Neuropsychopharmacology最新文献

{"title":"Splice isoforms of the histone variant macroH2A1 differentially regulate hippocampal gene expression and memory formation","authors":"Timothy A. B. McLean, Zhenhong Jin, Luca A. Hategan, Samantha D. Creighton, Jian Qi Luo, Fardad Pirri, Tarkan A. Dahi, Laura Neira Diaz, Stephen M. Winston, Mark A. Brimble, Brandon J. Walters, Iva B. Zovkic","doi":"10.1038/s41386-026-02479-y","DOIUrl":"10.1038/s41386-026-02479-y","url":null,"abstract":"Histone variants are critical components of neuronal chromatin that are emerging as key regulators of long-term memory formation. We previously showed that depleting the macrodomain-containing histone variant macroH2A1 (mH2A1) in the mouse hippocampus impairs long-term memory, establishing this histone as essential for memory consolidation. However, mH2A1 undergoes alternative splicing to generate two isoforms, mH2A1.1 and mH2A1.2, which differ by a single exon within the macrodomain. Though mH2A1.1 and mH2A1.2 have been reported to regulate unique molecular processes in non-neuronal cells, distinct functional contributions of hippocampal mH2A1.1 and mH2A1.2 to long-term memory formation in the adult brain are unknown. Here, we characterized genomic localization of mH2A1 splice isoforms in the mouse hippocampus and evaluated how isoform-specific knockdown impacts hippocampal transcription and memory. Although both isoforms localize to and regulate memory-relevant genes, their depletion affected largely non-overlapping gene sets, and only loss of mH2A1.1 impaired long-term memory. Notably, mH2A1.1 depletion increased expression of several genes that negatively regulate memory formation, including the well-established memory suppressor calcineurin. Thus, under normal conditions, mH2A1.1 may promote memory by repressing transcriptional programs that constrain plasticity. Together, these findings reveal isoform-specific functions of mH2A1 in the hippocampus and identify alternative splicing of mH2A1 as a key epigenetic mechanism that fine-tunes neural chromatin composition to enable long-term memory formation.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 10","pages":"1-10"},"PeriodicalIF":7.6,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148355520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kappa opioid receptors mediate aversion—and it matters","authors":"Rainer Spanagel, Filipe Reis Teodoro Andrade","doi":"10.1038/s41386-026-02478-z","DOIUrl":"10.1038/s41386-026-02478-z","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 10","pages":"1743-1745"},"PeriodicalIF":7.6,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148355521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In memoriam—Shigeto Yamawaki, M.D., Ph.D. (1954–2026)","authors":"Kazutaka Ikeda, John H. Krystal, Toshikazu Saito","doi":"10.1038/s41386-026-02482-3","DOIUrl":"10.1038/s41386-026-02482-3","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 10","pages":"1908-1909"},"PeriodicalIF":7.6,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02482-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148341877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Top-down control of sustained attention by medial prefrontal cortex—locus coeruleus (mPFC-LC) projection neurons during the rodent continuous performance test (rCPT)","authors":"Jason J. Rehg, Daniel E. Olivares, Ye Li, Raul García, Keri Martinowich, Gregory V. Carr, Jorge Miranda-Barrientos","doi":"10.1038/s41386-026-02452-9","DOIUrl":"10.1038/s41386-026-02452-9","url":null,"abstract":"The medial prefrontal cortex (mPFC) plays a pivotal role in attention by exerting top-down control to allocate cognitive resources toward behaviorally relevant stimuli based on learned context and expectations. mPFC neurons project to multiple cortical and subcortical regions, including the locus coeruleus (LC)—the brain’s primary source of norepinephrine (NE). The mPFC also receives inputs from the LC, which release NE to modulate mPFC neuronal activity and downstream cellular signaling. While enhanced functional connectivity between the mPFC and LC in mice during sustained attention tasks suggest an important role for the mPFC–LC circuit, and in particular for mPFC neurons projecting to the LC (mPFC-LC projectors), functional evidence directly implicating this population in attention is lacking. Here, we investigated the role of the mPFC–LC projectors in attention by comparing selective chemogenetic manipulation of these neurons to broad chemogenetic manipulation of mPFC neurons. Selective activation of mPFC–LC projectors in mice performing the rodent continuous performance test (rCPT), a translational sustained attention task, robustly improves attentional performance by enhancing discrimination while non-selective activation of mPFC neurons increases attentional performance by increasing responsiveness. Behavioral effects of mPFC-LC projector activation were mediated by recruitment of a microcircuit involving LC-NE neurons and glutamate and GABA peri-LC neurons that resulted in an increase in NE tone within the mPFC. while effects of non-selective activation of mPFC neurons were mediated by engaging downstream targets such as the nucleus accumbens (NAc) as well as the LC/peri-LC region. These findings demonstrate that subpopulations of mPFC neurons engaging distinct downstream targets control different domains of attentional performance, providing a circuit-level framework for understanding the mechanisms of sustained attention and for developing targeted therapies for attentional deficits across neuropsychiatric disorders.