Neuron最新文献

Gut dysbiosis has been implicated in epilepsy, yet probiotic efficacy and mechanisms remain unclear. Here, we identify that Bacteroides fragilis (B. fragilis) is markedly reduced in children with epilepsy and show that oral B. fragilis administration suppresses seizures in both pentylenetetrazole- and kainic-acid-induced mouse models. Mechanistically, B. fragilis activates colonic choline acetyltransferase-positive (ChAT⁺) cells and enhances gut-vagus-brain cholinergic signaling, as demonstrated by vagal recordings, pharmacological blockade, and chemogenetic manipulation, identifying a colonic ChAT⁺-nodose ganglion circuit mediating seizure suppression. Its antiseizure effects associate with enriched intestinal Lactobacillus colonization. A randomized clinical trial (CHiCTR2100042203) further confirms the therapeutic efficacy of B. fragilis in pediatric refractory epilepsy. These findings define a gut-brain cholinergic pathway through which B. fragilis exerts antiseizure effects and establish a mechanistic basis for microbiota-targeted therapies in epilepsy.

One of the largest glial populations outside the brain is in the gut. These enteric glia are involved in many functions, from intestinal peristalsis to immunity, yet it is unclear whether subtypes exist with distinct roles in homeostasis. Comparing glia from divergent microenvironments in the mouse intestine, we found that mucosal glia most resembled microglia, while muscularis glia resembled satellite glia. Tacr3, encoding the receptor for neuropeptide neurokinin B (NKB), was enriched within muscularis glia associated with neuronal soma and was undetectable in extraintestinal glia. Genetic or pharmacological manipulation of NKB-TACR3 signaling disrupted the establishment of enteric glial populations during postnatal development and dynamically modulated intestinal motor behaviors in adult mice. Collectively, we delineate spatially, transcriptionally, and functionally distinct populations of enteric glia; identify one as an unanticipated target of TACR3 antagonists in clinical use; and establish this pathway as necessary for enteric glial diversification and function.

Active ensembles of neurons form an engram during learning. However, engrams are not immutable, and their organization may change with time via systems consolidation. Here, we labeled engram ensembles in the prelimbic (PrL) cortex during contextual fear conditioning. We found that distinct engram subpopulations ("sub-engrams") contribute to memory recall at recent versus remote delays, with sub-engram contribution determined by their projection profile. At recent delays, sub-engrams projecting to the basal amygdala (BA) and lateral entorhinal cortex (LEC) are activated, and their activity is necessary and sufficient for memory retrieval. At remote delays, sub-engrams projecting to the nucleus reuniens (NRe) and nucleus accumbens (NAc) are additionally recruited, and their activity is necessary and sufficient for memory retrieval. Recruitment of NRe- and NAc-projecting sub-engrams to remote recall is an active process, depending on post-training activation of PrL parvalbumin-expressing interneurons. Post-training chemogenetic inhibition of PrL parvalbumin-expressing interneurons prevented sub-engram recruitment and impaired remote memory.

We previously reported that T96K is a gain-of-function mutation in TREM2 based on its ability to increase ligand-dependent activation. Here, we show that TREM2^T96K increases risk for Alzheimer's disease (AD) in a whole-genome sequencing dataset comprised of family-based and case-control samples. Trem2^T96K also reduced clustering of microglia around β-amyloid (Aβ) plaques exclusively in female 5xFAD mice. Furthermore, T96K decreased levels of soluble Trem2 in female 5xFAD mice and human microglial cell cultures. We also observed impaired uptake of Aβ in Trem2^T96K knockin microglial cells. Moreover, Trem2^T96K reduced total area of phagocytic microglia, specifically in female 5xFAD mice. Single-cell RNA sequencing (scRNA-seq) profiling of microglia revealed that Trem2^T96K impairs the transition of homeostatic microglia into disease-associated microglia (DAM) in female 5xFAD mice. Downregulated inflammatory pathways associated with Trem2^T96K included interleukin (IL)-6/JAK/STAT3, complement, and interferon (IFN)-γ response. Collectively, our results indicate that, like the loss-of-function mutation R47H, Trem2^T96K adversely affects microglial function in a sex-dependent manner.