Journal of Neurochemistry最新文献

{"title":"Multifaceted Immune Effects of the Scavenger Receptor CD36 on Long-Term Outcomes After Neonatal Arterial Focal Stroke","authors":"Elena Di Martino,&nbsp;Aditya Rayasam,&nbsp;Amin Mottahedin,&nbsp;Joel Faustino,&nbsp;Shivani Mahuvakar,&nbsp;Joakim Ek,&nbsp;Carina Mallard,&nbsp;Zinaida S. Vexler","doi":"10.1111/jnc.70553","DOIUrl":"10.1111/jnc.70553","url":null,"abstract":"<p>The scavenger receptor CD36 is a versatile receptor that regulates various inflammatory processes by interacting with different ligands in concert with other receptors in a context- and cell-type-specific manner. While CD36 is injurious in acute adult stroke, it is beneficial in acute perinatal stroke. This differing acute response may be influenced by the maturation-dependent availability of CD36 receptor partners in the brain, such as Toll-like receptors (TLRs), the developmental state of the blood–brain barrier, and leukocyte subtypes during injury. Here, we further explore CD36-TLR2 interactions in neonatal brain injury by examining whether CD36 similarly affects gene expression and leukocyte trafficking via the blood-CSF barrier/choroid plexus after transient middle cerebral artery occlusion and direct TLR2 stimulation in wild type and CD36 knockout mice. We then examine the consequences of CD36 deficiency for long-term injury outcomes after neonatal stroke. We demonstrate that CD36 deficiency affects long-term behavior performance under physiological conditions and a shift in the role of CD36 from beneficial during acute injury to detrimental in the chronic phase following neonatal stroke. We further show that CD36 contributes to sustained immune responses, as indicated by long-term alterations in microglial phenotypes, and influences long-term functional outcomes. Collectively, these findings underscore the complex time-dependent roles of CD36 and provide insight into the mechanisms by which it modulates ischemic injury in neonatal mice.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017127","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":"Correction to ‘Exercise Snacking in Alzheimer's Disease: A Mechanistic Rationale Based on Repeated Exerkine Signaling’","authors":"","doi":"10.1111/jnc.70560","DOIUrl":"10.1111/jnc.70560","url":null,"abstract":"<p>\u0000 <span>Sousa, R. A. L. D.</span>, <span>J. M. M. Costa</span>, <span>R. R. S. Pereira</span>, <span>L. C. R. Vieira</span>, <span>C. O. D. Magalhães</span>, and <span>M. F. Dias-Peixoto</span>. <span>2026</span>. “ <span>Exercise Snacking in Alzheimer's Disease: A Mechanistic Rationale Based on Repeated Exerkine Signaling</span>.” <i>Journal of Neurochemistry</i> <span>170</span>, no. <span>7</span>: e70517. https://doi.org/10.1111/jnc.70517.\u0000 </p><p>The paper by Sousa et al. (2026) was originally published as a Review. The correct article type is Invited Editorial. The original article has been corrected.</p><p>We apologize for this error.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70560","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012622","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":"Preface to the Special Issue “Nutritional Neurochemistry”","authors":"João M. N. Duarte,&nbsp;Andreza F. de Bem","doi":"10.1111/jnc.70558","DOIUrl":"10.1111/jnc.70558","url":null,"abstract":"&lt;p&gt;Nutrition not only constitutes a source of energy and structural building blocks for the brain, it shapes brain development, cellular metabolism, neurotransmission and behavior. The brain itself continuously senses and integrates peripheral metabolic information to regulate feeding and whole-body homeostasis. This Journal of Neurochemistry special issue on Nutritional Neurochemistry brings together a collection of original research and reviews that explore the intricate relationship between diet, metabolism, and brain function.&lt;/p&gt;&lt;p&gt;A recurring theme throughout this collection is that the consequences of nutrition depend strongly on when an exposure occurs. Early life represents a particularly sensitive period during which nutritional signals can leave persistent molecular and functional imprints on the brain. Fernández et al. demonstrate that neonatal overnutrition produces long-lasting epigenetic modifications in hypothalamic pathways regulating energy balance, namely reducing pro-opiomelanocortin (&lt;i&gt;Pomc&lt;/i&gt;) expression in the arcuate nucleus, which is likely to result from hypermethylation of the &lt;i&gt;Pomc&lt;/i&gt; promoter and was found to shape the responses to obesogenic stimuli in adulthood (Fernández et al. &lt;span&gt;2026&lt;/span&gt;). Schmitt et al. review evidence linking maternal obesity with gestational reprogramming of the fetal