Molecular Psychiatry最新文献

{"title":"Targeting FSHR is a highly promising strategy for improving cognitive impairment in postmenopausal women.","authors":"Da Peng Wang, Zhe Bao Wu","doi":"10.1038/s41380-025-03048-3","DOIUrl":"10.1038/s41380-025-03048-3","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":"3833-3834"},"PeriodicalIF":9.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12240834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120352","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":"Letter to the editor: Comments on 'Striking long-term beneficial effects of single-dose psilocybin and psychedelic mushroom extract in the SAPAP3 rodent model of OCD-like excessive self-grooming' by Brownstien et al. (2024).","authors":"James J Gattuso, Carey Wilson, Anthony J Hannan, Thibault Renoir","doi":"10.1038/s41380-025-03005-0","DOIUrl":"10.1038/s41380-025-03005-0","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":"3829-3832"},"PeriodicalIF":9.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12240841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795707","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":"Unfolding neural diversity: how dynamic three-dimensional genome architecture regulates brain function and disease.","authors":"Brandon L Logeman, Steven F Grieco, Todd C Holmes, Xiangmin Xu","doi":"10.1038/s41380-025-03056-3","DOIUrl":"10.1038/s41380-025-03056-3","url":null,"abstract":"<p><p>The advent of single cell multi-omic technologies has ushered in a revolution in how we study the impact of three-dimensional genome organization on brain cellular composition and function. Transcriptomic and epigenomic studies reveal enormous cellular diversity that is present in mammalian nervous systems, raising the question, \"how does this diversity arise and for what is its use?\" Advances in the field of three-dimensional nuclear architecture have illuminated our understanding of how genome folding gives rise to dynamic gene expression programs important in healthy brain function and in disease. In this review we highlight recent work defining how neuronal identity, maturation, and plasticity are shaped by genome architecture. We discuss how newly identified genetic variations influence genome architecture and contribute to the evolution of species-unique neuronal and behavioral functional traits. We include examples for both humans and model organisms in which maladaptive genomic architecture is a causal agent in disease. Finally, we make conclusions and address future perspectives of dynamic three-dimensional genome (4D nucelome) research.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":"3781-3791"},"PeriodicalIF":9.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131894","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 processing of self-produced sensations in psychosis at cortical and spinal levels","authors":"Paula C. Salamone, Adam Enmalm, Reinoud Kaldewaij, Marie Åman, Charlotte Medley, Michal Pietrzak, Håkan Olausson, Andrea Johansson Capusan, Rebecca Boehme","doi":"10.1038/s41380-025-03130-w","DOIUrl":"https://doi.org/10.1038/s41380-025-03130-w","url":null,"abstract":"<p>Psychosis is often characterized by disturbances in the sense of self, with patients frequently misattributing self-produced sensations to external sources. While somatic hallucinations and misperceptions are common, the underlying disruptions in basic bodily self-processing remain unclear. We aimed to investigate processing of self-evoked sensations, including touch and interoception, in psychosis using a multimodal, multi-method approach. This case-control-study included a total of 70 participants (35 patients diagnosed with psychotic disorders, 35 age- and sex-matched controls). Participants performed self-/other-touch-tasks and interoceptive assessments during functional MRI, evoked potentials measurements, and/or behavioral and psychophysical tests. Primary outcomes included neural and behavioral responses to self- and externally-generated sensations (touch and heartbeat). Brain activation, spinal evoked responses, heartbeat perception and processing (evoked responses), and behavioral measures were analyzed, with preregistered hypotheses. Patients demonstrated heightened right superior temporal gyrus activation during self-touch. Tactile self-other distinction impairments were evident at the spinal cord level. Behaviorally, patients showed reduced differentiation in tactile thresholds for self- vs. other-touch. Interoceptive impairments included diminished cortical responses to heartbeat signals, lower interoceptive accuracy (heartbeat detection), and reduced self-reported interoceptive sensitivity. These findings reveal pervasive sensory and self-related disturbances in psychotic disorders. Impairments in differentiating self- and externally-evoked responses, detectable as early as the spinal cord level, may contribute to higher-order symptoms of psychosis.