Journal of Neuroscience最新文献_第9页

Coronin1A Regulates the Trafficking of Alpha Synuclein in Microglia. Coronin1A调节小胶质细胞中α突触核蛋白的运输。

IF 4.4 2区医学

Journal of Neuroscience Pub Date : 2025-03-12 DOI: 10.1523/JNEUROSCI.1337-24.2025

Karl E Biggs, Emma N Fikse, Faith L Anderson, Arminja N Kettenbach, Matthew C Havrda

{"title":"Coronin1A Regulates the Trafficking of Alpha Synuclein in Microglia.","authors":"Karl E Biggs, Emma N Fikse, Faith L Anderson, Arminja N Kettenbach, Matthew C Havrda","doi":"10.1523/JNEUROSCI.1337-24.2025","DOIUrl":"10.1523/JNEUROSCI.1337-24.2025","url":null,"abstract":"Microglia respond to cytotoxic protein aggregates associated with the progression of neurodegenerative disease. Pathological protein aggregates activate the microglial NLRP3 inflammasome resulting in proinflammatory signaling, secretion, and potentially pyroptotic cell death. We characterized mixed sex primary mouse microglia exposed to microbial stressors and alpha synuclein preformed fibrils (αsyn PFFs) to identify cellular mechanisms related to Parkinson's disease. Microglia package and release the endosome fate regulator Coronin1A (Coro1A) in EVs in an Nlrp3-dependent manner in widely used experimental activation conditions. We were surprised to find that Coro1A packaging and release was not Nlrp3-dependent in αsyn PFF exposure conditions. Coro1A-/- microglia exposed to αsyn PFFs trafficked more αsyn to the lysosomal compartment increasing lysosomal membrane permeabilization. This corresponds to a decrease in αsyn released in EVs suggesting that Coro1A functions to shunt pathological proteins to a secretory pathway to attenuate lysosomal stress. αsyn PFF-driven lysosomal stress resulting from Coro1a loss was associated with enhanced cytotoxicity. Intrinsic apoptosis signaling was unaffected, but we observed elevated cytosolic cathepsin B and the presence of a cathepsin-associated 55 kD PARP cleavage product. Postmortem analysis of the PD mesencephalon supported a role for Coro1A in microglia, revealing elevated levels of Coro1A protein in human PD brains compared with those of healthy donors. Findings are relevant to the distribution of pathological αsyn and indicate that Coro1a protects microglia from lysosomal overload, inflammasome activation, and pyroptotic demise.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Local Regulation of Striatal Dopamine Release Shifts from Predominantly Cholinergic in Mice to GABAergic in Macaques. 纹状体多巴胺释放的局部调控从小鼠的胆碱能为主转变为猕猴的氨基丁酸能为主。

IF 4.4 2区医学

Journal of Neuroscience Pub Date : 2025-03-12 DOI: 10.1523/JNEUROSCI.1692-24.2025

Jung Hoon Shin, Hannah C Goldbach, Dennis A Burke, Michael E Authement, Evan S Swanson, Miriam E Bocarsly, Sean Hernandez, Han B Kwon, Sydney E Cerveny, Jacqueline B Mehr, Anya S Plotnikova, Arya Mohanty, Alexander C Cummins, Kenneth A Pelkey, Chris J McBain, Zayd M Khaliq, Mark A G Eldridge, Bruno B Averbeck, Veronica A Alvarez

