Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology最新文献

{"title":"High hopes, hard realities: cannabidiol shows no acute effects in youth with alcohol use disorder.","authors":"L Cinnamon Bidwell","doi":"10.1038/s41386-025-02160-w","DOIUrl":"https://doi.org/10.1038/s41386-025-02160-w","url":null,"abstract":"","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144562652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prefrontal cortex development and its implications in mental illness.","authors":"Caitlin M Goodpaster, Chloe R Christensen, Maryam-Batul Alturki, Laura A DeNardo","doi":"10.1038/s41386-025-02154-8","DOIUrl":"https://doi.org/10.1038/s41386-025-02154-8","url":null,"abstract":"<p><p>The medial prefrontal cortex (mPFC) plays an essential role in cognition and emotional regulation. The mPFC undergoes an extended development that is regulated by both genetic programs and activity-dependent processes. During this time, experiences feedback on developing mPFC circuits, allowing individuals to develop nuanced, age-appropriate responses to their environment. However, this protracted development also opens an extended window when adverse experiences such as neglect or maltreatment can alter the trajectory of mPFC development, leading to the emergence of mental health disorders like anxiety and depression. These disorders are characterized by excessive avoidance of perceived threats and impaired emotional regulation. These behavioral functions are encoded in the activity of mPFC neural circuits, particularly in mPFC connections with limbic centers like the basolateral amygdala and nucleus accumbens. To understand how mental health disorders emerge, it is critical to understand how frontolimbic circuits typically develop, and how early life adversity can alter their development. Here we review recent studies that examined the synaptic, cellular, and circuit development of frontolimbic circuits and the underlying molecular and activity-dependent mechanisms. We then review studies that measured the effects of early life stress on mPFC maturation and discuss the implications for therapeutic strategies.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting inhibitory control in youth irritability: challenges and opportunities.","authors":"Simone P Haller, Parmis Khosravi, Katherine Y Kim, Melissa A Brotman","doi":"10.1038/s41386-025-02151-x","DOIUrl":"https://doi.org/10.1038/s41386-025-02151-x","url":null,"abstract":"<p><p>Pediatric irritability, an increased proneness to anger relative to same aged peers, is linked to deficits in inhibitory control. Here, we examine issues of measurement and specificity of the construct of inhibitory control, with a focus on potential treatment implications. We cover lessons learned from prior training approaches. We dissect the role of inhibitory control in an efficacious psychosocial treatment and propose a research agenda to further test inhibitory control as a candidate behavioral treatment target for youth with irritability.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting depression circuitry with H1 coil Transcranial Magnetic Stimulation: a retrospective circuit mapping study.","authors":"Samantha Baldi, Nicole Chiulli, Stephan Palm, Summer Frandsen, Gaby S Pell, Samuel Zibman, Josias Rodriguez-Ponde, Joshua C Brown, Shan H Siddiqi","doi":"10.1038/s41386-025-02157-5","DOIUrl":"https://doi.org/10.1038/s41386-025-02157-5","url":null,"abstract":"<p><p>The efficacy of transcranial magnetic stimulation (TMS) for depression may depend on targeting specific brain circuits. However, this has not been tested for TMS with the H1 coil, a widely used device believed to target more broadly and deeply than TMS with figure-of-8 coils. This study examined whether targeting a specific brain circuit with H1 coil TMS treatment may impact depressive symptom improvement. We retrospectively analyzed data from 97 patients at McLean Hospital, who received at least 19 TMS sessions and had incidentally completed an anatomical brain MRI. We modeled each patient's electric (E-)field using SimNIBS and estimated the connectivity of the E-field using a normative connectome (n = 1000), which was correlated with depression improvement as measured by the Quick Inventory of Depressive Symptomatology. H1 E-fields improving depression were preferentially connected to a distinct brain circuit, validated with leave-one-out cross-validation (p = 0.0005). This circuit was significantly similar to a predefined causal depression circuit (spatial r = 0.59, p = 0.04) derived from TMS, deep brain stimulation, and lesion studies. E-fields with greater connectivity similarity to this circuit led to greater symptom improvement (r = 0.41, p < 0.001). Post-hoc analyses revealed that more posterior coil positioning increases H1 E-field overlap with the depression circuit, with high overlap at scalp locations 3-6 cm anterior to the motor hotspot. Thus, H1 coil stimulation sites that improve depression converge on a common causal depression circuit. Prospective studies are needed to validate these findings.