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"2290-2300"},"PeriodicalIF":7.6,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148341875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the effect of increased dopamine signaling on cerebral blood flow in Major Depressive Disorder: a double-blind randomized placebo-controlled study","authors":"Matti Gärtner, Marvin S. Meiering, David Weigner, Moritz Hempel, Rebecca Gruzman, Luisa Carstens, Christian Keicher, Maarten Mennes, Christian F. Beckmann, Gerd Luippold, Sigurd D. Süssmuth, Margot Popp, Andreas Wunder, Simone Grimm","doi":"10.1038/s41386-026-02471-6","DOIUrl":"10.1038/s41386-026-02471-6","url":null,"abstract":"Anhedonia, a core symptom of major depressive disorder (MDD), is linked to dysfunction in reward-related brain regions and impaired dopamine (DA) signaling. This study used arterial spin labeling (ASL) to investigate the effects of a single low dose of amisulpride, a selective DA antagonist, on cerebral blood flow (CBF) in MDD patients and healthy volunteers (HVs). In a double-blind, placebo-controlled, randomized, parallel-group design, participants received either 100 mg amisulpride or placebo. N = 111 participants (MDD: n = 57; HV: n = 54) were included in the final analysis and group differences were assessed in core regions of the reward network, particularly the ventral striatum. Individual CBF values were analyzed in relation to self-reported anhedonia and depression severity. Amisulpride was associated with higher perfusion in the ventral striatum compared to placebo in both HVs and MDD patients, consistent with enhanced dopaminergic activity in this region. No significant CBF changes were observed in other areas of the reward network. Ventral striatal perfusion was significantly associated with self-reported anhedonia. Exploratory whole-brain analyses revealed higher CBF in the right frontal operculum in MDD patients compared to HVs under placebo, but not under amisulpride. In the placebo group, both anhedonia and depression severity were associated with CBF in the right frontal operculum; these associations were absent following amisulpride administration. In conclusion, we provide initial evidence of region-specific effects of amisulpride administration on CBF that are consistent with modulation of dopaminergic signaling. Increased perfusion in the ventral striatum suggests a potential dopaminergic mechanism relevant to anhedonia. These findings underscore the ventral striatum’s role in reward processing and support its involvement in the pathophysiology of anhedonia across clinical and non-clinical populations.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 10","pages":"1808-1815"},"PeriodicalIF":7.6,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02471-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148335621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A ventral hippocampus to nucleus accumbens pathway regulates impulsivity in male but not female rats","authors":"Molly E. Klug, Léa Décarie-Spain, Logan Tierno Lauer, Bo W. Sortman, Bingxin Mo, Alicia E. Kao, Olivia P. Moody, Nicolas R. Morano, Haoyang Huang, Don B. Arnold, Emily E. Noble, Alexander W. Johnson, Scott E. Kanoski","doi":"10.1038/s41386-026-02477-0","DOIUrl":"10.1038/s41386-026-02477-0","url":null,"abstract":"Heightened impulsivity is associated with substance abuse disorders, gambling, and obesity. The ventral hippocampus (vHPC) has recently been linked with impulse control, yet the neurobiological and behavioral mechanisms through which this occurs are unknown. A subset of vHPC neurons projects to the nucleus accumbens shell (ACBsh), a brain region known for regulating reward and motivation. Here, we evaluated the role of vHPC-ACBsh signaling in food-directed impulsivity using fiber photometry and transsynaptic chemogenetic and behavioral approaches. Male and female rats were trained in the differential reinforcement of low rates of responding (DRL) test of impulsive action, where they learn to withhold lever presses for 20 s to obtain a palatable food reward. Photometry recordings during DRL revealed elevations in calcium-dependent activity in the vHPC during the 5 s immediately prior to a non-impulsive vs. an impulsive response in males but not females. Chemogenetic silencing of