ABSTRACT Memory generalization is essential for adaption to novel circumstances through experiential learning, leading to behavioral flexibility and survival capability. However, its underlying neural mechanisms remain to be elucidated. This study designed 8‐arm‐maze‐based tasks to reveal how the hippocampal CA3 associates with the generalization of spatial working memory. Mice successfully transferred the learned rule to novel task configurations, but the efficiency was inversely correlated with task difficulty. In vivo electrophysiological recordings of the CA3 showed that single‐unit and population activity in the CA3 reflected this behavioral transition. On testing day 1, neuronal firing and population trajectories robustly distinguished in relatively simple tasks, but not in more difficult tasks. On testing day 2, as behavioral performance improved, the representational differences of the CA3 neuronal population across different tasks gradually decreased. Decoding analysis revealed that task discriminability based on population activity decreased over time, indicating CA3 neural coding is shifting toward a more generalized pattern. Feature elimination analysis further demonstrated that CA3 neurons employ a sparse but redundant coding scheme to support generalization. Together, the observed neural and behavioral changes are consistent with the emergence of generalized task representations, indicating experience‐dependent reorganization of CA3 population activity during memory generalization across task configurations.
Da Song, Zi-Lu Zhu, Yujun Deng et al.· Advancement of science· 0 citations
While amyloid-β (Aβ) has historically dominated the research landscape of Alzheimer’s disease (AD), the limited clinical success of Aβ-centric therapies has redirected focus toward tau pathology, which correlates more robustly with cognitive deterioration and synaptic dysfunction. Transcending the traditional linear pathological model, this review reframes tau phosphorylation as a dynamic hub within a multi-scale regulatory network. We first synthesize recent breakthroughs in molecular mechanisms, detailing how the kinase-phosphatase equilibrium, cross-regulation of diverse post-translational modifications (PTMs), nuclear envelope damage, iron metabolism and ferroptosis collectively drive the transition from soluble tau species to neurofibrillary tangles (NFTs). Beyond neuronal boundaries, we elucidate how pathological tau orchestrates systemic neurotoxicity by synergizing with Aβ deposition to trigger neuroinflammation, blood-brain barrier breakdown, and gut-brain axis dysregulation. Finally, we bridge these mechanistic insights with translational advancements, evaluating next-generation biofluid biomarkers and innovative therapeutic modalities—ranging from small-molecule inhibitors to Dephosphorylation-Targeting Chimeras (DEPTACs)—currently under clinical investigation. This integrated perspective offers a holistic framework for understanding AD pathogenesis and provides a roadmap for the development of precision medicine strategies targeting the tau interactome.
Xue Li, Lei-Han Zhang, Li-Jun Zhao et al.· Journal of Translational Med...· 0 citations
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