immune, metabolic, endocrine, and neurological systems, which influence the metabolism and mental health of the offspring (Schmitt et al. &lt;span&gt;2025&lt;/span&gt;). Fortunato et al. further extend this principle of gestational reprogramming to the maternal gut–brain axis, showing that maternal tryptophan supplementation in the diet can alter offspring microbiota, neurochemistry and behavior in a sex-dependent manner (Fortunato et al. &lt;span&gt;2025&lt;/span&gt;). In particular, the female offspring exhibited disrupted microbiota diversity, reduced brain tryptophan and serotonin levels, and behavior alterations indicative of anxiety (Fortunato et al. &lt;span&gt;2025&lt;/span&gt;). Together, these studies emphasize that nutrition is a neurochemical modulator influencing brain function through mechanisms that depend on developmental stage, subsequent dietary patterns in adulthood and biological sex. Zanesco and Velloso further review the role of hypothalamic BDNF in sexually dimorphic metabolic regulation, emphasizing that sex is a biological variable fundamental to understanding systemic metabolic control by the brain (Zanesco and Velloso &lt;span&gt;2025&lt;/span&gt;).&lt;/p&gt;&lt;p&gt;The diversity of mechanisms through which the brain detects and responds to metabolic information has been addressed in the special issue “Nutritional Neurochemistry”. At the cellular level, Baumart et al. examine how LDL cholesterol modifies astrocyte metabolism, lipid handling and morphology, highlighting astrocytes as active metabolic sensors and responders to systemic lipid homeostasis (Baumart et al. &lt;span&gt;2026&lt;/span&gt;). This is of particular importance in the context of the role of o","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70558","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990218","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":"Altered Retinal Dopamine Homeostasis in Murine Models of Retinitis Pigmentosa","authors":"Katri Vainionpää,&nbsp;Eerik Lappalainen,&nbsp;Anna Nilsson,&nbsp;Ida Pavela,&nbsp;Tommi Torsti,&nbsp;Umair Seemab,&nbsp;Elina Mäkinen,&nbsp;Reza Shariatgorji,&nbsp;Per E. Andrén,&nbsp;Aaro Jalkanen,&nbsp;Markus M. Forsberg,&nbsp;Henri Leinonen","doi":"10.1111/jnc.70552","DOIUrl":"10.1111/jnc.70552","url":null,"abstract":"<p>Retinitis pigmentosa (RP) is a heterogeneous group of currently untreatable inherited retinal degenerations that share similar disease manifestations despite distinctive genetic causes. Dopamine (DA) is an important and tightly regulated catecholaminergic neurotransmitter required for multiple modulatory functions throughout the central nervous system, including the retina. Dysregulation of DA homeostasis has been reported during neurodegeneration, but how it is regulated in RP remains poorly understood. Here, we demonstrate that early RP is associated with marked dysregulation of the dopaminergic system using two distinct disease models, P23H and rd10 mice. We found increased DA levels in RP retinas collected from pre-weaned (P12), juvenile (P30), and adult (P60–90) mice by utilising ultra-high-performance liquid chromatography and matrix-assisted laser desorption/ionisation mass spectrometry. Consistently, DA levels were also elevated in the vitreous of P23H mice, where it likely diffuses from the retina. RP retinas additionally demonstrated higher levels of DA precursor l-3,4-dihydroxyphenylalanine (L-DOPA), as well as upregulated tyrosine hydroxylase gene expression, which suggests elevated DA synthesis. In parallel, we observed increased activity and expression of the catecholamine-metabolising enzyme catechol-O-methyltransferase (COMT) during retinal degeneration. Comparative tissue analysis with cortex, striatum, retina, and eye cup samples further highlighted COMT as a major contributor to catecholamine inactivation in the mouse retina. Finally, RNA sequencing of P23H retinal extracts revealed widespread alterations related to the catecholaminergic system during disease progression, including upregulation of the solute carrier family 6 member 2 gene, encoding norepinephrine transporter, and the protein phosphatase 1 regulatory subunit 1B gene, which encodes DA- and cAMP-regulated neuronal phosphoprotein. In conclusion, these data demonstrate elevated DA levels in P23H and rd10 mouse retinas, along with several other biochemical changes in the catecholamine system, suggesting a hyperexcited state in early RP progression.