A locus coeruleus-centric framework for novelty, salience, and gamma oscillations: implications for neurostimulation, aging, and disease

Abstract

Neuromodulation techniques in the gamma frequency range, such as chronic 40 Hz sensory stimulation, have gained attention for their potential to impact and preserve cognitive function in the context of neurodegenerative disorders such as Alzheimer’s disease (AD). This hypothesis and theory article aims to examine the overlap in biological phenotypes between gamma stimulation techniques and to propose a theoretical mechanism of action that may help to inform future empirical investigations. In Part 1, we provide a neuromodulatory framework related to a multifaceted novelty/salience circuit consisting of phasic activation of hind-, mid-, and basal forebrain nuclei, especially the locus coeruleus (LC); the release of norepinephrine (NE); the activation of cholinergic, dopaminergic, and serotonergic nuclei; and downstream modulation of the neurogliavascular unit through astrocyte-dependent pathways in order to reduce neuroinflammation, increase blood and glymphatic flow, promote synaptic plasticity and myelination, and improve hippocampal-dependent memory. We suggest various falsifiable experiments and testable modifications to stimulation paradigms based on this hypothesis. In Part 2, we review and explore the role of these hind- and midbrain nuclei and neuromodulators in terms of learning, allostatic load, consciousness, and sleep. To strengthen the initial hypothesis and highlight the significance of this proposed circuit, we cite observations of altered gamma oscillations across a variety of neuropsychiatric disorders, as well as speculate on the role of brainstem nuclei in current and potential treatments. This portion aims to emphasize the critical importance of the neural circuit proposed, its involvement in conscious experience, and to potentially inform future neuropsychiatric research and disease modeling, as well as indications for LC-NE or gamma frequency-based interventions. Part 3, in order to explain the significant impact of 40 Hz stimulation on Alzheimer’s disease and neurodegeneration, explores a hypothetical functional framework for the core role of the LC-NE system in novelty, evolutionary drive, and management of allostatic load, its potential role in vertebrate aging, and a hypothesis for LC-NE dysfunction and depletion as a significant upstream modulator of the development of amyloid plaques and Alzheimer’s disease, respectively. The goal of this work is to motivate future empirical investigations into 40 Hz stimulation paradigms and biomarkers proposed, studies assessing the role of the LC-NE system in the conduction of consciousness and alterations in neuropsychiatric disorders discussed, and into the potential role of the LC in vertebrate aging and the development of Alzheimer’s disease.