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Bidirectional regulation of social memory by two distinct types of GABAergic neurons in the lateral septum

ABSTRACT: Humans and animals memorize and recognize familiar conspecifics during social interactions, known associal memory. While the hippocampus is crucial for social memory, the dynamic regulation social memory, particularly the negative regulation, remains unclear. Here, we identified two molecularly distinct subpopulations of GABAergic neurons in the mouse lateral septum(LS) expressing somatostatin(SST) and calbindin1(CB), respectively, with complementary distribution patterns. Activation of SST+ neurons enhances social memory acquisition, whereas activation of CB+ neurons inhibits it. Optogenetic manipulation of SST+ neurons regulates theta rhythm oscillations, correlating with their impact on social memory. SST+-dLS neurons and CB+-vLS neurons preferentially receive stronger excitatory inputs from the dorsal (vCA1d) and ventral(vCA1v) parts of vCA1, respectively. The vCA1d→SST+-dLS→lateral hypothalamic area (LHA) circuit positively regulates social memory acquisition, whereas thevCA1v→CB+-vLS→anterior hypothalamic nucleus (AHN) pathway negatively regulates it. This study uncovers two parallel subcortical neural circuits underpinning the dynamic regulation of social memory.

ORGANISM(S): Mus musculus

PROVIDER: GSE273782 | GEO | 2026/01/13

REPOSITORIES: GEO

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Project description:Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease(AD), which is closely related to tau pathology and hippocampal impairment. Given the heterogeneity of brain neurons, the precise role of different brain neurons in terms of their sensitivity to tau accumulation and contribution to AD-like social memory loss remains unclear and requires further investigation. Methods: We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic experiments, social behavioral test, hippocampal electrophysiology, immunofluorescent staining and in vivo optical fiber recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine their effects on social memory in mice. Results: By proteomic and phosphoproteomic analyses, we identified the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, not dorsal CA1 (dCA1), but vCA1, especially its excitatory and PV neurons, were fully filled with mislocated and phosphorylated tau. Overexpression of human Tau (hTau) in excitatory and PV neurons respectively mimicked AD-like tau accumulation, significantly inhibited the neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythm and time-window efficiently ameliorated tau-impaired social memory. Significantly, one-month administration of UA efficiently decreased tau accumulation via autophagy in a TFEB (transcription factor EB)-dependent manner and recovered vCA1 microcircuit to ameliorate tau-impaired social memory.Conclusion: This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1, and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for AD treatment in the future.

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Bidirectional regulation of social memory by two distinct types of GABAergic neurons in the lateral septum

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