GABAergic basal forebrain integrity is compromised in aged monkeys with cognitive impairment

Authors

• C Banuelos
• KH Schulze
• JR Kittleson
• EJ Perez
• JM Long
• MT Roberts
• S Fong
• PR Rapp

Abstract

The search for strategies to promote healthy cognitive aging has taken on increased urgency as people live longer. Basal forebrain projections to the cortex are anatomically positioned to influence a broad range of cognitive capacities including attention, executive function and memory. Although a long history of research on neurocognitive aging has focused on the role of the cholinergic basal forebrain system, intermingled GABAergic cells are numerically as prominent and well-positioned to regulate the activity of their cortical projection targets, including the hippocampus and prefrontal cortex. The effects of aging on the non-cholinergic basal forebrain in primates, however, are largely unknown. In this study, we conducted quantitative morphometric analyses in brains from young adult and aged rhesus monkeys that displayed significant impairment on standard tests that require the prefrontal cortex and hippocampus. Cholinergic (ChAT+) and GABAergic (GAD67+) neurons were visualized by immunocytochemistry in evenly spaced histological sections through the medial septal nucleus, nucleus of the diagonal band, and the nucleus basalis of Meynert. Morphometric quantification revealed a significant decrease in GAD67+ cell number in the basal forebrain of aged monkeys compared to young. Parallel counts in adjacent sections demonstrated that ChAT+ cell number is preserved in the aged monkey basal forebrain. Additionally, GAD67+ neuron volume was increased selectively in aged monkeys that performed on par with young on the DNMS task. This effect may represent compensatory mechanisms resulting in preserved visual recognition memory at advanced age. These findings raise the possibility that GABAergic basal forebrain integrity represents a novel target for efforts to promote healthy trajectories of cognitive aging.

Scientific Focus Area: Neuroscience

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