搜索结果：Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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.

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.

Genetics can inform biologically relevant drug development and repurposing, which may improve patient care. Here, we leverage the genetics of psychiatric disorders to prioritize potential drug targets and compounds. We used the genome-wide association studies of four psychiatric disorders [attention deficit hyperactivity disorder (ADHD), bipolar disorder, depression, and schizophrenia] and genes encoding drug targets. We conducted drug enrichment analyses incorporating the novel and biologically specific GSA-MiXeR tool. We conducted multiple molecular trait analyses using large-scale transcriptomic and proteomic datasets sampled from brain and blood tissue. This included the novel use of the UK Biobank proteomic data for a proteome-wide association study of psychiatric disorders. With the accumulated evidence, we prioritize potential drug targets and compounds for each disorder. We reveal candidate drug targets associated with a single or multiple disorders that implicate glutamate signaling. Drug prioritization indicated genetic support for psychotropic medications, including several top-ranked antipsychotics for schizophrenia. We also observed genetic support for commonly used psychotropics for psychiatric treatment (e.g., clozapine, duloxetine, and lithium). Revealed opportunities for drug repurposing included cholinergic drugs for ADHD, estrogen modulators for depression, and matrix metalloproteinases for ADHD and depression. Our findings indicate the genetic liability to schizophrenia is associated with reduced brain and blood expression of CYP2D6, a gene encoding a metabolizer of drugs and neurotransmitters, suggesting a genetic risk for poor drug response and altered neurotransmission. Our extensive analyses highlight the utility of genetics for informing drug development and repurposing for psychiatric disorders, providing novel opportunities for improving patient outcomes. Depicted is the series of analyses conducted to generate a list of prioritized drug targets and compounds. First pairings of genome-wide association study (GWAS) traits with drugs are generated using enrichment analyses. Next, a series of molecular trait analyses is conducted to generate and rank a list of potential drug targets for each GWAS trait. Finally, enrichment and molecular trait results are combined to generate a ranked list of prioritized drugs for each GWAS trait based on supporting genetic evidence. ADHD = Attention deficit hyperactivity disorder, BIP = Bipolar disorder, DEP = Depression, SCZ = Schizophrenia, DBP = Diastolic blood pressure, T2D = Type 2 diabetes, RNA = ribonucleic acid, XWAS = both transcriptome and proteome-wide association studies, MR = Mendelian randomization, coloc = colocalization.

Pleasure plays a crucial role in positive reinforcement and motivation. Brain regions able to amplify positive hedonic reactions to sweetness, known as 'hedonic hotspots', are distributed within the mesocorticolimbic reward systems. The olfactory tubercle (OT), a part of the ventral striatum that receives olfactory input, contains distinct functional domains: the anteromedial domain mediates approach motivation toward odors associated with food, whereas the lateral domain mediates avoidance motivation away from odors associated with danger. However, it has remained unclear whether the OT modulates hedonic reactions to pleasant sensations. In this study, we made pharmacological microinjections in OT of rats to examine whether these OT subregions can modulate hedonic reactions, as assessed by the taste reactivity test. Sweet oral infusions of sucrose solution were delivered into the mouth via an intraoral cannula, and the rats' orofacial and somatic hedonic reactions were recorded and analyzed. We compared three pharmacological agents: mu-opioid receptor agonist DAMGO, orexin-A peptide, and GABAA receptor agonist muscimol. Microinjection of any of these drugs into the anteromedial OT subregion enhanced hedonic 'liking' reactions to sucrose. Furthermore, DAMGO injection into the anteromedial OT subregion recruited distant Fos expression in other 'hedonic hotspots', including in the caudal ventral pallidum and the rostromedial orbitofrontal cortex. By contrast, the same microinjections into the anterolateral OT subregion failed to enhance 'liking' reactions and, DAMGO oppositely increased aversive 'disgust' reactions. These findings suggest that the anteromedial OT contains a 'hedonic hotspot', whereas the anterolateral OT may contain a suppressive opioid 'hedonic coldspot'. Thus, OT subregions may help causally modulate hedonic reactions to sweetness and flavor perception.

