Neuroscience
Abstract
Authors
Ewa A. Ziółkowska, Letitia L. Williams, Elizabeth M. Eultgen, Grace R. Kick, Xukai Ding, Alexander Sorensen, Steven Q. Le, Balraj Doray, Patricia I. Dickson, Robert O. Heuckeroth, Jonathan D. Cooper
Abstract
The hypothalamic changes that occur after the loss of ovarian estrogen remain poorly characterized. Here, we performed a comprehensive temporal characterization of the mouse hypothalamus following ovariectomy (OVX), combining physiological measurements with bulk RNA-sequencing of the posterior hypothalamus (PH) and preoptic area (POA) at short-term (14 days) and long-term (4 months) post-OVX. Serum LH levels rose progressively and then declined, while core temperature peaked early and subsequently normalized, recapitulating the endocrine and thermoregulatory dynamics of reproductive aging in humans. Transcriptomic analysis revealed time-dependent activation of inflammatory pathways, glial markers, and KNDy neuron-related gene networks, with the most pronounced changes emerging at 4 months post-OVX, particularly in the PH. Immunofluorescence confirmed increased NKB release, declining KNDy neuronal activity, and heightened astrocytic reactivity in the arcuate nucleus after prolonged estrogen withdrawal. To contextualize these findings, we analyzed publicly available human hypothalamic RNA-seq data across chronological age. Age-related transcriptomic patterns in women, including progressive inflammatory signaling, glial activation, and altered KNDy gene expression, showed significant correlation with the OVX mouse model, particularly at the pathway level. These findings establish a temporal framework for hypothalamic molecular changes after estrogen withdrawal, identify conserved neuroinflammatory signatures across species, and provide a preclinical platform for testing interventions targeting menopausal-associated hypothalamic dysfunction.
Authors
Jordana C.B. Bloom, Encarnación Torres, Sidney A. Pereira, Liliana Arvizu-Sanchez, Audrey N. Fontes, Hadine Joffe, David C. Page, Victor M. Navarro
Abstract
Authors
Lun Li, Rhonda Lightle, Bader Ali, Georgeio Sader, Robert Shenkar, Sean P. Polster, Douglas A. Marchuk, Jan-Karl Burkhardt, Issam A. Awad, Mark L. Kahn
Abstract
Charcot-Marie-Tooth Disease (CMT) is a group of inherited progressive conditions affecting distal motor and sensory neurons, leading to muscle weakness, pain and loss of sensation in limbs. CMT type 2A (CMT2A) is the most common form of axonal CMT and is associated with a more severe clinical manifestation. However, there are no treatments currently available. To investigate disease mechanisms and facilitate treatment discovery, we developed an in vitro model for CMT2A by introducing the patient-specific MFN2R94Q/+ variant into human embryonic stem cells (hESCs). Isogenic variant and wild-type hESCs differentiated to spinal motor neurons with similar efficiency and gave rise to functional motor neurons in vitro. However, MFN2R94Q/+ spinal motor neurons displayed impaired mitochondrial trafficking, resulting in altered distribution of mitochondria in axons. Unbiased quantitative proteomic profiling of the endogenous MFN2 interactome revealed dose-dependent remodelling by the R94Q variant across 412 proteins, highlighting candidate mechanisms in disease pathology. Importantly, we showed that mitochondrial trafficking defects could be alleviated by treatment with an HDAC6 inhibitor. Chemical inhibition of HDAC6 also rescued the motor phenotype in a zebrafish CMT2A model. Taken together, our study reveals a variant-specific insight into CMT2A disease mechanisms and confirms HDAC6 as a promising target for further therapeutic development.