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70552","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990233","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":"Preface to the Special Issue: “Microbiota and Gut–Brain Axis”","authors":"Gerard Clarke","doi":"10.1111/jnc.70555","DOIUrl":"10.1111/jnc.70555","url":null,"abstract":"<p>The microbiota–gut–brain axis has emerged as a central framework for understanding how microbial communities influence nervous system development, function, and disease. This Special Issue highlights three interconnected themes: microbial metabolites and neurochemistry, developmental and neuroimmune mechanisms, and translation to neurological and psychiatric disease. The articles in the collection examine how microbial metabolites modulate neuroinflammatory and neurochemical pathways, how stress, development, immune signaling, and gut health shape gut–brain communication across the lifespan, and how these mechanisms contribute to disorders including autism spectrum disorder, depression, Parkinson's disease, spinal cord injury, and addiction. Together, these contributions advance a mechanistic and translational understanding of microbiota–gut–brain interactions and identify important directions for future research.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13578855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977070","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":"Rethinking γ-Secretase Dysfunction in Alzheimer's Disease: From APP Processing to Network Perturbation","authors":"Daniela Passarella,&nbsp;Claudio Russo","doi":"10.1111/jnc.70550","DOIUrl":"10.1111/jnc.70550","url":null,"abstract":"&lt;p&gt;γ-Secretase dysfunction in Alzheimer's disease (AD) has been interpreted primarily through altered amyloid precursor protein (APP) processing and amyloid-β (Aβ) generation (Selkoe and Hardy &lt;span&gt;2016&lt;/span&gt;). This APP-centered view has shaped both the interpretation of presenilin mutations and therapeutic efforts to modulate γ-secretase largely through the lens of APP/Aβ biology. However, the progressive identification of more than 140 reported γ-secretase substrates has profoundly expanded our understanding of this protease complex beyond APP processing, revealing that its biological impact extends across diverse physiological pathways through the proteolytic processing of functionally distinct substrates (Güner and Lichtenthaler &lt;span&gt;2020&lt;/span&gt;).&lt;/p&gt;&lt;p&gt;Among these substrates, a functionally diverse subset is particularly relevant to APP biology because its members regulate APP trafficking, processing, signaling, or Aβ homeostasis. These APP-regulatory γ-secretase substrates span different protein classes, including APP-like proteins (APLPs), Vps10p-domain receptors, LDLR-related receptors, and adhesion and signaling substrates (Figure 1). Illustrative, but not exhaustive, representatives are APLP1, SORLA, LRP8 (ApoER2), and N-cadherin, which share two relevant functional features: they act as regulators of APP biology (Fjorback et al. &lt;span&gt;2012&lt;/span&gt;; Fuentealba et al. &lt;span&gt;2007&lt;/span&gt;; Neumann et al. &lt;span&gt;2006&lt;/span&gt;; Uemura et al. &lt;span&gt;2009&lt;/span&gt;), while also fulfilling distinct physiological functions independently of APP. These include APLP1-mediated trans interactions implicated in cell–cell adhesion (Kaden et al. &lt;span&gt;2009&lt;/span&gt;), SORLA-dependent trafficking of neurotrophin receptors and modulation of neurotrophic signaling (Schmidt et al. &lt;span&gt;2017&lt;/span&gt;), LRP8-mediated regulation of N-methyl-D-aspartate receptor signaling, synaptic plasticity, and memory (Beffert et al. &lt;span&gt;2005&lt;/span&gt;), and N-cadherin-mediated trans-synaptic adhesion and activity-dependent stabilization and remodeling of excitatory synapses (Tai et al. &lt;span&gt;2008&lt;/span&gt;) (Figure 1). Together, these observations suggest a conceptual framework that extends beyond the simple recognition of γ-secretase as a multi-substrate protease, pointing instead to a putative APP-intersecting regulatory network. Perturbation of the shared proteolytic node could therefore propagate both through APP/Aβ biology and across broader neuronal pathways.&lt;/p&gt;&lt;p&gt;At the molecular level, γ-secretase dysfunction need not reflect a uniform loss of catalytic activity but may instead involve genetic or non-genetic alterations that differentially affect substrate processing. Such perturbations, rather than simply reducing proteolysis, would be expected to modify the balance among substrate-derived species, including altered production of membrane-retained C-terminal fragments and altered generation of intracellular domains, potentially accompanied by secondary changes in full-length su","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13578827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977194","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":"Bursting Parameters Alter Excitatory