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"1 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701539","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":"5-HT2C receptors in the nucleus accumbens constrain the rewarding effects of MDMA","authors":"Matthew B. Pomrenze, Sam Vaillancourt, Juliana S. Salgado, Kendall B. Raymond, Pierre Llorach, Hiroaki Sacai, Daniel Ryskamp Rijsketic, Tuuli M. Hietamies, Gavin C. Touponse, Daniel F. Cardozo Pinto, Zahra Rastegar, Austen B. Casey, Neir Eshel, Robert C. Malenka, Boris D. Heifets","doi":"10.1038/s41380-025-03128-4","DOIUrl":"https://doi.org/10.1038/s41380-025-03128-4","url":null,"abstract":"<p>MDMA is a promising adjunct to psychotherapy and has well-known abuse liability, although less than other amphetamine analogs. While the reinforcing dopamine (DA)-releasing properties of MDMA are on par with methamphetamine (METH), MDMA is a far more potent serotonin (5-HT) releaser, via the 5-HT transporter (SERT). MDMA-mediated 5-HT release in a major reward center, the nucleus accumbens (NAc), drives prosocial behaviors via 5-HT_1BR activation. We hypothesized that this prosocial mechanism contributes to the reduced reinforcing properties of MDMA compared to METH and used a platform of assays to predict the balance of prosocial and abuse-linked effects of (<i>R</i>)-MDMA, a novel entactogen in clinical development. NAc DA release, measured by GRAB-DA photometry in vivo, increased in proportion to MDMA (7.5 and 15 mg/kg, i.p.) and METH (2 mg/kg i.p.)-conditioned place preference (CPP). Using conditional knockouts (cKOs) for DAT and SERT, microdialysis, and photometry, we found that MDMA-released 5-HT limited MDMA-released DA through actions in the NAc, rather than at ventral tegmental area DAergic cell bodies. SERT cKO reduced the MDMA dose required for CPP three-fold. This enhanced MDMA-CPP and increased DA release were replicated by intra-NAc infusion of either a 5-HT reuptake inhibitor (escitalopram) to prevent MDMA interaction with SERT, or a 5-HT_2CR antagonist (SB242084), but not by the 5-HT_1BR antagonist NAS-181. These data support separate mechanisms for the low abuse potential versus prosocial effect of MDMA. Using this platform of assays, (<i>R</i>)-MDMA is predicted to have prosocial effects and low abuse potential.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"20 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701540","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":"Systemic medications and dementia risk: a systematic umbrella review","authors":"Clara Belessiotis-Richards, Joseph Hayes, Ying Feng Yap, Shivangi Talwar, Michelle Eskinazi, Wenqianglong Li, Harry Ward, Pilar A. Letrondo, Madeleine Morelli-Batters, Andrea Bruun, Rongyu Lin, Talen Wright, Naaheed Mukadam","doi":"10.1038/s41380-025-03129-3","DOIUrl":"https://doi.org/10.1038/s41380-025-03129-3","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Previous meta-analyses have found that systemic medications may modulate dementia risk. We aimed to provide an overview of this evidence to guide clinical practice and future research.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We conducted an umbrella review of meta-analyses (PROSPERO CRD42021226307), searching databases from inception to 15th April 2024. Only peer-reviewed meta-analyses examining dementia risk and systemic medications in humans were included. Two authors independently screened studies for inclusion, extracted study data and assessed quality of meta-analyses using the AMSTAR-2 tool. Three authors independently rated the certainty of evidence for each drug using the GRADE framework.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>68 meta-analyses were included, across 11 drug categories. Across meta-analyses, available data were primarily observational. Confounding by indication and potential reverse causality were important limitations. Randomised-controlled data were rare but supported an association between treatment of hypertension and reduced dementia incidence. Overall, we found moderate certainty evidence of reduced risk of dementia associated with anti-hypertensives, statins, sodium-glucose transport protein 2 (SGLT2) inhibitors, and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and moderate certainty of increased risk with anticholinergics.</p><h3 data-test=\"abstract-sub-heading\">Discussion</h3><p>Currently, there is insufficient evidence to advise repurposing any systemic drugs with the primary aim of reducing dementia risk. On the basis of our findings, we recommend proactive treatment of hypertension to reduce risk of all-cause dementia. Our findings did not find a difference between antihypertensive drug classes, but dementia risk was associated with blood pressure reading. In addition, we advise avoidance of anticholinergic drugs in cognitive impairment, with assessment of anticholinergic burden and consideration of alternatives during routine clinical contacts.