Neuropsychopharmacology最新文献

{"title":"Cathepsin B modulates microglial migration and phagocytosis of amyloid β in Alzheimer's disease through PI3K-Akt signaling.","authors":"Muzhou Jiang, Dan Zhao, Yue Zhou, Wei Kong, Zhen Xie, Yijie Xiong, Yanhui Li, Shuxuan Zhao, Xueshuai Kou, Simeng Zhang, Rui Meng, Yaping Pan, Zhou Wu, Hiroshi Nakanishi, Juan Zhao, Hui Li, Zhenzhen Quan, Li Lin, Hong Qing, Junjun Ni","doi":"10.1038/s41386-024-01994-0","DOIUrl":"https://doi.org/10.1038/s41386-024-01994-0","url":null,"abstract":"<p><p>The approval of anti-amyloid β (Aβ) monoclonal antibodies (lecanemab) for the treatment of patients with early preclinical stage of Alzheimer's disease (AD) by the Food and Drug Administration, suggests the reliability and importance of brain Aβ clearance for AD therapy. Microglia are the main phagocytes that clear Aβ in the brain, but the underlying regulatory mechanism is unclear. Here, we investigate the critical role of cathepsin B (CatB) in modulating microglial Aβ clearance from mouse brain. Wild-type or CatB^-/- mice were injected with Aβ into the hippocampus from 1 to 3 weeks. Mice were evaluated for cognitive change, Aβ metabolism, neuroinflammation. Microglia and neuron cultures were prepared to verify the in vivo results. The statistical analyses were performed by student's t test, one-way ANOVA with a post hoc Tukey's test using the GraphPad Prism software package. CatB deficiency significantly reduces Aβ clearance efficiency and aggravates mouse cognitive decline. Exogenous Aβ markedly increases CatB expression in activated microglia. Transcriptome analysis and in vitro cell culture experiments demonstrate that CatB is associated with gene clusters involved in migration, phagocytosis, and inflammation. In addition, transcriptome analysis and immunoblotting suggest that CatB modulates microglial Aβ clearance via PI3K-AKT activation. Our study unveils a previously unknown role of CatB in promoting microglial functionality during Aβ clearance.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292161","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":"Role of serotonin neurons in the dorsal raphe nucleus in heroin self-administration and punishment.","authors":"Chen Li, Nicholas S McCloskey, Saadet Inan, Lynn G Kirby","doi":"10.1038/s41386-024-01993-1","DOIUrl":"10.1038/s41386-024-01993-1","url":null,"abstract":"<p><p>One hallmark of substance use disorder is continued drug use despite negative consequences. When drug-taking behavior is punished with aversive stimuli, i.e. footshock, rats can also be categorized into punishment-resistant or compulsive vs. punishment-sensitive or non-compulsive phenotypes. The serotonin (5-hydroxytryptamine, 5-HT) system modulates responses to both reward and punishment. The goal of the current study was to examine punishment phenotypes in heroin self-administration and to determine the role of dorsal raphe nucleus (DRN) 5-HT neurons in both basal and punished heroin self-administration. First, rats were exposed to punished heroin self-administration and neuronal excitability of DRN 5-HT neurons was compared between punishment-resistant and punishment-sensitive phenotypes using ex vivo electrophysiology. Second, DRN 5-HT neuronal activity was manipulated in vivo during basal and punished heroin self-administration using chemogenetic tools in a Tph2-iCre rat line. While rats separated into punishment-resistant and punishment-sensitive phenotypes for punished heroin self-administration, DRN 5-HT neuronal excitability did not differ between the phenotypes. While chemogenetic inhibition of DRN 5-HT neurons was without effect, chemogenetic activation of DRN 5-HT neurons increased both basal and punished heroin self-administration selectively in punishment-resistant animals. Additionally, the responsiveness to chemogenetic activation of DRN 5-HT neurons in basal self-administration and motivation for heroin in progressive ratio each predicted resistance to punishment. Therefore, our data support the role for the DRN 5-HT system in compulsive heroin self-administration.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292166","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":"Role of dorsal striatum circuits in relapse to opioid seeking after voluntary abstinence.","authors":"Zilu Ma, Ying Duan, Ida Fredriksson, Pei-Jung Tsai, Ashley Batista, Hanbing Lu, Yavin Shaham, Yihong Yang","doi":"10.1038/s41386-024-01990-4","DOIUrl":"https://doi.org/10.1038/s41386-024-01990-4","url":null,"abstract":"<p><p>High relapse rate during abstinence is a defining characteristic of drug addiction. We previously found that opioid seeking progressively increases after voluntary abstinence induced by adverse consequences of oxycodone seeking (crossing an electric barrier). Functional MRI revealed that this effect is associated with changes in functional connectivity within medial orbitofrontal cortex (mOFC)- and dorsomedial striatum (DMS)-related circuits. Here, we used a pharmacological manipulation and fMRI to determine the causal role of mOFC and DMS in oxycodone seeking after electric barrier-induced abstinence. We trained rats to self-administer oxycodone (6 h/day, 14 days). Next, we induced voluntary abstinence by exposing them to an electric barrier for 2 weeks. We inactivated the mOFC and DMS with muscimol+baclofen (GABA_a and GABA_b receptor agonists) and then tested them for relapse to oxycodone seeking on abstinence days 1 or 15 without the electric