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating endocannabinoids in children and adolescents: associations with anxiety and the impact of selective serotonin reuptake inhibitors.","authors":"Hilary A Marusak, Clara G Zundel, Tehmina Shakir, Samantha L Ely, Carmen Carpenter, MacKenna Shampine, Reem Tamimi, Mariya Matsko, Sarah Rogers, Jennifer Losiowski, Emilie O'Mara, Alaina M Jaster, Kamakashi Sharma, Terri A deRoon-Cassini, Cecilia J Hillard, Heidi K Schroeder, Jeffrey A Mills, Jeffrey R Strawn, Jeanne Barcelona","doi":"10.1038/s41386-025-02155-7","DOIUrl":"https://doi.org/10.1038/s41386-025-02155-7","url":null,"abstract":"<p><p>Anxiety disorders are prevalent psychiatric conditions that frequently emerge during adolescence. Among the neurobiological systems implicated in these disorders, the endocannabinoid (eCB) signaling system plays a crucial role, making it a promising target for therapeutic interventions. In addition to its direct effects on anxiety regulation, eCBs may also influence response to first-line pharmacologic treatments, such as selective serotonin reuptake inhibitors (SSRIs). However, little is known about developmental changes in eCB lipids-N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG)-or their relationship to anxiety symptoms and treatment response. Circulating AEA and 2-AG concentrations were measured in youth (aged 9-17, N = 199) with varying anxiety symptoms, assessed using the Screen for Child Anxiety-Related Disorders (SCARED). We evaluated how eCBs relate to developmental factors (e.g., demographics, biological variables) and anxiety symptoms (SCARED total). Additionally, we examined how eCB concentrations change in response to acute SSRI treatment in a subsample of adolescents (age 12-17, N = 41) with generalized anxiety disorder (GAD), who participated in an 8-week randomized placebo-controlled trial of escitalopram (15 mg/day, titrated to 20 mg/day). Body mass index (BMI) was positively correlated with circulating AEA, while 2-AG showed negative associations with age, female sex, and time-of-day. After adjusting for these variables, more severe anxiety symptoms were associated with higher AEA and lower 2-AG. Greater increases in 2-AG from baseline (without changes in AEA) were linked to improved treatment response in adolescents with GAD. Our study suggests that circulating eCBs may serve as biomarkers for anxiety severity and predictors of treatment response in youth.ClinicalTrials.Gov Identifier: NCT02818751.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-seizure effects of WS-3, a TRPM8 agonist, on focal onset seizure mouse model via reduction of extracellular glutamate levels.","authors":"Hiroshi Moriyama, Sadahiro Nomura, Hirochika Imoto, Yuichi Maruta, Naomasa Mori, Natsumi Fujii, Kohei Haji, Michiyasu Suzuki, Hideyuki Ishihara","doi":"10.1038/s41386-025-02143-x","DOIUrl":"https://doi.org/10.1038/s41386-025-02143-x","url":null,"abstract":"<p><p>The development of novel anti-seizure drugs targeting novel mechanisms is crucial, especially for patients with intractable epilepsy. Previous studies using focal onset seizure rodent models have demonstrated that Icilin and WS-3, agonists of the transient receptor potential melastatin 8 (TRPM8) channel, suppress drug-induce epileptiform discharges (EDs) and seizures (ESs). In contrast, TRPM8 deficiency exacerbates EDs and ESs. This study investigated the mechanism underlying the anti-seizure effects of the TRPM8 agonist, WS-3, using a focal onset seizure mouse model. Mice were injected with WS-3 either before or after administering the seizure inducer, penicillin G potassium. EDs, ESs, and glutamate levels were subsequently evaluated. In wild-type (WT) mice, WS-3 injected after the seizure inducer reduced glutamate levels and ED power by 44% and 60%, respectively, with a positive correlation between WS-3 efficacy and these parameters. WS-3 injection before seizure induction suppressed the increase in glutamate levels and the development of ED and ES, with positive correlations observed among the three parameters. Conversely, TRPM8-knockout mice showed no anti-seizure effects from WS-3. TRPM8 deficiency led to a further increase in the glutamate levels, ED power, and ES severity after the seizure inducer injection. Additionally, TRPM8-deficient mice experienced EDs with fewer glutamate exposures and shortened latency to ED development following seizure induction. These findings suggest that TRPM8 agonists suppress the development of EDs and ESs by reduction of extracellular glutamate levels, indicating that TRPM8 channels may represent a promising treatment option for epilepsy.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144510469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurobiology of resilience to early life stress.","authors":"Angélica Torres-Berrío, Alessandro Bortolami, Catherine J Peña, Eric J Nestler","doi":"10.1038/s41386-025-02158-4","DOIUrl":"https://doi.org/10.1038/s41386-025-02158-4","url":null,"abstract":"<p><p>The early years of life are a critical period for brain development, encompassing high sensitivity to adverse experiences. Early life stress (ELS) is known to \"scar\" the brain and shape mental health trajectories later in life. Still, a great percentage of children faced with ELS develop adaptive competencies that maintain normal physiological and behavioral function across the lifespan, a process referred to as resilience. Work in humans