Neuropsychopharmacology最新文献

{"title":"Connectome-based fingerprinting: reproducibility, precision, and behavioral prediction.","authors":"Jivesh Ramduny, Clare Kelly","doi":"10.1038/s41386-024-01962-8","DOIUrl":"10.1038/s41386-024-01962-8","url":null,"abstract":"<p><p>Functional magnetic resonance imaging-based functional connectivity enables the non-invasive mapping of individual differences in brain functional organization to individual differences in a vast array of behavioral phenotypes. This flexibility has renewed the search for neuroimaging-based biomarkers that exhibit reproducibility, prediction, and precision. Functional connectivity-based measures that share these three characteristics are key to achieving this goal. Here, we review the functional connectome fingerprinting approach and discuss its value, not only as a simple and intuitive conceptualization of the \"functional connectome\" that provides new insights into how the connectome is altered in association with psychiatric symptoms, but also as a straightforward and interpretable method for indexing the reproducibility of functional connectivity-based measures. We discuss how these advantages provide new avenues for strengthening reproducibility, precision, and behavioral prediction for functional connectomics and we consider new directions toward discovering better biomarkers for neuropsychiatric conditions.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":"114-123"},"PeriodicalIF":6.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11525788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988470","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":"Orexinergic modulation of chronic jet lag-induced deficits in mouse cognitive flexibility.","authors":"Julius Duske, Nicole D'Souza, Dana Mayer, Daniela C Dieterich, Markus Fendt","doi":"10.1038/s41386-024-02017-8","DOIUrl":"https://doi.org/10.1038/s41386-024-02017-8","url":null,"abstract":"<p><p>Cognitive flexibility and working memory are important executive functions mediated by the prefrontal cortex and can be impaired by circadian rhythm disturbances such as chronic jet lag (CJL) or shift work. In the present study, we used mice to investigate whether (1) simulated CJL impairs cognitive flexibility, (2) the orexin system is involved in such impairment, and (3) nasal administration of orexin A is able to reverse CJL-induced deficits in cognitive flexibility and working memory. Mice were exposed to either standard light-dark conditions or simulated CJL consisting of series of advance time shifts. Experiment (1) investigated the effects of a mild CJL protocol on cognitive flexibility using the attentional set shifting task. Experiment (2) used a stronger CJL protocol and examined CJL effects on the orexin system utilizing c-Fos and orexin immunohistochemistry. Experiment (3) tested whether nasal orexin application can rescue CJL-induced deficits in cognitive flexibility and working memory, the latter by measuring spontaneous alternation in the Y-maze. The present data show that CJL (1) impairs cognitive flexibility and (2) reduces the activity of orexin neurons in the lateral hypothalamus. (3) Nasal administration of orexin A rescued CJL-induced deficits in working memory and cognitive flexibility. These findings suggest that executive function impairments by circadian rhythm disturbances such as CJL are caused by dysregulation of orexinergic input to the prefrontal cortex. Compensation of decreased orexinergic input by nasal administration of orexin A could be a potential therapy for CJL- or shift work-induced human deficits in executive functions.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546529","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":"PACAP regulates neuroendocrine and behavioral stress responses via CRF-containing neurons of the rat hypothalamic paraventricular nucleus.","authors":"Karl Ebner, Veronica Fontebasso, Federico Ferro, Nicolas Singewald, Jens Hannibal","doi":"10.1038/s41386-024-02016-9","DOIUrl":"https://doi.org/10.1038/s41386-024-02016-9","url":null,"abstract":"<p><p>Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide widely distributed in the brain including the hypothalamic paraventricular nucleus (PVN) implying a regulatory role in stress function. Recent evidence indicates that one of the main targets of PACAP within the PVN are corticotropin-releasing factor (CRF) neurons, which are key regulators of the hypothalamic-pituitary-adrenal (HPA) axis. However, the neural correlates that mediate PACAP effects on stress function are not fully understood. In the present study, we characterized the neuronal mechanism by which PACAP regulates neuroendocrine and behavioral stress responses in rats. We found that intracerebroventricular administration of PACAP increased the swim stress-induced c-Fos expression in distinct brain areas of the stress and anxiety circuitry including the parvocellular part of the PVN and changed behavioral stress coping during forced swimming to a more passive coping style (i.e., indicated by increased floating and reduced struggling behavior). Subsequently, PACAP administration directly into the PVN mimicked these behavioral effects and potentiated the plasma ACTH response to forced swim stress suggesting an excitatory role of PACAP on HPA stress axis reactivity. In addition, immunohistochemical analysis revealed a considerable portion of stress-activated CRF neurons in the medial parvocellular part of the PVN that co-localized PAC1 receptors suggesting that PACAP-induced effects on stress function are likely mediated directly by activation of CRF neurons in the PVN. Thus, these findings suggest that the PVN may represent one of the key areas where PACAP regulates the neuroendocrine and behavioral stress response.