Sleep has been linked to brain waste clearance and glymphatic/perivascular transport, yet whether insomnia shares genetic architecture with perivascular diffusivity remains unclear. Here we show that insomnia liability and diffusion tensor imaging measures along the perivascular space have little genome-wide genetic correlation but converge locally at chromosome 17q21.31. Polygenic enrichment, conjunctional false discovery rate, and Bayesian colocalization analyses support shared statistical signals in this region, which contains the MAPT inversion locus. Transcriptome-wide, gene-level fine-mapping, and summary-data Mendelian randomization analyses prioritize HEXIM1, ACBD4, EFTUD2, and MAPT. Tissue, cell-type, spatial transcriptomic, and sleep-perturbation analyses place these candidates in neuronal, glial, immune, vascular, and perivascular contexts, with effects varying by brain region and imaging phenotype. Together, these findings support localized genetic convergence rather than a genome-wide shared architecture and provide biological context for future studies of perivascular imaging phenotypes and neurodegeneration-related processes. Insomnia and MRI-derived perivascular diffusivity show little genome-wide genetic correlation but converge locally at 17q21.31, highlighting HEXIM1, ACBD4, EFTUD2 and MAPT.
The spindle assembly checkpoint (SAC) monitors kinetochore-microtubule interactions to ensure accurate chromosome segregation. In mitosis, investigation of its silencing at anaphase centers on whether attachment or tension is the key signal, while in meiosis for mammalian oocytes it remains unclear whether centromere stretching contributes to SAC deactivation, because in this reductional division sister chromatids co-segregate during meiosis I. While previous studies have linked bivalent tension to SAC control in oocytes, this measurement cannot be directly equated with mitotic chromatin stretching. Here, by tagging the N-terminus of NDC80/HEC1, we developed a mouse oocyte model that features stable microtubule attachments, yet exhibits persistent SAC signaling at metaphase I. Our comprehensive analysis reveals a strong correlation between centromere stretching and SAC signaling. Furthermore, high-resolution live imaging demonstrates that these modified kinetochores impair their oscillatory movements, a process vital for error correction, while chromosome congression remains largely unaffected. Collectively, our data suggest that stable microtubule attachment alone is insufficient to silence SAC in mammalian oocytes; instead, centromere stretching may serve as a critical signal to deactivate the checkpoint. These findings underscore the adaptability of core cell-cycle surveillance pathways.
Delta-dominated activity is a hallmark of anesthesia and non‑REM sleep, yet how neuronal firing evolves across these rhythms remains unclear. Here, by tracking cortical neuron firing in the ketamine‑xylazine model, we find that across continuing delta-dominated activity, population firing rates progress through successive epochs of excitation, suppression, and re-emergence. Concurrently, fine‑scale spike timing and burst dynamics exhibit non-monotonic modulation, revealing continuous reorganization beneath the ongoing delta-dominated oscillation. At the transition to theta-dominated activity, a restructuring of temporal patterning without a significant shift in the firing-rate distribution suggests that temporal structure, rather than firing rate, defines this transition. These population-level dynamics were firing-rate-dependent: high‑firing-rate neurons were more tightly modulated, whereas low‑firing-rate neurons exhibited more heterogeneous changes. Neither ketamine nor xylazine alone recapitulates these dynamics, suggesting their combined action creates a uniquely dynamic architecture. These findings reveal a continuous, firing-rate-dependent reorganization of single-neuron activity during ongoing delta-dominated states.
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by progressive loss of motor neurons and presents a critical need for effective treatments. To investigate the impact of TAR DNA-binding protein 43 (TDP-43) nuclear depletion in ALS, we established and characterized a human-induced pluripotent stem cell-derived motor neuron model carrying a mutation that disrupts TDP-43 nuclear localization. The model successfully recapitulates functional deficits observed in ALS patients, including impaired neurite outgrowth, reduced axonal regeneration, and neuronal hyperexcitability. Proteomic and metabolomic profiling revealed early mechanisms underlying ALS neuronal pathophysiology, involving altered oxidative stress and neurotransmitter release. TDP-43 nuclear depletion led to mis-splicing STMN2 and KCNQ2, defects characteristic of TDP-43-associated disease. Notably, a splice-switching antisense oligonucleotide successfully restored normal STMN2 splicing and function, demonstrating that directly correcting splicing defects can rescue motor neurons. This work provides a comprehensive understanding of TDP-43 nuclear depletion in the context of ALS pathogenesis and offers potential targets for RNA-targeted therapeutic intervention, pointing towards the development of precision medicine approaches and early diagnostic markers for ALS. A human iPSC-derived motor neuron model with TDP-43 nuclear loss reveals early ALS phenotypes including hyperexcitability and splicing defects, with antisense oligonucleotide therapy rescuing STMN2 function and neuronal deficits.
Adult hippocampal neurogenesis is perturbed in neurological disorders accompanied by seizures, including Alzheimer’s disease (AD). The molecular mechanisms by which seizures disrupt neurogenesis are unclear. Here, we report that follistatin (FST), an antagonist of TGFβ ligands, plays a pivotal role in seizure-induced dysregulation of neurogenesis. We find that FST expression is reduced in the dentate gyrus of a mouse model of AD neuropathology that exhibits infrequent spontaneous seizures similar to those in individuals with AD. Treatment with an antiseizure drug improves FST expression in AD mice, whereas a seizure-inducing agent suppresses FST expression in wild-type mice. We identify c-Fos, whose expression is suppressed by the seizure-induced transcription factor ∆FosB, as a transcriptional activator of Fst. Lastly, ablation of Fst dysregulates neurogenesis dynamics in wild-type mice, whereas FST treatment normalizes dynamics in AD mice. These findings reveal a previously unidentified activity-dependent mechanism in which the expression of FST controls neurogenesis dynamics.