Prenatal exposure to infectious or non-infectious maternal immune activation (MIA) represents a transdiagnostic environmental risk factor for psychiatric and neurodevelopmental disorders. Building on previous findings of locomotor hyperactivity in a subset of male MIA offspring, the present study investigated whether viral-like MIA in mice recapitulates features of attention-deficit/hyperactivity disorder (ADHD) in this subgroup. We show that 40-50% of MIA-exposed male offspring develop locomotor hyperactivity in a novel environment, which is most pronounced during early- to mid-adolescence and precedes the emergence of increased impulsive behavior and pre-attentive filtering deficits in early adulthood. We further identified subgroup-specific dopaminergic and noradrenergic alterations in cortical and subcortical brain regions of MIA offspring. These neuronal alterations were age-dependent and correlated with behavioral changes. Moreover, treatment with methylphenidate (MPH), a first-line pharmacological therapy for ADHD, normalized locomotor hyperactivity and restored abnormal mesolimbic and striatal activation patterns in susceptible MIA offspring. Collectively, our findings demonstrate that MIA in mice recapitulates key features of ADHD in a susceptible subset of offspring, supporting the notion that MIA may contribute etiologically to ADHD in some individuals. More broadly, our results suggest that the heterogeneous neurobehavioral outcomes of MIA offspring may result from distinct yet overlapping pathophysiological mechanisms across neurodevelopmental and psychiatric disorders.

Cue-induced seeking engages neuronal ensembles within the nucleus accumbens core (NAcore), with neuronal ensembles defined here as neurons coactivated during specific behavioral experiences that have been implicated in cued-reinstatement. Although transient synaptic plasticity has been widely observed in unidentified ensemble and non-ensemble neuronal populations in the NAcore during reinstatement, its expression within behaviorally relevant ensembles remains unclear. Here, we used c-Fos-TRAP2-based tagging to characterize structural and functional synaptic plasticity within ensembles during cocaine-seeking in mice following cocaine intravenous self-administration, extinction, and cue-induced reinstatement. Structural plasticity was measured via spine confocal imaging, and functional changes were evaluated by AMPA/NMDA ratios using whole-cell electrophysiology across reinstatement time points. Ensemble neurons exhibited increased dendritic spine head diameter during cue-induced reinstatement and were functionally potentiated relative to non-ensemble neurons. Spine classification showed reduced mature spines during reinstatement in both ensemble and non-ensemble cells, suggesting morphological remodeling rather than new spine formation. Non-ensemble neurons showed no change in spine head diameter during reinstatement but did exhibit an increased AMPA/NMDA ratio during cued-reinstatement. Paired-pulse ratio analysis suggested that yoked-cocaine exposure decreased presynaptic vesicle release probability, while operant cocaine exposure had no effect. Ensemble neurons showed an elevated AMPA/NMDA ratio following cocaine exposure, regardless of whether intake was yoked or contingent. Together, these findings suggest that ensemble and non-ensemble neurons undergo distinct forms of synaptic plasticity during cue-induced reinstatement. By distinguishing ensemble-specific structural plasticity from non-ensemble functional plasticity, this study refines the current understanding of mechanisms underlying cue-induced relapse. SIGNIFICANCE STATEMENT: In preclinical models of substance use disorder drug seeking is associated with cue-induced reactivation of neuronal ensembles in the nucleus accumbens core. While transient synaptic plasticity has been extensively described in non-selective neuronal populations pooling recordings of both ensemble and non-ensemble neurons of the nucleus accumbens core, ensemble-specific plasticity remains unclear. Here, we combined c-Fos-TRAP2 tagging, confocal imaging, and slice electrophysiology to show that structural synaptic plasticity is selectively expressed in behaviorally relevant ensembles. By linking ensemble identity with structural and functional plasticity during cue-induced cocaine seeking, these findings refine current models of relapse and identify plasticity within the ensemble as a potential target for therapeutic intervention.