{"title":"Local Regulation of Striatal Dopamine Release Shifts from Predominantly Cholinergic in Mice to GABAergic in Macaques.","authors":"Jung Hoon Shin, Hannah C Goldbach, Dennis A Burke, Michael E Authement, Evan S Swanson, Miriam E Bocarsly, Sean Hernandez, Han B Kwon, Sydney E Cerveny, Jacqueline B Mehr, Anya S Plotnikova, Arya Mohanty, Alexander C Cummins, Kenneth A Pelkey, Chris J McBain, Zayd M Khaliq, Mark A G Eldridge, Bruno B Averbeck, Veronica A Alvarez","doi":"10.1523/JNEUROSCI.1692-24.2025","DOIUrl":"10.1523/JNEUROSCI.1692-24.2025","url":null,"abstract":"Dopamine critically regulates neuronal excitability and promotes synaptic plasticity in the striatum, thereby shaping network connectivity and influencing behavior. These functions establish dopamine as a key neuromodulator, whose release properties have been well studied in rodents but remain understudied in nonhuman primates. This study aims to close this gap by investigating the properties of dopamine release in macaque striatum and comparing/contrasting them to better-characterized mouse striatum, using ex vivo brain slices from male and female animals. Using combined electrochemical techniques and photometry with fluorescent dopamine sensors, we found that evoked dopamine signals have smaller amplitudes in macaques compared with those in mice. Interestingly, cholinergic-dependent dopamine release, which accounts for two-thirds of evoked dopamine release in mouse slices, is significantly reduced in macaques, providing a potential mechanistic underpinning for the observed species difference. In macaques, only nicotinic receptors with alpha-6 subunits contribute to evoked dopamine release, whereas in mice, both alpha-6 and non-alpha6-containing receptors are involved. We also identified robust potentiation of dopamine release in both species when GABAA and GABAB receptors were blocked. This potentiation was stronger in macaques, with an average increase of 50%, compared with 15% in mice. Together, these results suggest that dopamine release in macaque is under stronger GABA-mediated inhibition and that weaker cholinergic-mediated dopamine release may account for the smaller amplitude of evoked dopamine signals in macaque slices.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prioritizing Working Memory Resources Depends on the Prefrontal Cortex.

IF 4.4 2区医学

Journal of Neuroscience Pub Date : 2025-03-12 DOI: 10.1523/JNEUROSCI.1552-24.2025

Grace E Hallenbeck, Nathan Tardiff, Thomas C Sprague, Clayton E Curtis

{"title":"Prioritizing Working Memory Resources Depends on the Prefrontal Cortex.","authors":"Grace E Hallenbeck, Nathan Tardiff, Thomas C Sprague, Clayton E Curtis","doi":"10.1523/JNEUROSCI.1552-24.2025","DOIUrl":"10.1523/JNEUROSCI.1552-24.2025","url":null,"abstract":"How the prefrontal cortex contributes to working memory remains controversial, as theories differ in their emphasis on its role in storing memories versus controlling their content. To adjudicate between these competing ideas, we tested how perturbations to the human (both sexes) lateral prefrontal cortex impact the storage and control aspects of working memory during a task that requires human subjects to allocate resources to memory items based on their behavioral priority. Our computational model made a strong prediction that disruption of this control process would counterintuitively improve memory for low-priority items. Remarkably, transcranial magnetic stimulation of retinotopically-defined superior precentral sulcus, but not intraparietal sulcus, unbalanced the prioritization of resources, improving memory for low-priority items as predicted by the model. Therefore, these results provide direct causal support for models in which the prefrontal cortex controls the allocation of resources that support working memory, rather than simply storing the features of memoranda.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Alpha-Synuclein Inhibits the Secretion of Extracellular Vesicles through Disruptions in YKT6 Lipidation. α -突触核蛋白通过破坏YKT6脂化抑制细胞外囊泡的分泌。

IF 4.4 2区医学

Journal of Neuroscience Pub Date : 2025-03-12 DOI: 10.1523/JNEUROSCI.2350-23.2024

Taiji Tsunemi, Yuta Ishiguro, Asako Yoroisaka, Dou Feng, Tomoyo Shimada, Shunichi Niiyama, Yukiko Sasazawa, Keiichi Ishikawa, Wado Akamatsu, Nobutaka Hattori

