Frontiers in Molecular Neuroscience最新文献

{"title":"Regulation of adult neurogenesis: the crucial role of astrocytic mitochondria.","authors":"Danping Liu, Pei Guo, Yi Wang, Weihong Li","doi":"10.3389/fnmol.2024.1516119","DOIUrl":"10.3389/fnmol.2024.1516119","url":null,"abstract":"<p><p>Neurogenesis has emerged as a promising therapeutic approach for central nervous system disorders. The role of neuronal mitochondria in neurogenesis is well-studied, however, recent evidence underscores the critical role of astrocytic mitochondrial function in regulating neurogenesis and the underlying mechanisms remain incompletely understood. This review highlights the regulatory effects of astrocyte mitochondria on neurogenesis, focusing on metabolic support, calcium homeostasis, and the secretion of neurotrophic factors. The effect of astrocytic mitochondrial dysfunction in the pathophysiology and treatment strategies of Alzheimer's disease and depression is discussed. Greater attention is needed to investigate the mitochondrial autophagy, dynamics, biogenesis, and energy metabolism in neurogenesis. Targeting astrocyte mitochondria presents a potential therapeutic strategy for enhancing neural regeneration.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1516119"},"PeriodicalIF":3.5,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11621070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of midbrain cholinergic neurons impairs decision-making strategies during reversal learning.","authors":"Yuwoong Kim, Nadine K Gut, Michael W Shiflett, Juan Mena-Segovia","doi":"10.3389/fnmol.2024.1481956","DOIUrl":"10.3389/fnmol.2024.1481956","url":null,"abstract":"<p><strong>Introduction: </strong>The pedunculopontine nucleus (PPN) plays a role in coordinating complex behaviors and adapting to changing environmental conditions. The specific role of cholinergic neurons in PPN function is not well understood, but their ascending connectivity with basal ganglia and thalamus suggests involvement in adaptive functions.</p><p><strong>Methods: </strong>We used a chemogenetic approach in ChAT::Cre rats to explore the specific contribution of PPN cholinergic neurons to behavioral flexibility, focusing on the adaptation to shifting reward contingencies in a Reversal Learning Task. Rats were first trained in a non-probabilistic reversal learning task, followed by a probabilistic phase to challenge their adaptive strategies under varying reward conditions.</p><p><strong>Results: </strong>Motor functions were evaluated to confirm that behavioral observations were not confounded by motor deficits. We found that inhibition of PPN cholinergic neurons did not affect performance in the non-probabilistic condition but significantly altered the rats' ability to adapt to the probabilistic condition. Under chemogenetic inhibition, the rats showed a marked deficiency in utilizing previous trial outcomes for decision-making and an increased sensitivity to negative outcomes. Logistic regression and Q-learning models revealed that suppression of PPN cholinergic activity impaired the adaptation of decision-making strategies.</p><p><strong>Discussion: </strong>Our results highlight the role of PPN cholinergic neurons in dynamically updating action-outcome expectations and adapting to new contingencies. The observed impairments in decision-making under PPN cholinergic inhibition align with cognitive deficits associated with cholinergic dysfunction in neurodegenerative disorders. These findings suggest that cholinergic neurons in the PPN are essential for maximizing rewards through the flexible updating of behavioral strategies.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1481956"},"PeriodicalIF":3.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11617536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptide discovery across the spectrum of neuroinflammation; microglia and astrocyte phenotypical targeting, mediation, and mechanistic understanding.","authors":"Benjamin A Benita, Kyle M Koss","doi":"10.3389/fnmol.2024.1443985","DOIUrl":"10.3389/fnmol.2024.1443985","url":null,"abstract":"<p><p>Uncontrolled and chronic inflammatory states in the Central Nervous System (CNS) are the hallmark of neurodegenerative pathology and every injury or stroke-related insult. The key mediators of these neuroinflammatory states are glial cells known as microglia, the resident immune cell at the core of the inflammatory event, and astroglia, which encapsulate inflammatory insults in proteoglycan-rich scar tissue. Since the majority of neuroinflammation is exclusively based on the responses of said glia, their phenotypes have been