ACBsh-projecting vHPC neurons elevated impulsive responses in DRL relative to vehicle treatment in males but not females, yet had no effect on home cage food intake, operant-based motivation to work for palatable food, impulsive choice, or anxiety-like behavior. To determine whether this impulse control circuit requires vHPC->ACBsh communication independent of collateral targets of ACBsh-projecting vHPC neurons, we utilized a novel transsynaptic viral approach to selectively silence ACB neurons that receive synaptic glutamatergic signaling from the vHPC. Results reveal that inhibition of ACBsh neurons receiving vHPC signaling elevates impulsive action in the DRL task relative to vehicle treatment. Collective results reveal a sex-specific hippocampal-striatal circuit that regulates impulsivity.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 10","pages":"1-11"},"PeriodicalIF":7.6,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02477-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148341862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered striatal dopamine regulation in Adgrl3 knockout mice","authors":"Nicole A. Perry-Hauser, Arturo Torres-Herraez, Siham Boumhaouad, Emily A. Makowicz, Danielle C. Lowes, Michelle Jin, Christine A. Denny, David Sulzer, Eugene V. Mosharov, Christoph Kellendonk, Jonathan A. Javitch","doi":"10.1038/s41386-026-02474-3","DOIUrl":"10.1038/s41386-026-02474-3","url":null,"abstract":"Dopamine signaling is essential for regulating movement, learning, and reward processing, and its dysregulation has been implicated in neuropsychiatric conditions such as ADHD and substance use disorder. ADGRL3, an adhesion G protein-coupled receptor enriched in the brain, has been genetically linked to these disorders, and Adgrl3 knockout in animals alters expression of dopaminergic markers and impacts dopamine-related behaviors. However, how ADGRL3 influences dopamine dynamics remains poorly understood. Here, we characterized striatal dopamine release in Adgrl3 knockout mice using complementary ex vivo and in vivo approaches. Fast-scan cyclic voltammetry in acute brain slices revealed increased electrically evoked dopamine release in both dorsal and ventral striatum of Adgrl3 knockout mice. In contrast, in vivo fiber photometry using the dopamine sensor dLight1.2 showed reduced cue-induced dopamine signals in the ventral striatum during an operant fixed interval task. This reduction was accompanied by longer latencies to lever press and retrieve rewards, consistent with altered cue-guided behavioral responses reminiscent of task-switching difficulties in individuals with ADHD. Amphetamine challenge experiments indicated that phasic release capacity was similar between genotypes, suggesting that dopamine stores are intact in Adgrl3 KO mice. Together, these findings reveal that ADGRL3 regulates striatal dopamine release and motivate mechanistic studies of how its loss may alter the spatial organization of dopaminergic terminals.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"2248-2257"},"PeriodicalIF":7.6,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02474-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148341879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Norepinephrine regulates hippocampal mitochondrial biogenesis via β2-adrenergic receptor signaling and PGC-1α","authors":"Darshana Kapri, Amogh Bhaskaran Jayaprasad, Praachi Tiwari, Mukund Sharma, Angarika Balakrishnan, Aastha Singla, Ishanee Mazumder, Ullas Kolthur-Seetharam, Sashaina E. Fanibunda, Ashok D. B. Vaidya, Vidita A. Vaidya","doi":"10.1038/s41386-026-02470-7","DOIUrl":"10.1038/s41386-026-02470-7","url":null,"abstract":"Neuronal mitochondria are central to not only maintaining cellular bioenergetics, calcium dynamics, and serving as signaling platforms, but are also critical for specialized functions including synaptic plasticity and neurotransmission. While mitochondria are postulated to have a fundamental role in the functioning of neurons, it is only recently that upstream factors that influence mitochondria in neurons have been systematically investigated. Here, we identify the critical role of the neurotransmitter, norepinephrine (NE) in modulating mitochondria in the rodent hippocampus. NE increases the expression of key regulators of mitochondrial biogenesis (SIRT1 and PGC-1α), enhances mitochondrial DNA content and ATP levels in hippocampal neurons in culture. These effects of NE are mediated via the recruitment of a β2-adrenergic receptor-Gs-cAMP-PKA signaling cascade and are dependent on PGC-1α. We find that increasing noradrenergic signaling in vivo, either through direct administration of NE into the hippocampus via osmotic minipumps or treatment with the NE reuptake inhibitor, Atomoxetine, as well administration of the β2-adrenergic receptor agonist, Formoterol, enhances mitochondrial DNA content in the hippocampus. Furthermore, increased spatial memory recall with Atomoxetine treatment was significantly correlated with both mitochondrial DNA content and ATP levels in the hippocampus. Our findings identify a novel role for NE in impacting mitochondrial biogenesis in the hippocampus, and suggest a link between bioenergetic status and spatial memory performance.