Restoring Septohippocampal Cholinergic Signaling Rescues Surgery-Induced Neurogenesis and Memory Deficits in Aged Mice.

Abstract

Central cholinergic dysfunction contributes to postoperative cognitive dysfunction (POCD) in the aged, yet the specific circuit mechanisms remain poorly defined. Here, we investigated the role of cholinergic projections from the medial septum/vertical limb of the diagonal band (MS/vDB) to the dentate gyrus (DG) in surgery-induced cognitive and neurogenic impairments in aged mice. Using a laparotomy model, we found that surgery led to memory deficits and suppressed adult hippocampal neurogenesis (AHN). In vivo fiber photometry revealed reduced hippocampal acetylcholine (ACh) release and decreased activity of MS/vDB cholinergic neurons. Local potentiation of DG cholinergic signaling with the acetylcholinesterase inhibitor galantamine rescued both memory deficits and AHN. Whereas acute chemogenetic activation of MS/vDB → DG projections alleviated anxiety-like behavior, only sustained activation of this pathway restored memory function and promoted neurogenesis. Together, these results establish a causal link between loss of MS/vDB → DG cholinergic signaling and POCD-related phenotypes, and demonstrate that restoring this specific input rescues neurogenesis and memory, highlighting its therapeutic potential.