Postsynaptic Currents in Nucleus Tractus Solitarius Neurons: Implications for Clinical Vagus Nerve Stimulation","authors":"Misty Marie Owens,&nbsp;Aleksandra Radovic,&nbsp;Eric Beaumont","doi":"10.1111/jnc.70557","DOIUrl":"10.1111/jnc.70557","url":null,"abstract":"<div>\u0000 \u0000 <p>Vagus nerve stimulation (VNS) is an approved therapy for multiple neurological and autonomic disorders; however, the mechanisms underlying its therapeutic effects and optimal stimulation parameters remain poorly understood. Vagal afferents activated by VNS terminate within the nucleus tractus solitarius (NTS), where sensory information is integrated and propagated throughout central autonomic networks. Although conventional VNS paradigms are used therapeutically, previous studies have demonstrated high rates of synaptic transmission failure within NTS circuits, suggesting that alternative stimulation strategies could enhance neural activity. Bursting VNS has emerged as a promising alternative to standard stimulation patterns, but its effects on NTS neuronal processing remain unclear. The present study used voltage-clamp recordings in rat brainstem slices to study NTS neurons, with solitary tract (ST) stimulation delivered using single-pulse or bursting parameters to evoke excitatory postsynaptic currents (EPSCs). Bursting paradigms varying in frequency (150–350 Hz) and pulse number (2–4 pulses per burst) were compared with single-pulse stimulation. EPSC amplitude and total area under the curve (AUC) were used to quantify stimulation responses. In NTS neurons monosynaptically connected to ST afferents, bursting paradigms significantly reduced the amplitude of the first EPSC relative to single-pulse stimulation, whereas no differences in overall AUC were observed. In contrast, polysynaptic neurons exhibited burst-dependent differences in excitatory transmission, with differences observed relative to baseline and across pulse conditions. Specifically, AUC was significantly greater during lower-frequency (150–250 Hz) 3- and/or 4-pulse bursts compared with single-pulse stimulation. Across all frequencies tested, 3- and/or 4-pulse bursts also produced significantly greater AUC than the corresponding 2-pulse paradigm. These findings indicate that bursting stimulation differentially modulates excitatory transmission in monosynaptic and polysynaptic NTS neurons, with specific pulse and frequency combinations preferentially influencing higher-order NTS circuitry and providing insight into stimulation strategies that may improve central network engagement during clinical VNS.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptobrevin-2 Containing Extracellular Vesicles Are Rapidly Incorporated Into Mammalian Neurons via a Dynamin-Dependent Pathway","authors":"Victoria Hannett,&nbsp;A. Alejandro Vilcaes,&nbsp;Siewert Hugelier,&nbsp;Qing Tang,&nbsp;Melike Lakadamyali,&nbsp;Natali L. Chanaday","doi":"10.1111/jnc.70551","DOIUrl":"https://doi.org/10.1111/jnc.70551","url":null,"abstract":"<p>Synaptobrevin-2 (Syb2) is a SNARE protein essential for neurotransmitter release and communication in the nervous system. We previously showed that Syb2 is also exchanged among neurons via extracellular vesicles (EVs). Host neurons rapidly integrate exogenous Syb2 into their synaptic vesicle cycle to support neurotransmitter release. However, the endocytic mechanism by which neurons incorporate Syb2-containing EVs is unknown. Here, we use a fusion of Syb2 with the pH-sensitive GFP (Syb2-pHluorin) to track the incorporation of Syb2-containing EVs into rat hippocampal and cortical neurons and the trafficking of exogenous Syb2 to synaptic vesicles at synapses. We determined that Syb2-containing EVs are endocytosed via a Dynamin-dependent pathway, largely independently of macropinocytosis. The same endocytic route is used in the somatodendritic and axonal compartment and it occurs very rapidly, with the majority of Syb2-pHluorin residing in internal acidic organelles at 30 min after EV addition, including synaptic vesicles at synapses. Leveraging this finding, we used EVs to sparsely deliver Syb2-pHluorin to synapses and track the fusion and endocytosis of single synaptic vesicles. The results indicate that Syb2-pHluorin-positive synaptic vesicles are endocytosed with either ultrafast (&lt; 1 s) or fast (~1–3 s) kinetics during synaptic transmission, suggesting limited diffusion and high fidelity in the fast retrieval of synaptic vesicle molecules immediately after fusion. Our findings expand our understanding of the mechanisms EVs use to enter neurons and open the door for future applications of EVs as vehicles to deliver fluorescent molecules in a neuron-specific, targeted manner.