Preoptic/Hypothalamic Mechanisms of Sleep-Wake Regulation

睡眠觉醒调节的视前/下丘脑机制

• 批准号: 10341046
• 负责人: Noor Alam
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341046
• 关键词: Aging; Alzheimer' s Disease; Anti-Inflammatory Agents; Anxiety; Attenuated; Calcium; Cell Differentiation process; Cell Proliferation; Cells; Chronic; Ciliary Neurotrophic Factor; Cytosine; Data; Depressive disorder; Dorsal; Dose; Elderly; Elements; Environment; Exhibits; Exposure to; Functional disorder; Galanin; Health; High Prevalence; Human; Hypothalamic structure; Image; Impaired cognition; Impairment; Inflammation; Inflammatory; Infusion procedures; Internal Ribosome Entry Site; Lipofuscin; Lipopolysaccharides; Measures; Medial; Medical; Mental disorders; Mus; Nerve Regeneration; Neurites; Neurons; Outcome; Pathology; Persons; Pharmacology; Phenotype; Physiological; Preoptic Areas; Quality of life; Recovery; Regulation; Research; Risk; Role; Series; Sleep; Sleep Architecture; Sleep Deprivation; Sleep Fragmentations; Sleep Wake Cycle; Sleep disturbances; System; TNF gene; Therapeutic; Time; Treatment Factor; Veterans; aged; circadian; experimental study; fall risk; functional decline; gamma-Aminobutyric Acid; immunoreactivity; improved; inflammatory marker; insight; interdisciplinary approach; migration; neurogenesis; neuroinflammation; novel; novel therapeutics; poor sleep; preclinical study; precursor cell; programs; response; senescence; sleep health

ABSTRACT Chronic sleep disturbance is a frequent and challenging problem of human aging. In the US an estimated 39.6 million people including 8.5 million Veterans are aged 65 or older and at risk of developing chronic sleep disturbance. Chronic insufficient or disrupted sleep is associated with multiple adverse health outcomes, including increased risk of fall, cognitive decline, anxiety, depressive disorders, and Alzheimer's disease. Also, elderly Veterans have a high prevalence of medical and psychiatric disorders that can further aggravate sleep disturbance. Recently, we found that chronic suppression of hypothalamic cell proliferation in young mice produced sleep-wake features of aging including sleep disruption and poor response to sleep loss. Here, we proposes a series of novel preclinical studies that will use complimentary and cutting edge approaches to examine: a) if hypothalamic neurogenesis regulates sleep function by maintaining a supply of new cells to replace senescent sleep-regulatory ventrolateral preoptic area galanin (VLPOGAL) and GABA (VLPOGABA) neurons; b) if a disruption of hypothalamic neurogenesis, caused by chronic inflammation that accompanies aging, contributes to physiological dysfunction and or loss of the critical sleep-regulatory VLPOGAL and VLPOGABA neurons and consequent sleep disturbance in aging; and c) if sleep disturbance in aging could be mitigated by neuro-regenerative and anti-inflammatory approaches. Specific aim-1: will determine if hypothalamic neurogenesis is vital for maintaining the functioning of the VLPO sleep regulatory neuronal groups and that its impairment is a driver of their functional decline and sleep disruption in aging. We will determine the extent of cell proliferation, migration, and differentiation of precursor cells into sleep regulatory VLPOGAL and VLPOGABA neurons and their sleep-associated activation in young and old mice, and in young mice after chronic suppression of neurogenesis (experiment-1). We predict that old mice or mice with impaired hypothalamic neurogenesis will exhibit: a) a decline in cell proliferation and differentiation of precursor cells into VLPOGAL and VLPOGABA neurons, b) fewer VLPOGAL and VLPOGABA neurons exhibiting seep-associated Fos-immunoreactivity; and c) more sleep disruption. We will use calcium imaging to determine if VLPOGAL neurons exhibit a functional decline, paralleling the deficits in spontaneous and impaired homeostatic sleep responses in aging (experiment-2). We will use chemogenetic activation to determine the ability of VLPOGAL neurons to promote sleep after disrupting neurogenesis, a low grade inflammation, and after disrupting neurogenesis in the presence of a neurogenic factor to determine if a decline in the ability of VLPOGAL neurons to promote sleep after chronic suppression of hypothalamic neurogenesis is attenuated by ciliary neurotrophic factor (CNTF). Specific aim-2: will determine if increasing hypothalamic cell proliferation and neurogenesis of VLPO sleep regulatory neurons improves sleep architecture and sleep continuity in old mice. We will determine if in aged mice, sustained induction of hypothalamic cell proliferation by ICV infusion of CNTF, a neurogenic factor with a protective role against neuroinflammatory pathologies, increases migration and differentiation of neurites into mature VLPOGAL neurons; decreases neuroinflammation and senescence; and reduces sleep fragmentation (experiment-4). We will use chemogenetic activation to determine if the ability of VLPOGAL neurons to promote sleep improves after CNTF treatment in old mice (experiment-5). The data obtained from these preclinical studies would provide insights into the mechanisms underlying sleep disruption in aging. Our studies also include pharmacological elements that could provide therapeutic options for optimizing sleep health in the elderly including elderly Veterans

摘要