Neural Basis of Aging

Gamma oscillations within the sensory cortices have been shown to play a key role in feature binding, multisensory information encoding, selective attention, and increased information transmission to the hippocampus. The process of the cortex promoting arousal, attention, and determining novelty is thought to rely on a complex interplay of dopaminergic and noradrenergic signaling for contextual novelty and cholinergic and noradrenergic signaling encoding absolute novelty. Gamma entrainment using sensory stimulation (GENUS) has been found to have significant impacts on 1) glial cells and neuroinflammation 2) increasing blood and glymphatic flow 3) plasticity, neurogenesis, and preventing neurodegeneration, and 4) hippocampal dependent memory in preclinical models of Alzheimer’s disease (AD) and neurodegeneration. Related phenotypes have been observed in a variety of disease models including chemobrain, multiple sclerosis, and stroke. Additionally, similar results have been observed using vagus nerve and transcranial stimulation in the gamma range. We propose a mechanism in which the positive impact of GENUS and gamma range stimulation is largely mediated by activation of midbrain nuclei, promotion of noradrenergic and cholinergic signaling, influencing of glial and synaptic dynamics, and promotion of circuit health. We would hypothesize that these phenotypes are based on neuromodulatory communication and diffusion rather than direct neuron-glia interactions within the cortex or corticocortical communication. We discuss the ways in which this circuit has been shown to be functionally impacted by the pathophysiology of AD and its relationship with cognitive reserve and decline. Finally, we discuss improvements in stimulation protocol to more directly promote this signaling pathway.