{"title":"Alpha-Synuclein Inhibits the Secretion of Extracellular Vesicles through Disruptions in YKT6 Lipidation.","authors":"Taiji Tsunemi, Yuta Ishiguro, Asako Yoroisaka, Dou Feng, Tomoyo Shimada, Shunichi Niiyama, Yukiko Sasazawa, Keiichi Ishikawa, Wado Akamatsu, Nobutaka Hattori","doi":"10.1523/JNEUROSCI.2350-23.2024","DOIUrl":"10.1523/JNEUROSCI.2350-23.2024","url":null,"abstract":"Parkinson's disease is characterized by the presence of alpha-synuclein (α-syn) primarily containing Lewy bodies in neurons. Despite decades of extensive research on α-syn accumulation, its molecular mechanisms have remained largely unexplored. Recent studies by us and others have suggested that extracellular vesicles (EVs), especially exosomes, can mediate the release of α-syn from cells and inhibiting this pathway could result in increased intracellular α-syn levels. In this study, we have discovered that elevated levels of α-syn themselves lead to reduced α-syn -containing EVs in α-syn-inducible H4 cells and induced pluripotent stem cell-derived dopaminergic (DA) neurons from both sexes. Our investigations have revealed that the impairment in EV secretion is not due to their generation but rather a consequence of changes in a soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein, YKT6. Specifically, as α-syn levels increase, membrane-associated YKT6 is reduced. Pharmacological inhibition of farnesylation using FTI has led to decreased EV secretion and subsequent elevated levels of α-syn. In summary, our findings suggest that increased levels of α-syn impair YKT6-mediated EV secretion, establishing a detrimental cycle of intracellular α-syn accumulation in human DA neurons.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Compromising Tyrosine Hydroxylase Function Extends and Blunts the Temporal Profile of Reinforcement by Dopamine Neurons in Drosophila. 损害酪氨酸羟化酶功能扩展和减弱了果蝇多巴胺神经元强化的时间剖面。

IF 4.4 2区医学

Journal of Neuroscience Pub Date : 2025-03-12 DOI: 10.1523/JNEUROSCI.1498-24.2024

Fatima Amin, Christian König, Jiajun Zhang, Liubov S Kalinichenko, Svea Königsmann, Vivian Brunsberg, Thomas D Riemensperger, Christian P Müller, Bertram Gerber

{"title":"Compromising Tyrosine Hydroxylase Function Extends and Blunts the Temporal Profile of Reinforcement by Dopamine Neurons in Drosophila.","authors":"Fatima Amin, Christian König, Jiajun Zhang, Liubov S Kalinichenko, Svea Königsmann, Vivian Brunsberg, Thomas D Riemensperger, Christian P Müller, Bertram Gerber","doi":"10.1523/JNEUROSCI.1498-24.2024","DOIUrl":"10.1523/JNEUROSCI.1498-24.2024","url":null,"abstract":"For a proper representation of the causal structure of the world, it is adaptive to consider both evidence for and evidence against causality. To take punishment as an example, the causality of a stimulus is unlikely if there is a temporal gap before punishment is received, but causality is credible if the stimulus immediately precedes punishment. In contrast, causality can be ruled out if the punishment occurred first. At the behavioral level, this is reflected in the associative principle of timing-dependent valence reversal: aversive memories are formed when a stimulus occurs before the punishment, whereas memories of appetitive valence are formed when a stimulus is presented upon the relieving termination of punishment. We map the temporal profile of memories induced by optogenetic activation of the PPL1-01 neuron in the fly Drosophila melanogaster (of either sex) and find that compromising tyrosine hydroxylase function, either acutely by pharmacological methods or by cell-specific RNAi, extends and blunts this profile. Specifically, it (1) enhances learning with a time gap between the stimulus and PPL1-01 punishment (better trace conditioning), (2) impairs learning when the stimulus immediately precedes PPL1-01 punishment (worse delay conditioning), and (3) prevents learning about a stimulus presented after PPL1-01 punishment has ceased (worse relief conditioning). Under conditions of low dopamine, we furthermore observe a role for serotonin that is pronounced in trace conditioning, weaker in delay conditioning, and absent in relief conditioning. We discuss the psychiatric implications if related alterations in the temporal profile of reinforcement were to occur in humans.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Local Differences in Network Organization in the Auditory and Parietal Cortex, Revealed with Single Neuron Activation.