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70551","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943125","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":"Dysregulation of Hippocampal Autophagic Machinery in the Activity-Based Anorexia Rat Model","authors":"Beatrice Rizzi,&nbsp;Giorgia Targa,&nbsp;Sofia Taddini,&nbsp;Susanna Parolaro,&nbsp;Letizia Rapini,&nbsp;Fabio Fumagalli,&nbsp;Lucia Caffino,&nbsp;Francesca Mottarlini","doi":"10.1111/jnc.70549","DOIUrl":"10.1111/jnc.70549","url":null,"abstract":"<p>In Anorexia Nervosa (AN), the combination of self-induced starvation and hyperactivity may initially recruit the autophagic machinery to sustain the function of energy-demanding brain regions; however, its dysregulation may ultimately contribute to impaired brain function. We therefore investigated the autophagic machinery in the dorsal hippocampus (dHip), a central hub for energy status modulation and for cognitive processing, in the activity-based anorexia (ABA) rat model, the gold standard in the field. To analyze autophagic markers in the dHip, adolescent female Sprague–Dawley rats were exposed to 2 h/day of food access + free wheel access (ABA induction) and were sacrificed when they reached the maximum body weight loss allowed concomitantly with an increase in the running activity (acute phase) or following a 7-day recovery period. Our results show that ABA induction persistently disrupts the regulation of the autophagic machinery. In the acute phase, the ABA condition increases the phosphorylation of mTOR/ULK1 while promoting TFEB-associated mechanisms, enhancing the expression of autophagic markers such as <i>Becn1</i>, <i>Ctsb</i> genes, Beclin-1, and LC3-II proteins. After weight recovery, TFEB-induced activation of <i>Becn1</i>, <i>Ctsb</i>, Beclin-1, and LC3-II remains elevated. In addition, the enhanced expression of autophagic markers is accompanied by an increase in p62 and Caspase3, pro-apoptotic signals. Our findings reveal a sustained activation of autophagy across different stages of the ABA protocol. Rather than functioning exclusively as a survival mechanism, this process could evolve into a driver of aberrant behaviors typical of individuals with AN, such as dieting behaviors and hippocampal-dependent deficits.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70549","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148919999","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":"Neuroinflammatory and Motor Alterations in LRRK2*G2019S Transgenic Mice Without Enhanced Vulnerability to Aging or Chronic MPTP-Induced Nigrostriatal Neurodegeneration","authors":"Roberto García-Swinburn,&nbsp;Laura Morón-Márquez,&nbsp;Carmen Conde-Naranjo,&nbsp;Ernesto García-Roldán,&nbsp;Isabel Espadas,&nbsp;Alfonso Rodríguez-Gil,&nbsp;Reposo Ramírez-Lorca,&nbsp;Javier Villadiego,&nbsp;Juan José Toledo-Aral","doi":"10.1111/jnc.70547","DOIUrl":"10.1111/jnc.70547","url":null,"abstract":"<p>LRRK2 G2019S mutation is the most common genetic cause of Parkinson's disease (PD) producing clinical manifestations similar to sporadic PD patients, hinting at the relevance of this mutation in the pathophysiological mechanisms of the disease. However, its role potentiating nigrostriatal neurodegeneration, particularly in response to mitochondrial dysfunction, remains unclear. Here, using histological, neurochemical and behavioral analyzes, we provide a complete characterization of a mouse model expressing the human LRRK2 G2019S mutation (hLRRK2*G2019S mice), in the context of aging and toxin-induced parkinsonism. hLRRK2*G2019S young adult mice showed significant microglial activation and deficits in motor coordination, whereas aged transgenic displayed a hyperactive phenotype, despite the absence of evidence for nigrostriatal neurodegeneration in either young adult or aged animals. Furthermore, we assessed the vulnerability of LRRK2*G2019S transgenic mice to the chronic exposure to the mitochondrial complex I inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Notably, no exacerbation of nigrostriatal neurodegeneration was observed in hLRRK2*G2019S mice, suggesting that this mutation does not increase sensitivity to mitochondrial stress. However, hLRRK2*G2019S MPTP-treated mice present alterations, relative to WT counterparts, in the glial response induced by the neurotoxic treatment. These findings suggest that the G2019S mutation modulates the neuroimmune response but does not exacerbate nigrostriatal neurodegeneration in response to mitochondrial dysfunction. This highlights the mutation's complex role in PD pathophysiology.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70547","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912300","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}