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546530","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":"Is the stereoisomer R-MDMA a safer version of MDMA?","authors":"Gillinder Bedi","doi":"10.1038/s41386-024-02009-8","DOIUrl":"https://doi.org/10.1038/s41386-024-02009-8","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504796","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":"Extended course accelerated intermittent theta burst stimulation as a substitute for depressed patients needing electroconvulsive therapy.","authors":"Michelle S Goodman, Alisson P Trevizol, Gerasimos N Konstantinou, David Boivin-Lafleur, Ram Brender, Jonathan Downar, Tyler S Kaster, Yuliya Knyahnytska, Fidel Vila-Rodriguez, Daphne Voineskos, Zafiris J Daskalakis, Daniel M Blumberger","doi":"10.1038/s41386-024-02007-w","DOIUrl":"https://doi.org/10.1038/s41386-024-02007-w","url":null,"abstract":"<p><p>In response to restrictions on electroconvulsive therapy (ECT) access during COVID-19, we designed a trial to assess the clinical outcomes service impacts, employing an extended course of accelerated intermittent theta burst stimulation (aiTBS), in patients with moderate to severe depression in need of ECT. This open label clinical trial was comprised of 3 phases: (i) an acute phase, where iTBS treatments were administered 8 times daily, for up to 10 days; (ii) a tapering phase of 2 treatment days per week for 2 weeks, followed by 1 treatment day per week for 2 weeks; and (iii) a symptom-based relapse prevention phase, whereby treatments were scheduled based on symptom re-emergence, for up to 6 months. Of the 155 patients who completed the acute phase of the study, the remission rate was 16.1%. The mean reduction from baseline on the HRSD-24 was 29.4% (p < 0.001) and the response rate was 25.2%. Of the 110 patients who completed the tapering phase, the mean reduction from baseline was 42.6% (p < 0.001) and response and remission rates were 49.6% and 34.8%, respectively. Of the 61 patients who were eligible for the relapse prevention phase, 43 completed, with a mean reduction from baseline of 60.1% (p < 0.001); 7 patients relapsed during this phase. This study demonstrated that an extended aiTBS protocol safely led to meaningful clinical outcomes in patients with severe depression, who otherwise would have received ECT, and thus reduced pressure on ECT services during the pandemic. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04384965 ( https://clinicaltrials.gov/study/NCT04384965?term=NCT04384965&rank=1 ).</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504795","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":"Deep phenotyping reveals CRH and FKBP51-dependent behavioral profiles following chronic social stress exposure in male mice.","authors":"Veronika Kovarova, Joeri Bordes, Shiladitya Mitra, Sowmya Narayan, Margherita Springer, Lea Maria Brix, Jan M Deussing, Mathias V Schmidt","doi":"10.1038/s41386-024-02008-9","DOIUrl":"https://doi.org/10.1038/s41386-024-02008-9","url":null,"abstract":"<p><p>The co-chaperone FKBP51, encoded by FKBP5 gene, is recognized as a psychiatric risk factor for anxiety and depressive disorders due to its crucial role in the stress response. Another key modulator in stress response regulation is the corticotropin releasing hormone (CRH), which is co-expressed with FKBP51 in many stress-relevant brain-regions and cell-types. Together, they intricately influence the balance of the hypothalamic-pituitary-adrenal (HPA) axis, one of the primary stress response systems. Previous research underscores the potential moderating effects these genes have on the regulation of the stressful life events towards the vulnerability of major depressive disorder (MDD). However, the specific function of FKBP51 in CRH-expressing neurons remains largely unexplored. Here, through deep behavioral phenotyping, we reveal heightened stress effects in mice lacking FKBP51 in CRH co-expressing neurons (CRH^FKBP5-/-), particularly evident in social contexts. Our findings highlight the importance of considering cell-type specificity and context in comprehending stress responses and advocate for the utilization of machine-learning-driven phenotyping of mouse models. By elucidating these intricacies, we lay down the groundwork for personalized interventions aimed at enhancing stress resilience and individual well-being.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504794","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":"NPP Editorial: tides of progress.","authors":"Lisa M Monteggia, Tony P George","doi":"10.1038/s41386-024-02006-x","DOIUrl":"https://doi.org/10.1038/s41386-024-02006-x","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504797","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":"Phytocannabinoids restore seizure-induced alterations in emotional behaviour in male rats.","authors":"Renaud C Gom, Pasindu Wickramarachchi, Antis G George, Savannah H M Lightfoot, Dana Newton-Gunderson, Matthew N Hill, G Campbell Teskey, Roberto Colangeli","doi":"10.1038/s41386-024-02005-y","DOIUrl":"https://doi.org/10.1038/s41386-024-02005-y","url":null,"abstract":"<p><p>Epilepsy often presents with severe emotional comorbidities including anxiety and abnormal fear responses which impose a significant burden on, and reduce, quality of life in people living with the disease. Our lab has recently shown that kindled seizures lead to changes in emotional processing resulting from the downregulation of anandamide signalling within the amygdala. Phytocannabinoids derived from the Cannabis sativa plant have attracted a lot of