IF 4.4 2区医学

Journal of Neuroscience Pub Date : 2025-03-12 DOI: 10.1523/JNEUROSCI.1385-24.2025

Christine F Khoury, Michael Ferrone, Caroline A Runyan

{"title":"Local Differences in Network Organization in the Auditory and Parietal Cortex, Revealed with Single Neuron Activation.","authors":"Christine F Khoury, Michael Ferrone, Caroline A Runyan","doi":"10.1523/JNEUROSCI.1385-24.2025","DOIUrl":"10.1523/JNEUROSCI.1385-24.2025","url":null,"abstract":"The structure of local circuits is highly conserved across the cortex, yet the spatial and temporal properties of population activity differ fundamentally in sensory-level and association-level areas. In the sensory cortex, population activity has a shorter timescale and decays sharply over distance, supporting a population code for the fine-scale features of sensory stimuli. In the association cortex, population activity has a longer timescale and spreads over wider distances, a code that is suited to holding information in memory and driving behavior. We tested whether these differences in activity dynamics could be explained by differences in network structure. We targeted photostimulations to single excitatory neurons of layer 2/3, while monitoring surrounding population activity using two-photon calcium imaging. Experiments were performed in the auditory (AC) and posterior parietal cortex (PPC) within the same mice of both sexes, which also expressed a red fluorophore in somatostatin-expressing interneurons (SOM). In both cortical regions, photostimulations resulted in a spatially restricted zone of positive influence on neurons closely neighboring the targeted neuron and a more spatially diffuse zone of negative influence affecting more distant neurons (akin to a network-level \"suppressive surround\"). However, the relative spatial extents of positive and negative influence were different in AC and PPC. In PPC, the central zone of positive influence was wider, but the negative suppressive surround was more narrow than in AC, which could account for the larger-scale network dynamics in PPC. The more narrow central positive influence zone and wider suppressive surround in AC could serve to sharpen sensory representations.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Astrocyte Modulation of Synaptic Plasticity Mediated by Activity-Dependent Sonic Hedgehog Signaling.

IF 4.4 2区医学

Journal of Neuroscience Pub Date : 2025-03-12 DOI: 10.1523/JNEUROSCI.1336-24.2025

Anh Duc Le, Marissa Fu, Ashley Carper, Elizabeth Zegarowicz, Riya Kumar, Gloria Zacharias, A Denise R Garcia

{"title":"Astrocyte Modulation of Synaptic Plasticity Mediated by Activity-Dependent Sonic Hedgehog Signaling.","authors":"Anh Duc Le, Marissa Fu, Ashley Carper, Elizabeth Zegarowicz, Riya Kumar, Gloria Zacharias, A Denise R Garcia","doi":"10.1523/JNEUROSCI.1336-24.2025","DOIUrl":"10.1523/JNEUROSCI.1336-24.2025","url":null,"abstract":"The influence of neural activity on astrocytes and their reciprocal interactions with neurons has emerged as an important modulator of synapse function. Astrocytes exhibit activity-dependent changes in gene expression, yet the molecular mechanisms by which neural activity is coupled to gene expression are not well understood. The molecular signaling pathway, Sonic hedgehog (Shh), mediates neuron-astrocyte communication and regulates the organization of cortical synapses. Here, we demonstrate that neural activity stimulates Shh signaling in cortical astrocytes and upregulates expression of Hevin and SPARC, astrocyte-derived molecules that modify synapses. Whisker stimulation in both male and female mice promotes activity-dependent Shh signaling selectively in the somatosensory, but not in the visual cortex, whereas sensory deprivation reduces Shh activity, demonstrating bidirectional regulation of the pathway by sensory experience. Selective loss of Shh signaling in astrocytes reduces expression of Hevin and SPARC and occludes activity-dependent synaptic plasticity. Taken together, these data identify Shh signaling as an activity-dependent, molecular signaling pathway that regulates astrocyte gene expression and promotes astrocyte modulation of synaptic plasticity.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Retraction: Larson et al., "Soluble α-Synuclein is a Novel Modulator of Alzheimer's Disease Pathophysiology". 撤回：Larson 等人，"可溶性α-突触核蛋白是阿尔茨海默病病理生理学的新型调节剂"。

IF 4.4 2区医学

Journal of Neuroscience Pub Date : 2025-03-12 DOI: 10.1523/JNEUROSCI.0300-25.2025

引用次数: 0

Early Life Stress Impairs VTA Coordination of BLA Network and Behavioral States.