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"23 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693992","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":"Upregulation of adenosine A2A receptor in astrocytes is sufficient to trigger hippocampal multicellular dysfunctions and memory deficits","authors":"Agathe Launay, Kevin Carvalho, Athénais Genin, Thibaut Gauvrit, Paola Nobili, Victoria Gomez-Murcia, Emma Augustin, Anaëlle Burgard, Johanne Gambi, Déborah Fourmy, Bryan Thiroux, Didier Vieau, Alexis-Pierre Bemelmans, Stephanie Le Gras, Luc Buée, Miranda E. Orr, Etienne Audinat, Anne-Laurence Boutillier, Gilles Bonvento, Karine Cambon, Emilie Faivre, David Blum","doi":"10.1038/s41380-025-03115-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03115-9","url":null,"abstract":"<p>Adenosine is an ubiquitous neuromodulator that ensures cerebral homeostasis. It exerts numerous functions through the activation of G-protein-coupled adenosine receptors (ARs), in particular A₁ (A₁R) and A_2A (A_2AR) receptors. Interestingly, A_2AR levels are upregulated in cortical and hippocampal regions in several pathological conditions such as Alzheimer’s disease, tauopathies or epilepsia. Such abnormal upregulations have been particularly reported in astrocytes, glial cells that play a key role in regulating synaptic plasticity. However, the overall impact and the underlying mechanisms associated with increased A_2AR in astrocytes remain poorly understood. In the present study, we induced the upregulation of A_2AR in hippocampal astrocytes using dedicated AAVs and comprehensively evaluated the functional consequences in 4 months-old C57Bl6/J mice. Our results show that A_2AR upregulation primarily promotes alterations of astrocyte reactivity, morphology and transcriptome, with a link to aging-like phenotype as well as secondary impairments of neuronal excitability and microglial phenotype. These changes driven by a restricted A_2AR upregulation in hippocampal astrocytes were sufficient to induce impairments of short-term spatial memory and spatial learning. This study highlights the impact of astrocytic A_2AR upregulation, as seen in various neurological conditions, on the development of a detrimental multicellular response associated with memory alterations and provides an additional proof-of-concept for the value of targeting this receptor in different neurodegenerative conditions.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"14 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684744","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":"Early postnatal dysfunction of ACC PV interneurons in Shank3B−/− mice","authors":"Yi-Chun Shih, Lars Nelson, Michael Janeček, Michael Matarazzo, Andrew D’Agostino, Rui T. Peixoto","doi":"10.1038/s41380-025-03114-w","DOIUrl":"https://doi.org/10.1038/s41380-025-03114-w","url":null,"abstract":"<p>Anterior cingulate cortex <b>(ACC)</b> dysfunction is implicated in the cognitive and social deficits associated with autism spectrum disorder <b>(ASD)</b>, yet the developmental trajectory of ACC circuit maturation in ASD remains poorly understood. Here, we examined the postnatal development of glutamatergic synaptic connectivity and intrinsic excitability in layer 2/3 pyramidal neurons <b>(PYRs)</b> and Parvalbumin-expressing interneurons <b>(PVINs)</b> in the ACC of mice harboring a deletion in SHANK3 <b>(Shank3B</b>^{<b>−/−</b>}), a well-established genetic cause of autism. We found that ACC PVINs in Shank3B^{<b>−/−</b>} mice exhibit reduced excitability and in vivo hypoactivity as early as postnatal day 15 <b>(P15)</b> despite receiving normal levels of glutamatergic input. Early PVIN hypoexcitability is associated with decreased feedforward inhibition from the mediodorsal thalamus and reduced hyperpolarization-activated <b>(I</b>_<b>h</b><b>)</b> currents mediated by hyperpolarization-activated cyclic nucleotide gated <b>(HCN)</b> channels. In contrast, PYRs display normal excitability and synaptic input at this stage but already exhibit reduced I_h currents, indicating an early emergence of HCN channel dysfunction in both PYRs and PVINs. By adulthood, both neuron populations undergo marked phenotypic changes, characterized by reduced glutamatergic synaptic input and divergent alterations in excitability. Together, these findings reveal a distinct sequence of early PVIN dysfunction followed by cell-type specific circuit reorganization within ACC layer 2/3 of Shank3B^{<b>−/−</b>} mice and identify HCN channelopathy and impaired PVIN-mediated inhibition as early