Cognitive deficits in Alzheimer's disease (AD) have been associated with synapse loss and chronic inflammatory activation of microglia in cortex and hippocampus. Arousal-promoting locus coeruleus (LC) neurons densely project to memory-related regions of association cortex, where they release norepinephrine (NE). This NE release facilitates synaptic plasticity in neurons and drives anti-inflammatory effects in local microglia. Notably, LC neurons are among the first to degenerate in AD. Together, these findings have led to the hypothesis that early loss of LC neurons may impair cognition in AD via decreased arousal, decreased synaptic plasticity, and increased synapse loss due to inflammatory activation of phagocytic microglia. Further, recent theories posit that sustained peripheral inflammation in aging and AD may ultimately drive degeneration of LC neurons, via dysregulation of the pathway from the vagus nerve to LC via the nucleus of the solitary tract. Accordingly, chronic vagus nerve stimulation (VNS) has been used to treat drug-resistant depression, a risk factor for AD. Further, chronic VNS has shown promise in preliminary studies in AD patients, resulting in improved cognition and delayed disease progression. The behavioral effects of VNS are hypothesized to be due to increased activation of the remaining LC neurons and a resulting increase in NE release in cortex and hippocampus. However, animal studies show that VNS does not drive release of NE at low stimulation intensities. At higher intensities, VNS delivery in humans can result in uncomfortable sensations (e.g. in the throat and neck) and cough/bradycardia due to off-target effects of bulk electric stimulation of the vagus nerve. These off-target effects represent serious obstacles to clinical efficacy. Here, we propose to develop novel strategies for improved VNS via chronic stimulation of specific subsets of vagal nerve afferents innervating particular organs. Our goal is to use mouse models to develop a stimulation protocol that effectively drives NE release in cortex at levels sufficient to regulate arousal, synaptic plasticity, and microglial activation, but that does not drive conscious awareness of the stimulation. First, we will develop protocols for stimulation of specific genetically and anatomically defined sets of vagal afferents, to improve both release of NE and tolerability. We will then use 3D two-photon imaging in awake mice to ask if, at vagal afferent stimulation intensities below the threshold for behavioral detection, sufficient NE is released to drive molecular signaling in cortical dendritic spines and microglia. We will then use this stimulation approach to revert inflammatory activation of microglia in a model of Alzheimer's disease. We are uniquely poised to rapidly achieve this goal, by building on efforts in our lab involving studies of conscious awareness of stimulation of specific vagal afferent subtypes in mice (DP1 parent grant), our preliminary data imaging/stimulating LC axons in cortex and imaging A?-evoked changes in cortical microglia. These experiments will support a novel research direction to strategies for understanding and treatment of AD.

Public Health Relevance

This proposal will investigate the mechanisms underlying attention to signals from various body organs. To achieve this goal, we will combine mouse genetics and behavior with optogenetic manipulation and recording of specific body signals to the brain, and of associated neuromodulatory activity. A detailed understanding of interoception ? the sensation of body signals -- will spur entirely new lines of treatment for disorders involving dysregulation of brain-body communication including depression, anxiety, cardiovascular diseases, respiratory-related disorders such as sleep apnea, arthrogryposis, and sudden infant death syndrome, eating disorders including obesity and anorexia nervosa, irritable bowel syndrome, chemotherapy-induced nausea/vomiting, pain, and, with this proposed Supplement, novel vagal nerve stimulation therapies for Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
3DP1AT010971-02S1
Application #
10117356
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Chen, Wen G
Project Start
2019-09-30
Project End
2024-07-31
Budget Start
2020-09-07
Budget End
2021-07-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215