Adult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging

Abstract

Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically in uence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections cumulatively across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in an accelerated decline in hippocampal acetylcholine signaling and a slow and progressing emergence of profound working memory de cits. These de cits were accompanied by compensatory reorganization of cholinergic dentate gyrus inputs with increased cholinergic innervation to the ventral hippocampus and recruitment of ventrally projecting neurons by the dorsal projection. While increased cholinergic innervation was dysfunctional and corresponded to overall decreases in cholinergic levels and signaling, it could be recruited to correct the resulting memory dysfunction even in old animals. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal cholinergic circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.

Metformin inhibits inflammatory response and endoplasmic reticulum stress to improve hypothalamic aging in obese mice

“…Previous studies have shown that neurons undergoe a progressive decline in functionality with age, resulting in a memory and cognition decline. 6 Aging is the leading risk factor for neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease. 7 As post-mitotic cells, senescent neurons, similar to other post-mitotic cells, exhibit senescent features such as increased SA-β-gal activity and enhanced expression of γH2AX and p16, rather than cell-cycle arrest.…”