Cocaine use disorder is characterized by persistent relapse vulnerability, which escalates with prolonged withdrawal. Corticostriatal circuits are key substrates for relapse, yet the role of the secondary motor cortex (M2) and its distinct projections to the dorsolateral striatum (DLS) and dorsomedial striatum (DMS) remains poorly understood. Here, we combined intravenous self-administration, pathway-selective optogenetic inhibition, and ex vivo patch-clamp recordings to measure comprehensive synaptic responses during withdrawal. Relative to withdrawal day 1, rats exhibited cocaine seeking incubation on withdrawal day 45, which was therefore selected as the primary experimental time point. Whole-cell recordings revealed heightened intrinsic excitability of M2 cortical pyramidal neurons and increased frequency, but not amplitude, of spontaneous excitatory postsynaptic currents (sEPSCs) in both DLS and DMS medium-sized spiny neurons (MSNs), suggesting the possibility of enhanced presynaptic glutamate release. Optogenetic inhibition of eNpHR-expressing M2 terminals produced opposite behavioral outcomes: suppression of cocaine seeking when targeted to the DLS, but paradoxical enhancement when targeted to the DMS. In cocaine-exposed, but not saline, rats, optogenetic inhibition increased sEPSC frequency in both DLS and DMS MSNs, suggesting altered integration of M2 or local inhibitory inputs and non-M2 excitatory afferents. Inhibitory adaptations diverged across striatal subregions: in the DLS, repeated inhibition persistently increased spontaneous inhibitory postsynaptic current (sIPSC) frequency, whereas in the DMS, sIPSC enhancement was transient, with frequency and amplitude increasing only during the first light-on period, but amplitude rapidly declined thereafter. Together, these findings suggest that M2-striatal projections contribute in a pathway-specific manner to relapse vulnerability and are associated with alterations in excitatory-inhibitory balance within M2-DLS and M2-DMS circuits.

N-methyl-D-aspartate receptors (NMDARs) in the prefrontal cortex (PFC) are critical regulators of neuronal excitability, synaptic plasticity, and cognitive function. NMDAR disruptions, including pharmacological blockade and anti-NMDAR encephalitis, can mimic symptoms of schizophrenia. These observations support the glutamate hypothesis of schizophrenia, which posits that symptoms arise from abnormal corticolimbic glutamatergic signaling. Further evidence for this theory includes abnormal expression of NMDARs and decreased dendritic spine density in the PFC of individuals with schizophrenia, as well as altered spine density and synaptic transmission caused by genetic manipulation of NMDARs. However, it is unknown how progressive loss of NMDAR function in the PFC during adolescence-a developmental time period associated with symptom onset in schizophrenia -affects excitatory synaptic structure and function. In this study, we used in vivo genome editing to ablate expression of the Grin1 gene, which encodes the obligate GluN1 subunit of NMDARs, in medial PFC neurons of female and male adolescent mice. We assessed synaptic density and function in layer V pyramidal neurons using whole-cell patch-clamp electrophysiology, integrated with confocal imaging of dendritic spine architecture in recorded neurons. NMDAR ablation caused an early decrease in basilar dendritic spine density, followed by a rebound in spine density and a corresponding increase in AMPAR-mediated synaptic transmission. These effects of pan-neuronal NMDAR ablation were not observed after a more specific manipulation of excitatory neurons. Our findings demonstrate that NMDAR ablation triggers a cascading reorganization of local PFC networks, which may include compensatory processes that maintain allostasis but are impaired in disease states.

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.

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.

Deficits in episodic memory are a debilitating feature of Fragile X syndrome (FXS) and other congenital autism spectrum disorders (ASDs). There is evidence that oxytocin (OXT) treatments can improve sociability in persons with ASD and related animal models, encouraging the idea that benefits might extend to cognitive function. We tested this possibility in male FXS model, Fmr1-knockout (KO) mice. Intranasal treatments with OXT or saline were given daily during the second or fifth postnatal week, and effects on social behavior, spatial and episodic memory, and hippocampal synaptic plasticity were assessed in adulthood. Saline-treated Fmr1-KOs exhibited profound deficits in social recognition, object location memory, what-when-where components of episodic memory and long-term potentiation (LTP) in both the CA3-CA1 and lateral perforant path (LPP) systems; NMDAR-mediated components of LPP responses were also impaired. OXT treatments during the second week postnatal normalized all of these functions in Fmr1-KOs assessed in adulthood; this included restoration of initial stages of CA3-CA1 LTP and granule cell NMDAR-mediated currents. In hippocampal slices from naïve adult male Fmr1-KO mice, bath-applied OXT treatment restored LTP in CA1 but not the LPP, indicating pathway-specific effects. Intranasal OXT treatments during the 5th week postnatal did not have enduring effects in either genotype. The present evidence that early OXT treatment corrects a broad range of cognitive and synaptic plasticity deficits in Fmr1-KO mice identifies a clinically plausible strategy for normalizing hippocampal function in ASD and FXS, and highlights the presence of a critical developmental window for effective intervention.

