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 失眠和睡眠不安是情绪和焦虑症的常见症状。夜 脑损伤（TBI）经常发生睡眠破坏。以前的工作 我的实验室已经确定了在原丘脑前下丘脑中GABA能神经元的系统 具有关键的睡眠调节功能。中值前核中的GABA能神经元 在睡眠期间（MNPO）和腹外侧前区域（VLPO）被激活。腺苷是 关键的内源性睡眠调节因素，对稳态反应的表达很重要 睡眠损失。我们已经表明MNPO/VLPO神经元被A2A腺苷受体激活 激动剂。我们最近证明了MNPO/VLPO神经元的排放是动态的 响应在睡眠不足和恢复睡眠期间改变体内稳态睡眠驱动器的能力。我们 进一步表明，在开发过程中，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 假设是由于presoptic的功能障碍而对睡眠损失的稳​​态反应破坏 下丘脑睡眠调节电路会导致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检验这一假设。我们将 还扩展了我们对下丘脑与 脑干唤醒状态调节电路在正常和无序的睡眠中。大脑水平 皮质营养素释放因子（CRF）是HPA轴的关键神经肽调节剂，是 焦虑症和创伤后应激障碍（PTSD）长期升高。 CRF很好 表征了启动唤醒/失眠的效果。我们假设CRF的激活 响应急性和慢性压力而发生的神经元破坏了睡眠稳态。我们 进一步假设CRF对睡眠稳态的影响是通过抑制来介导的 在原丘脑前和thostral中睡眠调节性GABA能神经元的活性 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 化学上的化学操纵大脑中的CRF信号，并确定对睡眠的影响 体内稳态，前和髓质睡眠调节性神经元种群的功能活性 以及急性和慢性应激源的睡眠破坏性作用。睡眠唤醒 遵循TBI包括白天嗜睡，夜间睡眠破碎，失眠和改变 在睡眠中。先前的工作表明，在TBI的鼠标模型中，过度嗜睡 与降低的Orexin神经元激活有关。与同事合作 在TBI中具有专业知识的波特兰弗吉尼亚州，我们产生了与睡眠有关的初步发现 小鼠皮质液体打击乐损伤后，MNPO神经元的激活大大降低。 我们将追求这些初步发现，并检查GABA能睡眠的功能状态 - 下丘脑外侧区域和Orexin神经元的调节神经元 遵循TBI，并将这些神经元系统中的功能活性与睡眠效益相关联 脑创伤后的不同时间表型。在NIH/Ninds支持的工作中，我们将 检查前下丘脑和脑干中的GABA能回路之间的相互作用 调节醒来，非REM和REM睡眠之间的切换。从 这些研究将是理解这些电路参与睡眠的基础 伴随精神病和神经系统疾病的破坏。

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