the left STG and decreased in the PCC and broader default mode network. Encoding in neither region tracked with PTSD symptom severity. These results reveal a hippocampal role in mediating recall of specific semantic content for traumatic and neutral autobiographical narratives and suggest hippocampal sensitivity to autobiographical semantic content underlies greater PTSD symptom severity. Clinical trial registration information: Improving Therapeutic Learning for PTSD, Study Details | NCT04558112 | Improving Therapeutic Learning for PTSD | ClinicalTrials.gov, NCT04558112.
Regulation of the decision threshold by the locus coeruleus.
Xia H, Maheu M, Kane GA … +1 more , Scott BB
Neuropsychopharmacology · 2026 Apr · PMID 41974997 · Publisher ↗
A fundamental challenge for decision-making under uncertainty lies in balancing speed and accuracy. Humans and animals solve this problem by adjusting decision thresholds-the criterion that determines how much informatio...
A fundamental challenge for decision-making under uncertainty lies in balancing speed and accuracy. Humans and animals solve this problem by adjusting decision thresholds-the criterion that determines how much information is required before committing to a choice. While brain regions associated with this process have been identified, the neural circuits that directly alter decision thresholds remain unknown. Here, we investigate the role of the locus coeruleus (LC) norepinephrine (NE) system in controlling this balance. Through cell-type-specific chemogenetic manipulations, we discovered that LC-NE activation increased decision thresholds. This effect is replicated by administration of the α2-adrenergic receptor (α2-AR) agonist clonidine. Notably, α2-AR activation altered decision threshold specifically, without reproducing other LC-NE activation effects such as promoting task engagement. Together, these results suggest that LC-NE regulates decision thresholds, possibly via downstream α2-ARs.
Sex-biased computations underlying differential set shift performance in mice.
Glewwe N, Dastin-van Rijn EM, Chen CS … +5 more , Giglio E, Knep E, Ebitz RB, Widge AS, Grissom NM
Neuropsychopharmacology · 2026 Apr · PMID 41963627 · Publisher ↗
Cognitive flexibility can be defined as the ability to adaptively shift between choices or strategies based on environmental feedback. Flexibility is disrupted in numerous neuropsychiatric conditions. Individual differen...
Cognitive flexibility can be defined as the ability to adaptively shift between choices or strategies based on environmental feedback. Flexibility is disrupted in numerous neuropsychiatric conditions. Individual differences in the computations supporting cognitive flexibility may reveal mechanisms of neuropsychiatric risk and resilience. One critical variable well known to influence individual differences in neuropsychiatric risk is sex. While previous research has identified sex differences in value based decision making in mice, whether sex reflects a major source of variation in cognitive flexibility remains unknown. To directly assess sex-biased individual differences in cognitive flexibility, we developed a novel touchscreen Set Shift task that permits robust and continuous testing in mice. Using this task, we discovered that female mice completed significantly more rule shifts with fewer errors than males. We next employed a suite of computational models that revealed sex-biased individual differences in the computations underlying cognitive flexibility. Our results suggest that following rule shifts, female mice learn the new rule faster and commit to exploiting rule choices sooner compared to males-sometimes because they follow multiple rules simultaneously. This suggests that increased choice stability in female rodents enhances commitment to a choice during periods of uncertainty and directly contributes to increased rule shifting. This supports the counterintuitive conclusion that a high degree of stable choice is a strong requirement for enhanced cognitive flexibility in the Set Shift task, one of the well-established cognitive flexibility tasks.
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