Loss of septal cholinergic input to lateral entorhinal cortex is an early indicator of cognitive impairment

Abstract

Abstract Although alterations to central cholinergic signaling are characteristic of late-stage cognitive deficits, the early temporal profile of these alterations and their relationship to more subtle changes in cognition are less clear. In a series of translational experiments in humans and mice, we evaluated whether changes to the cholinergic system were an early feature of pathological aging. Additional studies in mice assessed the effects of selective perturbations of cholinergic signaling on cognitive performance. We focus on the cholinergic innervation of the entorhinal cortex (EC), a region that is recognized to be susceptible early in aging and neurodegenerative disease. In human studies we recruited older adult volunteers that were physically healthy and without clinical diagnosis of cognitive impairment. Participants were divided based on their cognitive status during the intake session. Using positron emission tomography (PET) with a tracer specific for the vesicular acetylcholine transporter ([18F]VAT) we demonstrate that loss of cholinergic input to the EC is an early occurrence in cognitive impairment. These deficits are specific to the cholinergic circuit between the medial septum and vertical limb of the diagonal band (MS/vDB; CH1/2) to the EC. We further demonstrate impaired structural connectivity in the tracts between the MS/vDB and EC in cognitively impaired, older adults. Mouse experiments, designed to parallel the human studies, used high resolution terminal field imaging to compare normal aged mice with a genetically modified line with accumulation of amyloid beta plaques and spontaneous hyperphosphorylation of mouse tau. Across species we find that the integrity of cholinergic projections to the EC directly correlates with performance in EC-related object recognition memory tasks. We further establish the role of the MS/vDB regions of the cholinergic basal forebrain in object location memory by demonstrating that silencing EC-projecting cholinergic neurons in normal animals is sufficient to impair object recognition performance. Taken together we identify a role for acetylcholine in normal EC function and establish loss of cholinergic input to the EC as an early, conserved feature in age-related cognitive decline.