barrier or oxycodone. Inactivation of DMS (p < 0.001) but not mOFC decreased oxycodone seeking before or after electric barrier-induced abstinence. Functional MRI data revealed that DMS inactivation decreased cerebral blood volume levels in DMS and several distant cortical and subcortical regions (corrected p < 0.05). Furthermore, functional connectivity of DMS with several frontal, sensorimotor, and auditory regions significantly increased after DMS inactivation (corrected p < 0.05). Finally, an exploratory analysis of an existing functional MRI dataset showed that DMS inactivation restored voluntary abstinence-induced longitudinal changes in DMS functional connectivity with these brain regions (p < 0.05). Results indicate a role of DMS and related brain circuits in oxycodone seeking after voluntary abstinence, suggesting potential targets for intervention.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292165","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":"Dopamine transmission at D1 and D2 receptors in the nucleus accumbens contributes to the expression of incubation of cocaine craving.","authors":"Sophia J Weber, Alex B Kawa, Madelyn M Beutler, Hayley M Kuhn, Alana L Moutier, Jonathan G Westlake, Lara M Koyshman, Cloe D Moreno, Amanda M Wunsch, Marina E Wolf","doi":"10.1038/s41386-024-01992-2","DOIUrl":"10.1038/s41386-024-01992-2","url":null,"abstract":"<p><p>Relapse represents a consistent clinical problem for individuals with substance use disorder. In the incubation of craving model of persistent craving and relapse, cue-induced drug seeking progressively intensifies or \"incubates\" during the first weeks of abstinence from drug self-administration and then remains high for months. Previously, we and others have demonstrated that expression of incubated cocaine craving requires strengthening of excitatory synaptic transmission in the nucleus accumbens core (NAcc). However, despite the importance of dopaminergic signaling in the NAcc for motivated behavior, little is known about the role that dopamine (DA) plays in the incubation of cocaine craving. Here we used fiber photometry to measure DA transients in the NAcc of male and female rats during cue-induced seeking tests conducted in early abstinence from cocaine self-administration, prior to incubation, and late abstinence, after incubation of craving has plateaued. We observed DA transients time-locked to cue-induced responding but their magnitude did not differ significantly when measured during early versus late abstinence seeking tests. Next, we tested for a functional role of these DA transients by injecting DA receptor antagonists into the NAcc just before the cue-induced seeking test. Blockade of either D1 or D2 DA receptors reduced cue-induced cocaine seeking after but not before incubation. We found no main effect of sex or significant interaction of sex with other factors in our experiments. These results suggest that DA contributes to incubated cocaine seeking but the emergence of this role reflects changes in postsynaptic responsiveness to DA rather than presynaptic alterations.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292163","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":"The anxiogenic drug yohimbine is a reinforcer in male and female rats","authors":"Briana Renda, Francesco Leri","doi":"10.1038/s41386-024-01985-1","DOIUrl":"https://doi.org/10.1038/s41386-024-01985-1","url":null,"abstract":"<p>The indole alkaloid yohimbine is an anxiogenic drug that activates stress-responsive systems in the brain. However, because yohimbine also elicits approach behaviors, this study employed male and female Sprague-Dawley rats to explore its potential reinforcing effects. Thus, it was first determined if intravenous (IV) infusions of yohimbine (0.25 mg/kg/infusion) could maintain lever pressing, whether intake could be modulated by dose/infusion, and if lever pressing would persist in the absence of yohimbine or yohimbine-paired cues. Next, to assess yohimbine’s effect on memory consolidation, 0.3, 1.25 or 3 mg/kg yohimbine was administered post-training using an object recognition memory task. Finally, place conditioning assessed whether doses of yohimbine that elevate blood serum corticosterone levels (1.25 or 3 mg/kg) could elicit a conditioned place preference. It was found that both sexes acquired yohimbine IV self-administration, that intake was modulated by dose/infusion, and that lever pressing persisted during extinction and in the absence of the yohimbine-paired cue. As well, post-training injections of 1.25 mg/kg yohimbine enhanced consolidation of object memory, and 1.25 and 3 mg/kg elevated corticosterone levels and elicited a place preference in both sexes. Finally, in behavioral tests of psychomotor functions, acute yohimbine increased lever pressing for a visual cue and elevated locomotor activity. These findings reveal a profile of yohimbine’s behavioral effects that is consistent with that of psychostimulant reinforcing drugs.