identified to be on an inflammatory spectrum encompassing developmental, homeostatic, and reparative behaviors as opposed to their ability to affect devastating cell death cascades and scar tissue formation. Recently, research groups have focused on peptide discovery to identify these phenotypes, find novel mechanisms, and mediate or re-engineer their actions. Peptides retain the diverse function of proteins but significantly reduce the activity dependence on delicate 3D structures. Several peptides targeting unique phenotypes of microglia and astroglia have been identified, along with several capable of mediating deleterious behaviors or promoting beneficial outcomes in the context of neuroinflammation. A comprehensive review of the peptides unique to microglia and astroglia will be provided along with their primary discovery methodologies, including top-down approaches using known biomolecules and naïve strategies using peptide and phage libraries.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1443985"},"PeriodicalIF":3.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11616451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomic profile of cerebral tissue after acoustically-mediated blood-brain barrier opening in a healthy rat model: a focus on the contralateral side.","authors":"Antoine Presset, Sylvie Bodard, Antoine Lefèvre, Anaïs Millet, Edward Oujagir, Camille Dupuy, Tarik Iazourène, Ayache Bouakaz, Patrick Emond, Jean-Michel Escoffre, Lydie Nadal-Desbarats","doi":"10.3389/fnmol.2024.1383963","DOIUrl":"10.3389/fnmol.2024.1383963","url":null,"abstract":"<p><p>Microbubble (MB)-assisted ultrasound (US) is an innovative modality for the non-invasive, targeted, and efficient delivery of therapeutic molecules into the brain. Previously, we reported the first metabolomic signature of blood-brain barrier opening (BBBO) induced by MB-assisted US. In the present study, the neurometabolic consequences of acoustically-mediated BBBO on cerebral tissue were investigated using multimodal metabolomics approaches. Sinusoid US waves (1 MHz, peak negative pressure 0.6 MPa, burst length 10 ms, total treatment time 30 s, MB bolus dose 0.7 × 10⁵ MBs/g) were applied on the rats' right striatum (ipsilateral side). Brain was collected and both striata were then dissected 3 h, 2 days, and 1 week after BBBO. After tissue preparation, the samples were analyzed using nuclear magnetic resonance spectrometry (NMRS) and high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS). Our findings showed a slight disruption of metabolic pathways in contralateral striata of animals. Analyses of metabolic pathways indicated changes in amino acid metabolisms. In addition, tryptophan derivate dosages revealed the perturbation of a central metabolite of the kynurenine pathway (i.e., 3-hydroxy-kynurenine). In conclusion, the acoustically-mediated BBBO of the ipsilateral cerebral hemisphere induced significant change in metabolism of contralateral one.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1383963"},"PeriodicalIF":3.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reported race-associated differences in control and schizophrenia post-mortem brain transcriptomes implicate stress-related and neuroimmune pathways.","authors":"Shay Simmons, Keon Arbabi, Daniel Felsky, Michael Wainberg, Shreejoy J Tripathy","doi":"10.3389/fnmol.2024.1450664","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1450664","url":null,"abstract":"<p><strong>Background: </strong>The molecular mechanisms underlying racial disparities in schizophrenia (SCZ) illness courses and outcomes are poorly understood. While these differences are thought to arise partly through stressful social gradients, little is known about how these differences are reflected in the brain, nor how they might underlie disparate psychiatric outcomes.</p><p><strong>Methods: </strong>To better understand the neuro-molecular correlates of social gradients, SCZ, and their overlap, we analyzed post-mortem dorsolateral prefrontal cortex (DLPFC) RNAseq data from two racially diverse cohorts in the CommonMind Consortium (235 reported Black and 546 White, 322 SCZ cases and 459 controls) using differential expression and gene set variation analyses.</p><p><strong>Results: </strong>We observed differences in brain gene expression that were consistent across cohorts and reported race. A combined mega-analysis identified 1,514 genes with differential expression (DE) between reported race groups after accounting for diagnosis and other covariates. Functional enrichment analyses identified upregulation of genes involved in stress and immune response, highlighting the potential role of environmental differences between reported race groups. In a race-by-diagnosis interaction analysis, no individual genes passed statistical significance. However, 109 gene sets showed statistically significant differences, implicating metabolic and immune pathways.