The Neural Basis of Aging

This review aims to examine the overlap in biological phenotypes following chronic 40 Hz sensory stimulation and other neuromodulation techniques in the gamma frequency range and to propose a theoretical mechanism of action that may help to inform future preclinical and clinical investigations. In Part 1, we provide a neuromodulatory framework as the mechanism of action of gamma range neurostimulation, dependent on a novelty/salience circuit consisting of phasic activation of hind-mid-, and basal forebrain nuclei, especially the locus coeruleus(LC); and downstream modulation of the neurogliavascular unit through astrocyte-dependent pathways. In Part 2, we review and emphasize the role of these hind-and midbrain nuclei in terms of attention, learning, consciousness, and sleep, as well as across a variety of neuropsychiatric disorders. This portion aims to highlight the critical importance of the brain regions and neural circuit proposed and their involvement in conscious experience. Part 3, to explain the significant impact of 40 Hz stimulation on Alzheimer's disease(AD), attempts to provide an evolutionary and functional framework for the core role of the LC-NE-(DA) system in novelty, evolutionary drive, and management of allostatic load, its potential role in normal vertebrate aging, and a hypothesis for LC-NE dysfunction and depletion as the key mechanism behind the development of amyloid plaques and AD, respectively. The goal of this work is to motivate future empirical investigations into 40 Hz stimulation, studies assessing the role of the LC-NE system in consciousness and neuropsychiatric disorders, and the fundamental role of the LC in vertebrate aging and AD.