Abstract
BackgroundCholinergic neuronal dysfunction of the basal forebrain is observed in patients with Alzheimer's disease and dementia, and has been linked to decreased neurogenesis in the hippocampus, a region involved in learning and memory. Running is a robust inducer of adult hippocampal neurogenesis. This study aims to address the effect of running on hippocampal neurogenesis in lesioned mice, where septohippocampal cholinergic neurones have been selectively eliminated in the medial septum and diagonal band of Broca of the basal forebrain by infusion of mu-p75-saporin immunotoxin.ResultsRunning increased the number of newborn cells in the dentate gyrus of the hippocampus in cholinergic denervated mice compared to non-lesioned mice 24 hours after injection of bromodeoxyuridine (BrdU). Although similar levels of surviving cells were present in cholinergic depleted animals and their respective controls four weeks after injection of BrdU, the majority of progenitors that proliferate in response to the initial period of running were not able to survive beyond one month without cholinergic input. Despite this, the running-induced increase in the number of surviving neurones was not affected by cholinergic depletion.ConclusionThe lesion paradigm used here models aspects of the cholinergic deficits associated with Alzheimer's Disease and aging. We showed that running still increased the number of newborn cells in the adult hippocampal dentate gyrus in this model of neurodegenerative disease.
Highlights
Cholinergic neuronal dysfunction of the basal forebrain is observed in patients with Alzheimer's disease and dementia, and has been linked to decreased neurogenesis in the hippocampus, a region involved in learning and memory
We showed that running still increased the number of newborn cells in the adult hippocampal dentate gyrus in this model of neurodegenerative disease
According to the "cholinergic hypothesis of Alzheimer's disease (AD)" posited more than two decades ago, the symptoms of failing cognitive function associated with AD and advanced age are attributed to cholinergic neuronal dysfunction [8,9]
Summary
Cholinergic neuronal dysfunction of the basal forebrain is observed in patients with Alzheimer's disease and dementia, and has been linked to decreased neurogenesis in the hippocampus, a region involved in learning and memory. According to the "cholinergic hypothesis of AD" posited more than two decades ago, the symptoms of failing cognitive function associated with AD and advanced age are attributed to cholinergic neuronal dysfunction [8,9] This idea is backed by studies linking the mnemonic functions of the cortex and hippocampus to the cholinergic system [10,11] and the association of cognitive deficits with the severity of the loss of basal forebrain cholinergic neurones [12,13]. One of the most striking inducers of neural progenitor cell division in the dentate gyrus is the simple behavioural act of running [35,36,37,38]
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