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BLR&D Research Career Scientist Award

BLR

基本信息

批准号：
9899085
负责人：
Ronald Szymusiak
金额：
--
依托单位：
VA GREATER LOS ANGELES HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9899085
关键词：
ADORA2A gene Acute Adenosine Adenovirus Vector Adult Agonist Amygdaloid structure Anatomy Animal Model Anxiety Disorders Arousal Award Brain Brain Stem Cell Nucleus Chronic Chronic stress Collaborations Corticotropin-Releasing Hormone Development Disease Disease model Dorsal Drowsiness Electroencephalography Exposure to FOS gene Felis catus Financial compensation Foundations Functional disorder Goals Homeostasis Hypoglossal nerve structure Hypothalamic structure Laboratories Lateral Link Mediating Mental Depression Mental disorders Metabolism Microdialysis Mood Disorders Motor Neurons Mus Muscle National Institute of Neurological Disorders and Stroke Neurobiology Neurological outcome Neurons Neuropeptides Neurotransmitters Odors Phenotype Population Post-Traumatic Stress Disorders Preoptic Areas REM Sleep Rattus Recovery Recurrence Research Rodent Model Role Scientist Severities Signal Transduction Sleep Sleep Deprivation Sleep Disorders Sleep Fragmentations Sleep disturbances Sleeplessness Source Stress Symptoms Synapses System Testing Therapeutic Intervention Time Tracer Transgenic Organisms Traumatic Brain Injury United States National Institutes of Health Veterans Wakefulness Work acute stress career combat common symptom design experimental study extracellular fluid percussion injury functional status hypocretin hypothalamic-pituitary-adrenal axis improved outcome mouse model nervous system disorder non rapid eye movement optogenetics paraventricular nucleus postsynaptic preoptic nucleus preservation pressure resilience response sleep abnormalities sleep regulation stressor targeted treatment

项目摘要

PROJECT SUMMARY Insomnia and disturbed sleep are common symptoms in mood and anxiety disorders. Nocturnal sleep disruption is a frequent complaint following traumatic brain injury (TBI). Previous work in my laboratory has identified systems of GABAergic neurons in the preoptic hypothalamus that have critical sleep regulatory functions. GABAergic neurons in the median preoptic nucleus (MnPO) and the ventrolateral preoptic area (VLPO) are activated during sleep. Adenosine is a critical endogenous sleep regulatory factor, important in the expression of homeostatic responses to sleep loss. We have shown that MnPO/VLPO neurons are activated by A2A adenosine receptor agonists. We have recently demonstrated that discharge of MnPO/VLPO neurons is dynamically responsive to changing homeostatic sleep drive during sleep deprivation and recovery sleep. We have further shown that during development, functional maturation of MnPO/VLPO GABAergic sleep regulatory systems underlies the development of sleep homeostasis. Our overarching hypothesis is that disruption of homeostatic responses to sleep loss due to dysfunction of preoptic hypothalamic sleep regulatory circuits contributes to sleep disturbances in mood and anxiety disorders and TBI. We will test this hypothesis using animal models of these disorders. We will also expand our understanding of the fundamental interactions between hypothalamic and brainstem arousal state-regulatory circuits in normal and disordered sleep. Brain levels of corticotrophin-releasing factor (CRF), a critical neuropeptide regulator of the HPA axis, are chronically elevated in anxiety disorders and posttraumatic stress disorder (PTSD). CRF has well characterized wake-promoting/sleep-disruptive effects. We hypothesize that activation of CRF neurons occurring in response to acute and chronic stress disrupts sleep homeostasis. We further hypothesize that CRF effects on sleep homeostasis are mediated through suppression of the activity of sleep-regulatory GABAergic neurons in the preoptic hypothalamus and rostral medulla. We will use transgenic CRF-cre mice and adenoviral vectors to optogenetically and chemogenetically manipulate CRF-signaling in the brain, and determine the effects on sleep homeostasis, functional activity of preoptic and medullary sleep regulatory neuronal populations and the sleep disruptive effects of acute and chronic stressors. Sleep-wake disturbances following TBI include daytime sleepiness, nocturnal sleep fragmentation, insomnia and alterations in the sleep EEG. Previous work has shown that in mouse models of TBI, excessive sleepiness is associated with reduced activation of orexin neurons. In collaboration with colleagues at the Portland VA who have expertise in TBI, we have generated preliminary findings that sleep-related activation of MnPO neurons is dramatically reduced after cortical fluid percussion injury in mice. We will pursue these preliminary findings and examine the functional status of GABAergic sleep- regulatory neurons in the preoptic area and of orexin neurons in the lateral hypothalamus following TBI, and correlate the functional activity in these neuronal systems with the sleep-wake phenotype at different times after brain trauma. In work supported by NIH/NINDS, we will examine interactions between GABAergic circuits in the preoptic hypothalamus and brainstem that regulate the switching among waking, nonREM and REM sleep. The findings derived from these studies will be a foundation for understanding the involvement of these circuits in sleep disruption accompanying psychiatric and neurological disorders.

项目总结