The cholinergic system during normal and pathological aging

National Institute Of Neurological Disorders And Stroke

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Abstract

Our studies of cognitive changes with aging employ behavioral, high resolution live imaging, in vivo and ex vivo electrophysiological assays and assays of cognitive function with an emphasis on changes in cholinergic modulation of entorhinal cortex and ventral subicular circuits. In addition, intersectional genetic markers are used to monitor changes in level and extent of activation of the BFCNs that innervate entorhinal and ventral subicular networks as a function of aging. These studies examine behavioral performance with a focus on displaced object recognition and cue and context evoked aversive memories. The aging program also includes (a) assay of cholinergic axonal terminal field with respect to mitochondrial morphology and mobility and (b) examination of inflammatory markers relative to changes in cholinergic input, alterations in terminal field morphology and loss of somatic markers of cholinergic neurons in the basal forebrain. The major changes as function of aging and cognitive decline that we have documented to date indicate a retrograde loss of cholinergic terminal fields long before any changes in BFCN number can be discerned. Considerable effort has been on comparative studies related to age associated changes in cognitive processing in rodent, human and non-human primate (NHP). These involve comparisons of basal forebrain cholinergic neurons and their terminal field density as a f(age). The NHP studies, which are currently restricted to ex vivo (slice) examination have been greatly aided by joining the trans NIH NHP collaborative consortium a group of electrophysiologists from multiple ICs that share post-surgical / post-mortem brain tissue in an effort to maximally utilize this precious resource. These collaborative studies should shortly yield a manuscript detailing intrinsic properties and morphological features of basal forebrain cholinergic and non-cholinergic neurons from mouse and monkey tissue. Our results span multiple ages in all species and to date are consistent with related changes in BFCNs with aging. Some aspects of the Aging project also involved continued collaboration with individuals at universities that were more open to operation. Multiple publications on the comparative studies of mouse and humans with cognitive decline are still in preparation.