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"20 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266349","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: Burton M. Angrist, MD","authors":"Erica Duncan,&nbsp;John Rotrosen,&nbsp;Adam Wolkin","doi":"10.1038/s41386-024-01986-0","DOIUrl":"10.1038/s41386-024-01986-0","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"49 12","pages":"1947-1948"},"PeriodicalIF":6.6,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-024-01986-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266351","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":"Reframing addiction: It’s not the destination, but the journey","authors":"Emma Childs","doi":"10.1038/s41386-024-01989-x","DOIUrl":"10.1038/s41386-024-01989-x","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"49 12","pages":"1807-1808"},"PeriodicalIF":6.6,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266350","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 imaging in rat brain shows opposite effects of acute and chronic alcohol exposure on phosphodiesterase-4B, an indirect biomarker of cAMP activity","authors":"Shiyu Tang, Sung Won Kim, Amanda Olsen-Dufour, Torben Pearson, Michael Freaney, Erick Singley, Madeline Jenkins, Nathaniel J. Burkard, Aaron Wozniak, Paul Parcon, Shawn Wu, Cheryl L. Morse, Susovan Jana, Jeih-San Liow, Sami S. Zoghbi, Janaina C. M. Vendruscolo, Leandro F. Vendruscolo, Victor W. Pike, George F. Koob, Nora D. Volkow, Robert B. Innis","doi":"10.1038/s41386-024-01988-y","DOIUrl":"https://doi.org/10.1038/s41386-024-01988-y","url":null,"abstract":"<p>The cyclic adenosine monophosphate (cAMP) cascade is thought to play an important role in regulating alcohol-dependent behaviors, with potentially opposite effects following acute versus chronic administration. Phosphodiesterase 4 (PDE4) is the primary brain enzyme that metabolizes cAMP, thereby terminating its signal. Radioligand binding to PDE4 serves as an indirect biomarker of cAMP activity, as cAMP-protein kinase A (PKA)-mediated phosphorylation of PDE4 increases its affinity for radioligand binding ~10-fold. Of the four PDE4 subtypes, PDE4B polymorphisms are known to be strongly associated with alcohol and substance use disorders. This study imaged rats with the PDE4B-preferring positron emission tomography (PET) radioligand [¹⁸F]PF-06445974 following acute and chronic ethanol administration, aiming to explore the potential of PDE4B PET imaging for future human studies. Compared to the control group treated with saline, acute alcohol administration (i.p. ethanol 0.5 g/kg) significantly increased whole brain uptake of [¹⁸F]PF-06445974 as early as 30 minutes post-exposure. This effect persisted at 2 hours, peaked at 4 hours, and diminished at 6 hours and 24 hours post-exposure. In contrast, in a rat model of alcohol dependence, [¹⁸F]PF-06445974 brain uptake was significantly reduced at 5 hours post-exposure and was normalized by 3 days. This reduction may reflect long-term adaptation to repeated alcohol-induced activation of cAMP signaling with chronic exposure. Taken together, the results suggest that PET imaging of PDE4B in individuals with alcohol use disorder (AUD) should be considered in conjunction with ongoing trials of PDE4 inhibitors to treat alcohol withdrawal and reduce alcohol consumption.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"49 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266365","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":"A covert cortical ensemble for learned fear suppression","authors":"Rebecca M. Shansky,&nbsp;Eliza M. Greiner","doi":"10.1038/s41386-024-01991-3","DOIUrl":"10.1038/s41386-024-01991-3","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"49 13","pages":"1949-1950"},"PeriodicalIF":6.6,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-024-01991-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292160","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":"The might of light for revealing neuropsychiatric mechanisms","authors":"","doi":"10.1038/s41386-024-01974-4","DOIUrl":"https://doi.org/10.1038/s41386-024-01974-4","url":null,"abstract":"<p>Human in vivo optical neuroimaging has strong potential to advance neuropsychiatric disease elucidation and treatment. Akin to functional magnetic resonance imaging (fMRI) for a proxy for brain hemodynamics and activity, functional near-infrared spectroscopy (fNIRS) systems apply two near-infrared wavelengths of light and read out reflections from the head to quantify real-time changes in hemoglobin oxygenation. Moreover, fNIRS measures are non-invasive, achieved using wearable devices, and have less movement sensitivity, facilitating feasibility and patient acceptability, and permitting measures in movement-prone populations, including children or individuals with movement disorders. Portable fNIRS devices permit study in ecologically salient environments, elucidating responses of brain systems subserving social processes in “real-world” settings. For example, fNIRS recently showed sensitivity in detecting differences in regional brain responses to in-person, compared to videoconferenced, face processing [1]. As social dysfunction is central to suffering and disability of psychiatric conditions, study in real-world settings may provide critical new information about disorder mechanisms that prior were elusive.</p><p>FNIRS’ feasibility also makes it amenable to repeated measurements to follow treatment response or disease progression. Temporal patterns of brain activity and related behaviors are increasingly thought to hold essential information about the pathophysiology of neuropsychiatric conditions [2] and can provide early indicators of worsening to prevent progression and improve prognosis.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"45 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142195224","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}