and rodent models has demonstrated that resilience is an active process mediated largely by the induction of unique molecular, cellular, and circuit adaptations. In this review, we highlight evidence from rodent studies exploring the behavioral, circuit, cellular, and molecular effects of ELS and discuss resilient phenotypes that emerge from specific ELS paradigms. To this end, we focus on models comprising ELS exposure within pre-weening and adolescence. We next address critical factors that influence the effects of ELS, such as behavioral readouts, environmental conditions, or sex differences, and we compare these findings in light of human studies. Finally, we advocate for the use of novel and more sophisticated behavioral tasks for rodents that capture, at least in part, resilient phenotypes observed in humans and that can be directly linked to specific brain circuits.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using causal network mapping to clarify pre-clinical brain stimulation results.","authors":"Ryan D Webler, Diana King, Nicholas L Balderston, Shan H Siddiqi","doi":"10.1038/s41386-025-02153-9","DOIUrl":"https://doi.org/10.1038/s41386-025-02153-9","url":null,"abstract":"","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mesolimbic reward pathway is necessary for disruptions in cocaine-seeking behavior following mediated devaluation.","authors":"Bingxin Mo, Victoria K Fex, Alice McQueney, Doris I Olekanma, Christopher A Reeves, Luciano S Voutour, Sarah Simmons, A J Robison, Amy A Arguello, Alexander W Johnson","doi":"10.1038/s41386-025-02119-x","DOIUrl":"https://doi.org/10.1038/s41386-025-02119-x","url":null,"abstract":"<p><p>We developed an approach to disrupt cocaine-seeking behaviors using mediated devaluation. Male rats underwent cocaine self-administration training in which active lever responses led to cocaine infusions and the presentation of a tone-light conditioned stimulus (CS). Subsequently, during mediated devaluation rats received non-contingent presentations of the cocaine-associated CS in a second distinct context, which led to the cue-evoked retrieval of associated memories. This was immediately followed by an intraperitoneal injection of lithium chloride (LiCl) and served to pair the memory of cocaine reward with gastric malaise. Consequently, this led to a substantial reduction in cocaine-seeking behavior during extinction training, relative to rats that received CS-saline or LiCl alone during mediated devaluation. Cue- and cocaine-evoked reinstatement testing indicated that the manipulations did not devalue the CS or the reinforcing properties of cocaine. A separate cohort of rats received a dual-viral chemogenetic strategy that permitted circuit-specific inactivation of midbrain ventral tegmental area (VTA) cells projecting to the nucleus accumbens (NAc). Inactivation of VTA→NAc circuitry during mediated devaluation prevented the subsequent reduction of cocaine-seeking behavior during extinction training. Overall, these findings suggest that intact mesolimbic signaling is required to enable disruptions in cocaine-seeking behavior following mediated devaluation.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fatty acid amide hydrolase in major depressive episodes: A [¹¹C]CURB positron emission tomography study.","authors":"Dorsa Rafiei, Michelle De Pol, Jeffrey H Meyer, Kimberly Desmond, Ruth Ross, Isabelle Boileau, Jerry Warsh, Pablo Rusjan, Neil Vasdev, Ryan Aloysius, Lauren Gray, Nathan J Kolla","doi":"10.1038/s41386-025-02150-y","DOIUrl":"https://doi.org/10.1038/s41386-025-02150-y","url":null,"abstract":"<p><p>The role of the endocannabinoid system (ECS) in major depressive disorder (MDD) is under-investigated despite reports of increased activity and/or concentration of fatty acid amide hydrolase (FAAH), a key ECS enzyme, in fronto-limbic brain regions in some animal models of depressive behavior. We hypothesized that [¹¹C]CURB λk₃, an index of FAAH density, would be elevated in the prefrontal cortex, hippocampus, and anterior cingulate cortex in major depressive episodes of MDD compared to healthy controls. Fifteen unmedicated MDD participants and 15 age- and sex-matched healthy controls underwent [¹¹C]CURB positron emission tomography and FAAH genotyping. Psychological tests of depressive severity, apathy, and anxiety were administered and measurements were assessed as covariates in exploratory analyses. No significant group differences in [¹¹C]CURB λk₃ were observed between MDD participants and controls (F_1,27 = 0.32; p = 0.58). A mixed effects model revealed that Marin Apathy Evaluation Scale scores in the MDD group had a significant main effect on [¹¹C]CURB λk₃ binding across the collective regions of medial prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, ventral striatum, and midbrain (F_1,11 = 6.75; p = 0.02). Depressive severity and anxiety did not have a significant relationship to [¹¹C]CURB λk₃ binding. The relationship of greater fronto-limbic [¹¹C]CURB λk₃ to greater apathy along with the metabolic role of FAAH in the ECS, the latter which supports maintaining feelings of interest, initiative, and motivation, has important implications for the pathophysiology of apathy in MDD.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}