Preoptic/Hypothalamic Mechanisms of Sleep-Wake Regulation

睡眠觉醒调节的视前/下丘脑机制

• 批准号: 10014924
• 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/10014924
• 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; 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 慢性睡眠障碍是人类衰老过程中常见且极具挑战性的问题。在美国和 据估计，有3960万人，其中包括850万退伍军人，年龄在65岁或以上，有罹患 慢性睡眠障碍。慢性睡眠不足或睡眠障碍与多种不良健康状况有关 结果，包括摔倒风险增加、认知能力下降、焦虑、抑郁障碍和阿尔茨海默氏症 疾病。此外，老年退伍军人的医疗和精神障碍患病率很高，可能会进一步 加重睡眠障碍。 最近，我们发现慢性抑制幼鼠下丘脑细胞的增殖 产生衰老的睡眠-觉醒特征，包括睡眠中断和对睡眠缺失的反应不佳。这里, 我们提出了一系列新的临床前研究，将使用免费和尖端的方法 检查：a)下丘脑神经发生是否通过维持新细胞的供应来调节睡眠功能 替代衰老的睡眠调节腹外侧视前区甘丙素(VLPOGAL)和GABA(VLPOGABA) 神经元；b)如果下丘脑神经发生中断，由伴随的慢性炎症引起 衰老，导致生理功能障碍和或失去关键的睡眠调节VLPOGAL和 VLPOGABA神经元和随之而来的衰老中的睡眠障碍；以及c)衰老中的睡眠障碍 通过神经再生和抗炎方法缓解。 特定目标-1：将确定下丘脑神经发生是否对维持脑组织功能至关重要 VLPO睡眠调节神经元群，其功能障碍是其功能下降和 在衰老过程中的睡眠障碍。我们将确定细胞增殖、迁移和分化的程度 睡眠调节性VLPOGAL和VLPOGABA神经元的前体细胞及其睡眠相关激活 在年轻和老年小鼠中，以及在慢性抑制神经发生后的年轻小鼠中(实验1)。我们 预测老年小鼠或下丘脑神经发生受损的小鼠将表现出：a)细胞减少 前体细胞的增殖和分化为VLPOGAL和VLPOGABA神经元，b)VLPOGAL较少 VLPOGABA神经元表现出与SEEP相关的Fos免疫反应；以及c)更多的睡眠干扰。我们 将使用钙成像来确定VLPOGAL神经元是否表现出与缺陷平行的功能衰退 衰老中的自发和受损的稳态睡眠反应(实验2)。我们将使用 VLPOGAL神经元干扰后促进睡眠能力的化学激活 神经发生，一种低度炎症，在神经原性存在的情况下中断神经发生 决定慢性抑制后VLPOGAL神经元促进睡眠能力是否下降的因素 睫状神经营养因子(CNTF)可抑制下丘脑的神经发生。 特异性目标-2：将确定是否增加VLPO睡眠的下丘脑细胞增殖和神经发生 调节神经元改善了老年小鼠的睡眠结构和睡眠连续性。我们将确定是否在 脑室注射神经源性CNTF持续诱导老龄小鼠下丘脑细胞增殖 对神经炎性病变具有保护作用的因子，促进迁移和分化 将神经突起转化为成熟的VLPOGAL神经元；减少神经炎症和衰老；并减少 睡眠碎片化(实验4)。我们将使用化学发生激活来确定是否有能力 促进睡眠的VLPOGAL神经元在CNTF治疗后改善老龄小鼠(实验5)。 从这些临床前研究中获得的数据将为深入了解这种机制提供帮助。 衰老中潜在的睡眠障碍。我们的研究还包括药理成分，可以提供 优化包括老年退伍军人在内的老年人睡眠健康的治疗选择