Based on its in vitro profile and preliminary evidence, 4-bromo-2,5-dimethoxyphenethylamine (2C-B) may have psychoactive properties that are similar to 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin, which are investigated for the treatment of posttraumatic stress disorder and depressive disorders. We compared acute effects of 2C-B (10, 20, and 30 mg), 125 mg MDMA, and 25 mg psilocybin in 24 healthy participants (12 women, 12 men) using a double-blind, randomized, placebo-controlled, crossover design. Outcome measures included acute subjective effects, autonomic effects, adverse effects, effects on emotional and cognitive empathy, plasma oxytocin and neurophysin I concentrations, and pharmacokinetics up to 9 h. 2C-B produced dose-dependent subjective effects, with the 30 mg dose exerting comparable "any drug effects" to MDMA but lower "any drug effects" than psilocybin. Only psilocybin induced "bad drug effects" and "anxiety" compared with placebo. The 30 mg dose of 2C-B induced psychedelic-type alterations of state of consciousness and increased emotional empathy similarly to MDMA. The average subjective effect duration of 30 mg 2C-B was 4.9 h and similar to MDMA (4.8 h) and shorter than psilocybin (6.1 h). MDMA produced the highest cardiovascular stimulation, followed by psilocybin and 2C-B. Only MDMA increased plasma oxytocin and neurophysin I concentrations. 2C-B exhibited dose-proportional pharmacokinetics, with a plasma elimination half-life of ~1.3 h. The 30 mg dose of 2C-B induced entactogenic and psychedelic effects similarly to MDMA and psilocybin, respectively. MDMA is more cardiostimulant than psilocybin and 2C-B. At the tested dose-level, psilocybin is more distressing than MDMA and 2C-B. These results may assist with dose-finding for future 2C-B research and provide a direct comparison with standard doses of the prototypical compounds MDMA and psilocybin. Trial registration: ClinicalTrials.gov identifier: NCT05523401.

Substance use has been associated with blunted brain responses to non-drug rewards, but findings in people who use cannabis are mixed. Adolescents may be uniquely vulnerable to cannabis-related disruption to reward processing due to ongoing neuromaturation, but longitudinal research is lacking. In this longitudinal fMRI study, we compared brain measures of reward anticipation in 46 adolescents (16-17 years) and adults (26-29 years) who used cannabis (1-7 days/week) and 50 age-matched controls with the Monetary Incentive Delay task at baseline and 12-month follow-up. Region of interest (ROI) analyses adjusted for cigarette/roll-up use, depression, and risk-taking found that reward anticipation activity decreased in the right (p = 0.05, ηp2 = 0.04) and left (p = 0.02, ηp2 = 0.05) ventral striatum from baseline to follow-up in participants who used cannabis compared with control participants. These effects remained in unadjusted models and when including only participants who consistently used or abstained from cannabis during the study period. There were no significant interactions between the cannabis user-group and age-group, or between the user-group, age-group, and time. There were also no cannabis user-group main or interaction effects in full sample ROI analyses for the thalamus, insula, or supplementary motor area, or in exploratory whole-brain analyses. The current results suggest that cannabis use may be associated with reductions in non-drug reward anticipation activity in the ventral striatum, a key part of the brain's reward system. However, there was no evidence of adolescent resilience or vulnerability to cannabis-related changes in brain reward anticipation activity.

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.

Afflicting over 50 million people worldwide and demonstrating growing global trends of abuse, amphetamine-type stimulant abuse poses a significant public health burden. No effective pharmacological treatments exist for amphetamine-type stimulant use disorders, underscoring a critical need to identify novel, effective therapeutic targets. Amphetamine exerts its actions in part by targeting high-affinity, low-capacity monoamine transporters, particularly the dopamine transporter (DAT). However, therapeutic interventions targeting DAT have been so far unsuccessful. Emerging evidence supports a role for the low-affinity, high-capacity organic cation transporter 3 (OCT3) in the actions of amphetamine. Here we use in vivo electrochemical and behavioral approaches, as well as constitutive and temporally-inducible OCT3 knockout mice, to establish OCT3 as a critical mediator of neurochemical and behavioral actions of amphetamine. We demonstrate that OCT3 substantially contributes to amphetamine-evoked dopamine efflux in dorsal striatum and is key to reinforcing effects of amphetamine in intravenous self-administration assays. Our novel findings provide convergent evidence to suggest that OCT3 plays a central role in mediating abuse-related effects of amphetamine, establishing OCT3 as a potential novel target for the development of therapeutics to treat amphetamine-type stimulant use disorders.