pathogenic features of SHANK3-related neurodevelopmental disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"95 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664511","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":"Effects of antipsychotics on human cognitive function: causal evidence from healthy volunteers following sustained D2/D3 antagonism, D2/D3 partial agonism and placebo","authors":"Martin Osugo, Uzma Zahid, Pierluigi Selvaggi, Alexandria Chilimidos, Valeria Finelli, George E. Chapman, Thomas Whitehurst, Ellis Chika Onwordi, Robin M. Murray, Matthew B. Wall, Tiago Reis Marques, Mitul A. Mehta, Oliver D. Howes","doi":"10.1038/s41380-025-03116-8","DOIUrl":"https://doi.org/10.1038/s41380-025-03116-8","url":null,"abstract":"<p>Dopamine D2/D3 receptor modulation with antipsychotics is thought to affect cognitive function, but causal evidence in humans is scant, and largely limited to single administrations. Clarifying this is of importance given the widespread use of antipsychotics, and to understand the role of D2/D3 signalling in human cognition. We therefore conducted a double-blind, placebo-controlled crossover study following sustained administration of either a dopamine D2/D3 receptor antagonist (amisulpride at 400 mg daily) or a D2/D3 partial agonist (aripiprazole at 10 mg daily) to two separate samples of healthy humans (total n = 50) for 7 days per condition. We assessed cognitive function using a computerised visuospatial working memory (VS-WM) task, and sustained attention and response inhibition using the Sustained Attention to Response Task (SART). We found that both amisulpride and aripiprazole caused impairments in VS-WM function compared to placebo on the Balanced Integration Score (amisulpride: p = 0.0079; aripiprazole: p = 0.015). Both antipsychotics impaired VS-WM performance in terms of response latency (amisulpride: p = 5.5 × 10⁻⁷; aripiprazole: p = 0.022), but did not affect response accuracy. Response latency deficits were not correlated with motor impairments induced by either drug, and we also found no effect of either drug on the SART measures, or on subjective alertness, suggesting that D2/D3 antagonism or partial agonism did not cause a generalised cognitive or motor deficit but specifically impaired cognition during VS-WM. This study provides the first causal evidence in healthy humans that working memory function is impaired following either sustained antagonism or partial agonism of D2/D3 receptors by antipsychotic drugs.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"544 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664486","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":"Metabolic plasticity: an evolutionary perspective on metabolic and circadian dysregulation in bipolar disorder","authors":"Iain H. Campbell, Mark A. Frye, Harry Campbell","doi":"10.1038/s41380-025-03123-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03123-9","url":null,"abstract":"<p>The emerging field of metabolic psychiatry has brought mechanisms of metabolic dysfunction into focus in bipolar disorder research. In this manuscript, we propose that the metabolic features of bipolar disorder provide a new vector from which to understand the role of circadian dysfunction in this condition. A notable feature of bipolar disorder is the photoperiod driven, seasonal occurrence of symptoms and episodes mediated by circadian systems, with mania occurring more frequently in the spring and autumn at times of rapid rate of change in photoperiod, and depression being more prevalent in the winter when photoperiod is attenuated. In this manuscript we note that seasonal adaptations in metabolism are highly conserved evolutionary traits across diverse taxa. Several of the underlying mechanisms mediating seasonal changes in metabolism are conserved in human biology and are implicated in bipolar disorder pathophysiology. Such mechanisms encompass targets of lithium involved in insulin signaling (the phosphatidylinositol cycle, GSK3β and Akt), clock genes (CLOCK and BMAL1), targets of psychiatric and metabolic medications (mTOR and AMPK) and hormonal signaling (melatonin and cortisol). We propose that bipolar disorder may represent a dysregulation of conserved mechanisms of chronometabolic regulation and provide a discussion of the evolutionary context of such mechanisms. Genetic predisposition coupled to novel environmental inputs to human biology including artificial light at night and sustained refined sugar and carbohydrate intake may contribute to states of metabolic and circadian dysregulation in bipolar disorder underlying episodes of mania and depression.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"109 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664488","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}