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 10","pages":"1767-1778"},"PeriodicalIF":7.6,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148335625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a nose-poke restricted vaporized cocaine self-administration model in mice","authors":"Byoung Mo Choi, Yong-Qing Zhang, Hyeokjun Kwon, Jae Sang Han, Bang Yeon Hwang, Jaesuk Yun","doi":"10.1038/s41386-026-02472-5","DOIUrl":"10.1038/s41386-026-02472-5","url":null,"abstract":"The need for preclinical models that better reflect human substance use patterns has increased due to the rising misuse of electronic cigarettes (e-cigarettes) for drug inhalation. However, Self administration studies using mice in this context remain limited. To address this, we developed a self-administration model in which mice voluntarily insert their nose into a nose poke port, where vaporized cocaine passes through an airway, allowing controlled inhalation. Mice were exposed to vaporized cocaine at 50, 100, 200, and 300 mg/mL, and active nose-poke response was significantly increased compared to vehicle across concentrations, except at 300 mg/mL. At 100 mg/mL, plasma cocaine was 284 nM, with no significant sex differences detected. During extinction, active responses decreased over time and were reinstated following exposure to cocaine vapor-associated cues and cocaine priming. We also observed differences between the cocaine and vehicle groups in rewards earned, and active nose-poke responding during the progressive-ratio (PR) sessions. This model provides a preclinical approach for studying vaporized cocaine self-administration. A key advantage of this system is that it enables temporally precise, self-administered bolus delivery of drug exposure. This feature allows for improved experimental control over the timing and pattern of drug intake, facilitating investigation of the reinforcing effects of vaporized cocaine.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 10","pages":"1-10"},"PeriodicalIF":7.6,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148335630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential and state-dependent effects of the GluN2A-selective positive allosteric modulator GNE-5729 on executive functions","authors":"Johannes Lauer, Julia Poppke, Thomas Nickl-Jockschat, Daniela C. Dieterich, Markus Fendt, Samia Afzal","doi":"10.1038/s41386-026-02476-1","DOIUrl":"10.1038/s41386-026-02476-1","url":null,"abstract":"Cognitive deficits in executive functions such as working memory and cognitive flexibility are central to many brain disorders, yet effective treatments remain limited. Dysfunction of GluN2A-containing NMDA receptors (NMDAR) contributes to these impairments, and positive allosteric modulators (PAM) that selectively enhance GluN2A function offer a promising strategy to rescue cognitive deficits while preserving physiological neurotransmission. However, it remains unclear whether PAM-driven GluN2A potentiation can rescue mechanistically distinct, pharmacologically induced impairments and whether the efficacy of GluN2A-PAMs differs across executive domains and sexes. Here, we assessed the effects of GNE-5729, a brain-penetrant GluN2A-selective PAM, on executive functions in mice. GNE-5729 showed no overall effect on working memory performance in the Y-maze, but improved performance in mice with low baseline spontaneous alternations, indicating a baseline-dependent effect. It also rescued working memory deficits induced by dl-amphetamine and scopolamine, which disrupt neuromodulatory regulation while leaving NMDAR channels functionally accessible. In contrast, GNE-5729 failed to reverse MK-801-induced impairments, consistent with MK-801’s non-competitive pore blockade of NMDAR. Notably, GNE‑5729 effects showed sex‑dependent patterns, with female mice displaying more pronounced effects. GNE-5729 had no effects on cognitive flexibility in the attentional set-shifting task (ASST) and did not alter prefrontal GluN2A expression, though it disrupted the association between endogenous GluN2A levels and ASST performance observed in controls. Together, these findings indicate that GNE-5729 exerts effects under conditions of reduced baseline performance or disrupted neuromodulatory signaling and demonstrates differential effects across executive domains, supporting a state-dependent therapeutic profile of GluN2A-targeted modulation.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"1980-1990"},"PeriodicalIF":7.6,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02476-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148321619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}