interest as a new class of drugs with potential anticonvulsant effects. Among the wide number of compounds occurring in Cannabis sativa, Δ9- tetrahydrocannabinol (THC), the one responsible for its main psychoactive effects, and the nonpsychoactive cannabidiol (CBD) have been extensively examined under pre-clinical and clinical contexts to control seizures, however, neither have been assessed in the context of the management of emotional comorbidities associated with seizure activity. We used two behavioural procedures to assess anxiety- and fear-like responding in adult male Long-Evans rats: elevated plus maze and auditory fear conditioning. In agreement with previous reports, we found seizure-induced increases in anxiety- and fear-like responding. These effects were reversed by either CBD (vaporized) or THC (oral). We also found that antagonism of serotonin 1 A receptors prior to CBD exposure prevented its protective effects. Phytocannabinoids offer a novel and reliable opportunity to treat seizure induced comorbid emotional alterations.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470817","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":"Small-molecule natural product sophoricoside reduces peripheral neuropathic pain via directly blocking of NaV1.6 in dorsal root ganglion nociceptive neurons.","authors":"Weijie Guo, Haoyi Yang, Yuwei Wang, Tao Liu, Yunping Pan, Xiying Chen, Qiuyin Xu, Dizhou Zhao, Zhiming Shan, Song Cai","doi":"10.1038/s41386-024-01998-w","DOIUrl":"https://doi.org/10.1038/s41386-024-01998-w","url":null,"abstract":"<p><p>Peripheral neuropathic pain poses a significant global health challenge. Current drugs for peripheral neuropathic pain often fall short in efficacy or come with severe side effects, emphasizing the critical need for the development of highly effective and well-tolerated alternatives. Sophoricoside (SOP) is a nature product-derived isoflavone that possesses various pharmacological effects on inflammatory and neuropathy diseases. Here, in this study, analgesic effect was investigated by intrathecally administration of SOP/vehicle to spared nerve injury (SNI) or paclitaxel-induced peripheral neuropathic pain (PINP) rodent models, and mechanical allodynia was measured in Von Frey tests. Ipsilateral L4-L6 dorsal root ganglia (DRG) were used for protein expression. In silico molecular docking analysis was applied for assessing compound-target binding affinity. Primary cultured DRG neurons were utilized to investigate SOP's effect on veratridine-triggered nociceptor activities and its selective inhibition of voltage-gated sodium channels subtype 1.6 (NaV1.6). The results showed SOP treatment alleviated mechanical allodynia in SNI and PINP rodent models (paw withdrawal threshold after 1 h of injection: SNI-vehicle: 1.385 ± 0.338 g; SNI-SOP: 9.963 ± 2.029 g, P < 0.001; PINP-vehicle: 5.040 ± 0.985 g; PINP-SOP: 8.287 ± 3.812 g, P = 0.004). SOP presented effects on both inhibiting veratridine-triggered nociceptor activities (oscillatory population: vehicle: 39.9 ± 7.3%; SOP: 30.7 ± 9.8%, P = 0.021) and selectively blocking NaV1.6 in DRG sensory neurons. Molecular docking analysis indicated direct binding between SOP and NaV1.6, leading to its endocytosis in DRG Sensory Neurons. In conclusion, SOP alleviated nociceptive allodynia induced by peripheral nerve injury via selectively blocking of NaV1.6 in DRG nociceptive neurons. we highlight its potential as an analgesic and elucidate its mechanism involving NaV1.6 endocytosis. This research opens avenues for exploring the analgesic effects of SOP and its potential impact on neuropathic pain therapy.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470819","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":"PET clinical study of novel antipsychotic LB-102 demonstrates unexpectedly prolonged dopamine receptor target engagement.","authors":"Dean F Wong, Ganesh B Chand, Nicole Caito, Anna Eramo, Vincent T Grattan, Mark S Hixon, Ginger Nicol, Erin Lessie, Zachary Prensky, Hiroto Kuwabara, Lucy Tian, Ines Valenta, Thomas H Schindler, Gerhard Gründer, Andrew R Vaino","doi":"10.1038/s41386-024-01951-x","DOIUrl":"https://doi.org/10.1038/s41386-024-01951-x","url":null,"abstract":"<p><p>Regulation of dopamine activity has important clinical consequences, most notably in schizophrenia. LB-102, N-methyl amisulpride, is a novel dopamine D_2/3/5-HT₇ inhibitor being developed as a treatment for schizophrenia and other psychiatric disorders. The characteristic that is common to all current antipsychotics is their engagement of D₂ dopamine receptors. The goal of this study was to measure the dopamine receptor occupancy of orally administered LB-102 at three different doses (50, 75, and 100 mg as single doses and 50 and 100 mg as multiple doses) and at different timepoints in healthy volunteers using positron emission tomography (PET) with ¹¹C raclopride as a radiotracer. Results of this study (NCT04588129) showed that steady-state once daily oral dosing of 50 mg LB-102 afforded striatal dopamine occupancy (RO) in the desired 60-80% range consistently over the course of 24 h. Contrary to the often observed relationship between RO vs plasma concentrations, maximum dopamine RO significantly lagged maximum plasma concentration and showed little variability under steady state conditions. A similar phenomenon has recently been reported with a non-racemic version of amisulpride [1]. LB-102 was generally safe and well-tolerated at all doses. Results of this study were used to inform dosing in a subsequent Phase 2 clinical study in schizophrenia patients.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470816","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}