BLR&D Research Career Scientist Award

BLR

• 批准号: 10265388
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265388
• 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; Wakefulness; Work; acute stress; career; combat veteran; 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

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.

项目摘要 失眠和睡眠障碍是情绪和焦虑症的常见症状。夜间 睡眠中断是创伤性脑损伤（TBI）后常见的主诉。以前的工作 我的实验室已经在视前下丘脑中鉴定出GABA能神经元系统， 具有重要的睡眠调节功能。正中视前核的GABA能神经元 （MnPO）和腹外侧视前区（VLPO）在睡眠期间被激活。腺苷是一种 一种关键的内源性睡眠调节因子，在稳态反应的表达中起重要作用 睡眠不足我们已经证明MnPO/VLPO神经元被A2 A腺苷受体激活， 激动剂我们最近已经证明了MnPO/VLPO神经元的放电是动态的， 在睡眠剥夺和恢复睡眠期间对改变稳态睡眠驱动作出反应。我们 进一步表明，在发育过程中，MnPO/VLPO GABA能的功能成熟 睡眠调节系统是睡眠稳态发展的基础。我们的总体 一种假说认为，由于视前神经功能障碍， 下丘脑睡眠调节回路有助于情绪和焦虑的睡眠障碍 疾病和TBI。我们将使用这些疾病的动物模型来验证这一假设。我们将 也扩大了我们对下丘脑和 脑干觉醒状态--正常睡眠和睡眠障碍中的调节回路。的脑水平 促肾上腺皮质激素释放因子（CRF）是HPA轴的关键神经肽调节因子， 焦虑症和创伤后应激障碍（PTSD）的发病率长期升高。CRF良好 以促进觉醒/破坏睡眠的作用为特征。我们假设CRF的激活 神经元对急性和慢性应激的反应破坏了睡眠的稳态。我们 进一步假设CRF对睡眠稳态的影响是通过抑制 下丘脑视前区和吻侧区睡眠调节GABA能神经元的活动 髓质我们将使用转基因CRF-cre小鼠和腺病毒载体进行光遗传学和 化学遗传学操纵CRF信号在大脑中，并确定对睡眠的影响 视前区和延髓睡眠调节神经元群稳态、功能活动 以及急性和慢性压力源对睡眠的破坏性影响。睡眠-觉醒障碍 TBI后的症状包括白天嗜睡、夜间睡眠碎片、失眠和改变 在睡眠脑电图中。先前的研究表明，在TBI的小鼠模型中，过度嗜睡 与食欲素神经元的激活减少有关。在与同事的合作下， 波特兰弗吉尼亚州谁在创伤性脑损伤的专业知识，我们已经产生了初步的研究结果，睡眠相关的 在小鼠中皮质流体撞击损伤后MnPO神经元的活化显著降低。 我们将继续这些初步的发现，并检查GABA能睡眠的功能状态， 视前区的调节神经元和外侧下丘脑的食欲素神经元 并将这些神经元系统的功能活动与睡眠-觉醒相关联 在脑外伤后不同时间的表型。在NIH/NINDS支持的工作中，我们将 检查视前下丘脑和脑干中GABA能回路之间的相互作用 调节清醒、非快速眼动和快速眼动睡眠之间的转换。研究结果来自 这些研究将为了解这些回路参与睡眠奠定基础 伴随精神和神经障碍的分裂。

项目成果

Caregiver burden and COVID-19: How epilepsy caregivers experienced the pandemic.

• DOI: 10.1016/j.yebeh.2023.109151
• 发表时间: 2023-04
• 期刊: EPILEPSY & BEHAVIOR
• 影响因子: 2.6
• 作者: Viny, Mikayla;Trevino, Amira Y.;Bouldin, Erin D.;Kalvesmaki, Andrea;Roghani, Ali;Pugh, Mary Jo
• 通讯作者: Pugh, Mary Jo