Authors
Lydia H. Jestice, Larissa Butler, Rebecca A. Lea, Kathryn I. Adamson, Jonas Van Lent, Stuart L. Johnson, Hollie Weedon, Eldriena D’Silva, Gabriele Gelezauskaite, Bob Asselbergh, Eloise Brown, Owen Laing, Christopher J. Price, Dylan Stavish, Anestis Tsakiridis, Mark O. Collins, Vincent Timmerman, Kurt J. De Vos, Alison E. Twelvetrees, Andrew J. Grierson, Ivana Barbaric
Abstract
Authors
Enrique Gonzalez Saez-Diez, Xutong Xue, Amy Tam, Hyo-Min Kim, Siofra Carty, Joshua Rong, Monica Ferrer-Socorro, Kathryn Yang, Darius Ebrahimi-Fakhari
Abstract
Spinal cord injury (SCI) leads to severe neurological and functional impairments, yet reliable biomarkers for assessing injury severity and predicting recovery remain limited. Cerebrospinal fluid (CSF) is in direct contact with the central nervous system and provides a valuable source for detecting molecular changes after SCI. Although exosomal microRNAs and proteins are increasingly recognized as mediators of intercellular communication, the role of human CSF exosomes in SCI has not been systematically investigated. To identify exosome-based biomarkers and potential therapeutic targets, we analyzed CSF and serum exosomes from patients with acute SCI using RNA sequencing and proteomic profiling. Weighted Gene Co-expression Network Analysis (WGCNA) identified six gene modules significantly associated with injury severity and neurological recovery at three months. Proteomic analysis revealed a five-protein panel that distinguished complete from incomplete SCI and a four-protein panel that predicted neurological improvement. Additionally, fifteen CSF-specific and nine serum-specific exosomal miRNAs were identified independent of injury severity. Among ten tested miRNAs associated with neurological recovery, seven regulated astrocyte proliferation, and six promoted neurite extension and synapse formation. Overall, this study provides a comprehensive characterization of CSF exosomal miRNAs and proteins in human SCI and identifies molecular signatures associated with injury severity and recovery.
Authors
Dallas L. Sheinberg, Haichao Wei, Joseph S. Withrow, Farshad Homayouni Moghadam, Chia-Chen Lu, Jyotirmoy Rakshit, Jennifer Zaragoza, John R. Williams, Wen Li, Jacques J. Morcos, Jia Qian Wu
Abstract
The discovery of genes encoding the volume-regulated anion channel (VRAC) has enabled detailed exploration of its cell type–specific roles in the brain. LRRC8A (SWELL1) is the essential VRAC subunit. We observed seizure-induced, subunit-specific changes in microglial VRAC expression and investigated its function using conditional KO (cKO) of LRRC8A in microglia. SWELL1 cKO mice exhibited a male-specific increase in kainate-induced seizure severity, yet showed paradoxical neuroprotection against seizure-associated neuronal loss. Mechanistically, SWELL1 deletion led to a cell-autonomous reduction in microglial density and decreased release of VRAC-permeable neuroactive metabolites, including taurine, GABA, and glutamate in culture. Additionally, impaired phagocytic kinetics and reduced lysosomal biogenesis contributed to the observed neuroprotection. These findings reveal potentially novel roles for microglial VRAC in regulating seizure outcomes and microglia-neuron interactions.
Authors
Abhijeet S. Barath, Aastha Dheer, Laura Montier, Mekenzie M Peshoff, Emily Dale, Flavia Goche, Thanh Thanh Le Nguyen, Mastura Akter, FangFang Qi, Dimitrios Kleidonas, Lauren Harris, Sarah A. Jewanee, Anthony D. Umpierre, Dale B. Bosco, Koichiro Haruwaka, Rajan Sah, Long-Jun Wu
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the selective loss of upper and lower motor neurons. There is a considerable variability in the disease progression of sporadic ALS, but the molecular basis for phenotypic heterogeneity remains largely unknown. ALS patients often manifest systemic metabolic abnormalities such as glucose intolerance and hypermetabolic state. We conducted reverse translational research to explore therapeutic targets in ALS based on the systemic metabolic alterations in patients and identified several metabolites associated with the disease progression, including metabolites involved in the expanded endocannabinoid system (ECS). In particular, the levels of N-acyl taurines (NATs) were correlated with the longitudinal change in the revised ALS functional rating scale and survival. Experiments with ALS cellular models, iPS cells derived from ALS patients and SOD1G93A transgenic mice revealed that PF-04457845, a fatty acid amide hydrolase inhibitor, upregulated the expanded ECS, particularly the levels of NATs and ameliorated motor neuron degeneration through the regulation of microglial environment, synapse plasticity, and neuronal development. These results collectively indicate that dysregulation of NATs is associated with ALS progression and PF-04457845 may represent a potential disease-modifying therapy for ALS.