</p><p><strong>Conclusion: </strong>Our results suggest molecular mechanisms uniquely perturbed across reported race groups and identify several candidate pathways associated with SCZ in a reported race-dependent manner. Our results underscore the importance of diverse cohort ascertainment to better capture population-level differences in SCZ pathogenesis.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1450664"},"PeriodicalIF":3.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of chronodisruption and alcohol consumption on gene expression in reward-related brain areas in female rats.","authors":"Christiane Meyer, Konrad Schoettner, Shimon Amir","doi":"10.3389/fnmol.2024.1493862","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1493862","url":null,"abstract":"<p><p>Circadian dysfunction caused by exposure to aberrant light-dark conditions is associated with abnormal alcohol consumption in humans and animal models. Changes in drinking behavior have been linked to alterations in clock gene expression in reward-related brain areas, which could be attributed to either the effect of chronodisruption or alcohol. To date, however, the combinatory effect of circadian disruption and alcohol on brain functions is less understood. Moreover, despite known sex differences in alcohol drinking behavior, most research has been carried out on male subjects only, and therefore implications for females remain unclear. To address this gap, adult female rats housed under an 11 h/11 h light-dark cycle (LD22) or standard light conditions (LD24, 12 h/12 h light-dark) were given access to an intermittent alcohol drinking protocol (IA20%) to assess the impact on gene expression in brain areas implicated in alcohol consumption and reward: the prefrontal cortex (PFC), nucleus accumbens (NAc), and dorsal striatum (DS). mRNA expression of core clock genes (<i>Bmal1</i>, <i>Clock</i>, <i>Per2</i>), sex hormone receptors (<i>ERβ</i>, <i>PR</i>), glutamate receptors (<i>mGluR5</i>, <i>GluN2B</i>), a calcium-activated channel (<i>Kcnn2</i>), and an inflammatory cytokine (<i>TNF-α</i>) were measured at two-time points relative to the locomotor activity cycle. Housing under LD22 did not affect alcohol intake but significantly disrupted circadian activity rhythms and reduced locomotion. Significant changes in the expression of <i>Bmal1</i>, <i>ERβ</i>, and <i>TNF-α</i> were primarily related to the aberrant light conditions, whereas changes in <i>Per2</i> and <i>PR</i> expression were associated with the effect of alcohol. Collectively, these results indicate that disruption of circadian rhythms and/or intermittent alcohol exposure have distinct effects on gene expression in the female brain, which may have implications for the regulation of alcohol drinking, addiction, and, ultimately, brain health.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1493862"},"PeriodicalIF":3.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-translational modifications of beta-amyloid modulate its effect on cell mechanical properties and influence cytoskeletal signaling cascades.","authors":"Kseniya B Varshavskaya, Evgeny P Barykin, Roman V Timoshenko, Vasilii S Kolmogorov, Alexander S Erofeev, Petr V Gorelkin, Vladimir A Mitkevich, Alexander A Makarov","doi":"10.3389/fnmol.2024.1501874","DOIUrl":"10.3389/fnmol.2024.1501874","url":null,"abstract":"<p><p>Post-translational modifications of beta-amyloid (Aβ) play an important role in the pathogenesis of Alzheimer's disease (AD). Aβ modifications such as Ser8 phosphorylation (pS8-Aβ₄₂) and Asp7 isomerization (iso-Aβ₄₂) can significantly alter the properties of Aβ and have been detected <i>in vivo</i>. One of the reasons for the different pathogenicity of Aβ isoforms may be the activation of different signaling cascades leading to changes in the mechanical properties of cells. In this paper, we used correlative scanning ion-conductance microscopy (SICM) and Pt-nanoelectrodes to compare the effects of Aβ isoforms on the Young's modulus of SH-SY5Y cells and the level of ROS. It was found that unmodified Aβ₄₂ resulted in the largest increase in cell Young's modulus of all isoforms after 4 h of incubation, while pS8-Aβ₄₂ induced the greatest increase in stiffness and ROS levels after 24 h of incubation. Analysis of signaling proteins involved in the regulation of the actin cytoskeleton showed that Aβ₄₂, pS8-Aβ₄₂ and iso-Aβ₄₂ have different effects on cofilin, GSK3β, LIMK, ERK and p38. This indicates that post-translational modifications of Aβ modulate its effect on neuronal cells through the activation of various signaling cascades, which affects the mechanical properties of cells.