Neurodevelopmental psychiatric diseases such as schizophrenia or affective disorders share common symptomatic dimensions, in particular reward processing dysfunctions, associated with dysregulation of dopamine (DA) transmission. Retinoic acid (RA) homeostasis, the active metabolite of vitamin A, is altered across psychiatric disorders but whether impaired developmental RA signaling impacts the functionality of DA-related reward processing at adulthood remains poorly explored. Herein, we found that vitamin A (i.e., retinol) deficiency (VAD) from gestation to adulthood potentiates instrumental responding in motivational tasks and increases choice impulsivity in male, but not female mice. These behavioral alterations in males are coherent with reduced DA transporter (DAT) expression in the midbrain and increased mesolimbic DA dynamics associated with instrumental responding. In accordance, chemogenetic inhibition of midbrain DA neurons normalizes motivational performance in VAD males. Our results support that developmental VAD induces sex-specific reward processing alterations at adulthood through hyperactivity of the mesolimbic DA pathway. Such findings reinforce the idea that RA signaling is an important modulator of the brain reward system by shaping DA transmission.

Posttraumatic stress disorder (PTSD) is a highly heterogeneous psychiatric disorder, complicating efforts to identify consistent biological markers and develop targeted treatments for individuals exposed to trauma. Recent research has identified a distinct intrusive-hypervigilant (IH) phenotype, which is characterized by heightened intrusive reexperiencing and hypervigilance symptoms along with elevated levels of pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide involved in stress response via amygdala signaling. In an independent sample of 172 symptomatic trauma-exposed adults, we replicated this IH phenotype using latent profile analysis of Clinician-Administered PTSD Scale for DSM-5 symptom severity ratings and expanded its biological characterization using resting-state functional magnetic resonance imaging (rs-fMRI). Consistent with prior work, the identified IH group demonstrated more severe intrusive reexperiencing (Cohen's d's = 0.61-6.93) and hypervigilance symptoms (d's = 0.57-0.88) and higher PACAP levels compared to groups with generally High (d = 0.35) or Low (d = 0.44) symptom severity. Additionally, the IH phenotype exhibited stronger functional connectivity of the centromedial, but not basolateral, amygdala with regions in the occipital cortex (d's = 0.78-0.95), precuneus (d's = 1.20-1.21), and medial prefrontal cortex (d's = 0.81-1.18)-areas primarily within the Default Mode and Visual Networks. Meta-analytic decoding linked these regions to mental imagery, memory processing, fear, and threat perception. These findings support the existence of an IH phenotype of posttraumatic stress that may exhibit a distinct biological profile, characterized by exaggerated interactions between memory, threat, and arousal systems that may be mediated by PACAP and its effects on amygdala connectivity. This phenotype may serve as a promising target for precision psychiatry approaches, including pharmacological and neurotherapeutic interventions that modulate PACAP signaling and amygdala connectivity.

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.

Puberty demarcates the start of adolescence, a critical period of marked changes in motivated behavior (e.g., approach, avoidance) and socio-affective processing supported by development of the mesocorticolimbic circuitry-prefrontal cortex (PFC), amygdala, and nucleus accumbens (NAcc). Puberty-related increases in psychiatric risk have been linked to alterations in mesocorticolimbic circuitry function and sensitivity to rewards and punishments. Yet, how puberty influences the development of mesocorticolimbic circuitry supporting motivational traits remains unclear. We examined resting-state functional connectivity (RSFC) in 126 adolescents, studied longitudinally (216 total scans over 2 years), assessed reward/punishment sensitivity via questionnaires, and collected multimodal measures of puberty. As hypothesized, fronto-striatal RSFC was associated with reward sensitivity, but both fronto-striatal and fronto-amygdala RSFC were linked to punishment sensitivity. Puberty moderated several associations in males but not females: weaker fronto-striatal RSFC related to higher reward sensitivity in males more advanced in pubertal maturation. Further, whereas in early puberty stages stronger fronto-striatal RSFC related to higher punishment sensitivity in males, by late puberty stages, stronger fronto-amygdala RSFC was related to higher punishment sensitivity. Testosterone levels moderated the association between anterior ventromedial PFC - NAcc RSFC and reward sensitivity such that weaker RSFC related to higher reward sensitivity in males with lower testosterone levels than expected for their age and pubertal status. These data support sex-specific puberty effects on the relationship between mesocorticolimbic circuitry connectivity and reward/punishment sensitivity. Future research is needed to determine how these findings represent markers of risk for or resilience against psychiatric disorders.