Neural Circuit Mechanisms of Stress-Induced Insomnia and Metabolic Dysfunction
Abstract
FY21 PRMRP Topic Areas: Sleep disorders and restriction; musculoskeletal health; diabetes Insomnia (inability to have consolidated, restorative sleep) is highly prevalent across the developed world. A leading theory about the cause of insomnia posits that it is due to hyper-activation of parts of the brain that control arousal (called hyperarousal). A well-known and major contributor to insomnia is stress, that is, a chronic stressful experience (either real or perceived) is frequently associated with the development of long-lasting insomnia. Stress-induced insomnia is frequently associated with other serious conditions involving the regulation of energy stores in the body. These include atherosclerosis, type II diabetes, obesity, and metabolic syndrome. Recent research has demonstrated that a major population of brain cells (neurons) in the hypothalamus that control stress responses directly connect to neurons that promote arousal. This suggests that stress and arousal are fundamentally linked via discrete brain circuits. However, despite these advances, scientists still do not know how stress-associated insomnia drives the development of metabolic disease. This is a major concern as these types of conditions are common and are frequently debilitating and/or deadly. Additionally, these diseases are more common in members of the military and those that undergo substantial stress as part of their day-to-day life, highlighting the critical need for basic research in this domain. To address this gap in knowledge, the team will turn to mouse models of stress to tease apart the underlying circuitry driving these phenomena. Based on prior work, the team hypothesizes that stress-induced insomnia and metabolic dysfunction share common neural circuit components within the brain. To test this, the team will monitor the activity of genetically defined cells within the hypothalamus during and following chronic stress. To link this to insomnia and hyperarousal, the team will simultaneously measure sleep/wake states throughout and after the stressful experience. The researchers will assess how stress alters metabolic state by measuring energy expenditure (calories), running activity, and the levels of gene expression within various tissues (e.g., muscle, liver, fat). Once the team has a clear understanding of the effects of stress on sleep and metabolism, they will test whether specific cells within the hypothalamus are sufficient to promote the same problems in the absence of stress. This will link the subjective experience of stress to a real and malleable neural circuit. Then, the team will map the projections of these neurons to understand what other brain areas these cells communicate with, allowing for the identification of potential targets controlling stress-associated insomnia and metabolic disruption. Then, they will test the role each of these targets plays by stimulating hypothalamic cells that only project to these regions. Finally, they will test whether the observed effects are reliant on an intact stress axis (also known as the HPA axis) by using viruses to knock down a major gene in hypothalamic neurons (i.e., crf), removing the adrenal glands (which produce the stress hormone corticosterone), and removing the fight-or-flight nervous system in the body (called the sympathetic nervous system). Together, these studies will causally link stress-induced insomnia to subsequent metabolic disruption via a targetable, discrete neural circuit. If the ideas are supported by the experiments, this will open up new targets and strategies to combat diseases and conditions that are intimately related to stress. Additionally, it will set the stage for further work to characterize major pathways of brain-body communication, which will contribute to many other areas of biology and health. Given the prevalence of stress-associated conditions within members of the military and Veterans, this work has the potential to improve
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210045
Entities
People
- Jeremy Borniger
Organizations
- Cold Spring Harbor Laboratory
- United States Army