Authors
Daisuke Ito, Madoka Iida, Yohei Iguchi, Atsushi Hashizume, Shinichiro Yamada, Yoshiyuki Kishimoto, Shota Komori, Kazuki Obara, Shuto Nishisaki, Satoshi Yokoi, Teppei Shimamura, Yuto Takemoto, Masahiro Nakatochi, Tomohiro Akashi, Kunihiko Hinohara, Hyeon-Cheol Lee-Okada, Yohei Okada, Junichi Niwa, Gen Sobue, Shinji Tanaka, Ken Takashina, Takehiko Yokomizo, Masahisa Katsuno
Abstract
Central insulin action in the brain is thought to contribute to metabolic regulation, but the specific hypothalamic nuclei affected in type 2 diabetes (T2D) remain poorly characterized. We performed high-resolution functional MRI (fMRI) during intranasal insulin administration to assess nucleus-level hypothalamic responses in 21 Japanese men with T2D and 20 individuals acting as healthy controls. In controls, insulin rapidly suppressed fMRI signals within 5 minutes in the posterior hypothalamic nucleus; this early suppression was not observed in T2D, indicating impaired hypothalamic insulin responsiveness. In an independent older cohort, structural MRI further revealed decreased gray matter volume in the corresponding posterior hypothalamus in participants with diabetes. These converging functional and structural findings implicate the posterior hypothalamus as a candidate locus associated with brain insulin resistance in T2D, warranting longitudinal and interventional validation.
Authors
Hideyoshi Kaga, Akitoshi Ogawa, Takahiro Osada, Mai Kiya, Satoshi Oka, Yusuke Adachi, Mengping Yu, Shota Sakamoto, Saori Kakehi, Toshiki Kogai, Tsubasa Tajima, Hitoshi Naito, Naoaki Ito, Satoshi Kadowaki, Yuya Nishida, Ryuzo Kawamori, Seiki Konishi, Hirotaka Watada, Yoshifumi Tamura
Abstract
Spreading depolarizations (SDs) are propagating waves of near-complete breakdown of transmembrane ion gradients that occur during acute ischemic stroke and worsen outcome by driving calcium overload and glutamate release in neurons and astrocytes. The plasmalemmal sodium-calcium exchanger (NCX) plays a key role in such changes, in that the complex ionic disequilibrium during ischemia induces reverse-mode activity of NCX, leading to cellular calcium overload in exchange for sodium. However, the cell type-specific roles of NCX in neurons and astrocytes during SDs remain unclear. Here, we used ion and glutamate reporters in an in vivo stroke model in mice carrying inducible, cell-specific deletions of NCX isoform-1. Neuronal NCX1 deletion reduced neuronal and astrocytic calcium transients, increased neuronal sodium transients, decreased extracellular glutamate levels, and raised SD initiation threshold. In contrast, astrocytic NCX1 deletion increased sodium transients in both neurons and astrocytes, and increased neuronal calcium as well as extracellular glutamate levels. A computational model of ischemia confirmed that these effects are consistent with reverse-mode NCX1 activity. Together, these findings indicate opposing roles of reverse-mode NCX1 during ischemia. Neuronal NCX1 promotes SD susceptibility, calcium overload and glutamate release, whereas astrocytic NCX1 exerts protective effects by attenuating glutamate elevation and neuronal calcium accumulation.
Authors
Somayyeh Hamzei Taj, Pawan Kumar Thapaliya, Cordula Rakers, Niklas J. Gerkau, Christine R. Rose, Ghanim Ullah, Gabor C. Petzold
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