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1501874"},"PeriodicalIF":3.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Molecular mechanisms of neuropsychiatric diseases, volume II.","authors":"Mónica Moreira-Rodrigues","doi":"10.3389/fnmol.2024.1517196","DOIUrl":"10.3389/fnmol.2024.1517196","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1517196"},"PeriodicalIF":3.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11599241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>α</i>-Synuclein ubiquitination - functions in proteostasis and development of Lewy bodies.","authors":"Hung-Hsiang Ho, Simon S Wing","doi":"10.3389/fnmol.2024.1498459","DOIUrl":"10.3389/fnmol.2024.1498459","url":null,"abstract":"<p><p>Synucleinopathies are neurodegenerative disorders characterized by the accumulation of <i>α</i>-synuclein containing Lewy bodies. Ubiquitination, a key post-translational modification, has been recognized as a pivotal regulator of <i>α</i>-synuclein's cellular dynamics, influencing its degradation, aggregation, and associated neurotoxicity. This review examines comprehensively the current understanding of <i>α</i>-synuclein ubiquitination and its role in the pathogenesis of synucleinopathies, particularly in the context of Parkinson's disease. We explore the molecular mechanisms responsible for <i>α</i>-synuclein ubiquitination, with a focus on the roles of E3 ligases and deubiquitinases implicated in the degradation process which occurs primarily through the endosomal lysosomal pathway. The review further discusses how the dysregulation of these mechanisms contributes to <i>α</i>-synuclein aggregation and LB formation and offers suggestions for future investigations into the role of <i>α</i>-synuclein ubiquitination. Understanding these processes may shed light on potential therapeutic avenues that can modulate <i>α</i>-synuclein ubiquitination to alleviate its pathological impact in synucleinopathies.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1498459"},"PeriodicalIF":3.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11588729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142727578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spinal afferent neurons: emerging regulators of energy balance and metabolism.","authors":"Mohammad Jarrah, Dana Tasabehji, Aviva Fraer, Mohamad Mokadem","doi":"10.3389/fnmol.2024.1479876","DOIUrl":"10.3389/fnmol.2024.1479876","url":null,"abstract":"<p><p>Recent advancements in neurophysiology have challenged the long-held paradigm that vagal afferents serve as the primary conduits for physiological signals governing food intake and energy expenditure. An expanding body of evidence now illuminates the critical role of spinal afferent neurons in these processes, necessitating a reevaluation of our understanding of energy homeostasis regulation. This comprehensive review synthesizes cutting-edge research elucidating the multifaceted functions of spinal afferent neurons in maintaining metabolic equilibrium. Once predominantly associated with nociception and pathological states, these neurons are now recognized as integral components in the intricate network regulating feeding behavior, nutrient sensing, and energy balance. We explore the role of spinal afferents in food intake and how these neurons contribute to satiation signaling and meal termination through complex gut-brain axis pathways. The review also delves into the developing evidence that spinal afferents play a crucial role in energy expenditure regulation. We explore the ability of these neuronal fibers to carry signals that can modulate feeding behavior as well as adaptive thermogenesis in adipose tissue influencing basal metabolic rate, and thereby contributing to overall energy balance. This comprehensive analysis not only challenges existing paradigms but also opens new avenues for therapeutic interventions suggesting potential targets for treating metabolic disorders. In conclusion, this review highlights the need for a shift in our understanding of energy homeostasis, positioning spinal afferent neurons as key players in the intricate web of metabolic regulation.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1479876"},"PeriodicalIF":3.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11583444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}