IF 4.4 2区医学

Journal of Neuroscience Pub Date : 2025-03-12 DOI: 10.1523/JNEUROSCI.0088-24.2025

Bradly T Stone, Pantelis Antonoudiou, Eric Teboul, Garrett Scarpa, Grant Weiss, Jamie L Maguire

{"title":"Early Life Stress Impairs VTA Coordination of BLA Network and Behavioral States.","authors":"Bradly T Stone, Pantelis Antonoudiou, Eric Teboul, Garrett Scarpa, Grant Weiss, Jamie L Maguire","doi":"10.1523/JNEUROSCI.0088-24.2025","DOIUrl":"10.1523/JNEUROSCI.0088-24.2025","url":null,"abstract":"Motivated behaviors, such as social interactions, are governed by the interplay between mesocorticolimbic structures, such as the ventral tegmental area (VTA), basolateral amygdala (BLA), and medial prefrontal cortex (mPFC). Adverse childhood experiences and early life stress (ELS) can impact these networks and behaviors, which is associated with increased risk for psychiatric illnesses. While it is known that the VTA projects to both the BLA and mPFC, the influence of these inputs on local network activity which govern behavioral states-and whether ELS impacts VTA-mediated network communication-remains unknown. Our study demonstrates that VTA inputs influence BLA oscillations and entrainment of mPFC activity in mice and that ELS weakens the ability of the VTA to coordinate BLA network states, while also impairing dopaminergic signaling between VTA and BLA. Optogenetic stimulation of VTABLA terminals decreased social interaction in ELS mice, which can be recapitulated in control mice by inhibiting VTA→BLA communication. These data suggest that ELS impacts social reward via the VTA→BLA dopamine network.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Shared Pathophysiological Mechanisms and Genetic Factors in Early Menarche and Polycystic Ovary Syndrome

IF 5.3 2区医学

Journal of Neuroscience Pub Date : 2025-03-12 DOI: 10.1523/jneurosci.1681-24.2024

Flavia Rezende Tinano, Iza Franklin Roza Machado, Ana Claudia Latronico, Larissa Garcia Gomes

{"title":"Shared Pathophysiological Mechanisms and Genetic Factors in Early Menarche and Polycystic Ovary Syndrome","authors":"Flavia Rezende Tinano, Iza Franklin Roza Machado, Ana Claudia Latronico, Larissa Garcia Gomes","doi":"10.1523/jneurosci.1681-24.2024","DOIUrl":"https://doi.org/10.1523/jneurosci.1681-24.2024","url":null,"abstract":"Early age at menarche (early AAM) and polycystic ovary syndrome (PCOS) are reproductive and metabolic disorders with overlapping pathophysiological and genetic features. Epidemiological studies suggest a link between these two conditions, both of which are characterized by dysregulation of the neuroendocrine pathways that control pulsatile gonadotropin-releasing hormone secretion, thus affecting gonadotropin release, particularly luteinizing hormone secretion. A common pathophysiology involving positive energy balance and abnormal metabolic status is evident in both disorders. Genetic and epigenetic factors influence the onset of puberty and reproductive outcomes. Genome-wide association studies have identified common genetic variants associated with AAM and PCOS, particularly in genes related to the neuroendocrine axis (e.g., FSHB) and obesity (e.g., FTO). In addition, high-throughput sequencing has revealed rare loss-of-function variants in the DLK1 gene in women with central precocious puberty (CPP), early menarche, and PCOS, who experienced adverse metabolic outcomes in adulthood. This review explores the shared pathophysiological mechanisms between CPP/early AAM and PCOS, examines potential genetic and epigenetic factors that may link these neuroendocrine reproductive conditions, and offers insights into future research and treatment strategies. Understanding these connections may provide new targets for therapeutic interventions and improve outcomes for individuals with these reproductive disorders.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"22 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0