Single-nucleus transcriptome atlas of the basal forebrain reveals diverse ageing-related pathways

Abstract The basal forebrain is a critical brain region involved in various neurobiological processes, including learning, memory, and attention. Basal forebrain cells undergo structural and functional changes during ageing, increasing their vulnerability to neurodegenerative diseases. To reveal the molecular landscape of distinct cell types during developmental and early ageing, we constructed a comprehensive single-nucleus transcriptomic atlas spanning postnatal day 4 (P4), postnatal day 14 (P14), 3 month (3M), 9 months (9M) and 15 months (15M). Distinct molecular regulatory patterns of basal forebrain subclasses and ageing-related pathways were unveiled. The transcriptional regulation analysis and pseudo-time analysis revealed the dynamic regulatory network of cholinergic neurons during postnatal development. To gain insights into the relationship between ageing and Alzheimer's disease (AD), we conducted an integrative analysis. We identified four potential regulatory networks involved in cholesterol/lipid metabolism, DNA damage repair, and death receptor signal in 5×FAD mice. The cholinergic subtype CN-2 exhibited heightened activity of regulons associated with Srebf2 and Zmiz1, which, in turn, target hub genes implicated in these networks. Meanwhile, CN-2 is the main cholinergic subtype contributing to the alteration of the NRXN signalling pathway. This study offers a significant data source to elucidate the molecular underpinnings of ageing-related and pathological changes in the basal forebrain, paving the way for future research and therapeutic interventions that target specific basal forebrain subclasses and signalling pathways.