Specification of sleep-wake control neurons in the basal forebrain

基底前脑睡眠-觉醒控制神经元的规范

基本信息

批准号：
10618862
负责人：
Ritchie Edward Brown
金额：
--
依托单位：
VA BOSTON HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618862
关键词：
Ablation Adult Affect Area Arousal Attention Auditory Autopsy Behavior Bilateral Brain Calibration Cerebral cortex Clinical Trials Clozapine Data Dementia Development Developmental Biology Diagnosis Disease Ectopic Expression Electroencephalography Electrophysiology (science)Embryo Enterobacteria phage P1 Cre recombinase Enzymes FOXP2 gene Future Genes Genetic Genetic Techniques Glutamates Goals Guide RNA Homeobox Human Immunohistochemistry Injections Knock-in Mouse Lateral Lesion Ligands Link Location Maps Medial Methods Military Personnel Modeling Motor Activity Mouse Strains Mus Neurons Neurotransmitters Outcome Oxides Parvalbumins Phenotype Population Predisposition Preoptic Areas Prosencephalon Proteins Reporter Reporting Research Rewards Risk Role Saline Schizophrenia Sleep Sleep Disorders Sleep Stages Sleep Wake Cycle Sleep disturbances Sleeplessness Specific qualifier value Stains Subgroup Techniques Testing Time Toxin Transcriptional Regulation Transgenic Mice Veterans Viral Vector Vulnerable Populations Wakefulness adeno-associated viral vector basal forebrain biomarker validation brain circuitry cell type cholinergic neuron combat density design experimental study gamma-Aminobutyric Acid genetic approach innovation interest mind control neuropsychiatric disorder neuropsychiatry new therapeutic target novel novel strategies progenitor programs receptor response risk variant selective expression sensory stimulus sleep abnormalities sleep regulation sleep spindle suicidal risk targeted treatment transcription factor translational approach translational study

项目摘要

Deployment and combat exposure substantially increase the risk for insomnia and other sleep disorders in military personnel. These findings match with the 6-fold increase in the diagnosis of sleep disorders in the VA in recent years. The most prevalent sleep disorder, insomnia, is associated with an increased risk for suicide. Furthermore, disrupted sleep and abnormal cortical activity are common in severe neuropsychiatric conditions affecting veterans such as dementia and schizophrenia. Thus, a better mechanistic understanding of the brain circuitry controlling sleep-wake cycles and cortical oscillations are urgently needed to develop novel treatments for veterans and other vulnerable populations. Accordingly, the broad objective of this research program in mice is to identify new therapeutic targets to correct abnormalities of sleep and cortical electrical activity. We will use an innovative approach in mice which characterizes subgroups of neurons based on their developmental origin and identifies the transcription factors which control their activity in adults, allowing targeted therapies which recalibrate their activity to restore normal sleep and cortical rhythms. We focus on the basal forebrain, a region involved in sleep-wake activity, attention and reward which degenerates in dementia, and on the largest group of neurons in this region which release the inhibitory neurotransmitter, gamma-amino-butyric acid (GABA). We target neurons which express three transcription factors linked to insomnia and other neuropsychiatric disorders common in veterans by genetic and postmortem studies. The roadmap to helping veterans is: We will identify new groups of neurons based on their developmental origin (Aim 1). We will use transgenic mice which allow manipulation of their activity to determine how they affect sleep-wake behavior and cortical oscillations (Aim 2). Finally, we will state-of-the-art genetic techniques to identify the transcription factors which control their activity in adults (Aim 3), allowing us to correct abnormal sleep-wake behavior and cortical electrical activity in neuropsychiatric disorders by designing viral vector based therapies which act on those transcription factors (long-term goal). Forebrain GABAergic neurons are generated in the subpallium, an area of the developing brain implicated in the risk for developing diverse neuropsychiatric disorders affecting veterans. Within the subpallium, different groups of GABAergic neurons are generated by progenitors in the caudal, medial and lateral ganglionic eminences and embryonic preoptic regions. In each region, different transcription factors specify unique groups of neurons. We will use genetically modified mice which express an enzyme, Cre recombinase (Cre), under the control of these transcription factors to identify them and manipulate their activity. Crossing these mouse strains with another mouse strain which expresses a red fluorescent protein in the presence of Cre, in combination with immunostaining will allow us to map their location and phenotype (Aim 1). In Aim 2 we will study their function by increasing their activity or ablating them using injections of viral vectors which express proteins in the presence of Cre. These experiments will reveal the role of these neurons in sleep-wake behavior and control of cortical electrical activity for the first time and set the stage for translational studies to alter their activity. Finally, in Aim 3, we will begin the first step towards a translational approach by using state-of-the art genetic techniques to modulate the activity of one of these transcription factors, Lhx6, whose expression is altered in a GABAergic cell-type implicated in schizophrenia. We will use a state-of-the-art gene editing technique called Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR), which is currently being tested in clinical trials for various disorders. If successful, as suggested by our strong preliminary data, this project will allow novel translational approaches to study and correct disease-related abnormalities in veterans by manipulating the activity of basal forebrain neurons and genes which regulate sleep-wake behavior and cortical electrical activity.

部署和战斗暴露大大增加了失眠和其他睡眠障碍的风险在军事人员中。这些发现与睡眠障碍诊断的6倍相匹配近年来VA。最普遍的睡眠障碍，失眠症，与增加的风险有关自杀。此外，在严重的神经精神上，睡眠干扰和皮质活性异常很常见影响退伍军人（例如痴呆症和精神分裂症）的条件。因此，更好的机械理解迫切需要控制睡眠效果周期和皮质振荡的脑电路退伍军人和其他脆弱人群的新型治疗方法。因此，这个广泛的目标小鼠的研究计划是确定新的治疗靶标，以纠正睡眠和皮质异常电活动。我们将在小鼠中使用一种创新的方法，该方法以神经元的亚组为特征关于它们的发育起源，并确定控制成人活性的转录因子，允许重新校准其活性以恢复正常睡眠和皮质节律的靶向疗法。我们专注于基础前脑，这是一个参与睡眠效果活动，注意力和奖励的地区在痴呆症和该区域中最大的神经元中，释放抑制性神经递质， γ-氨基丁酸（GABA）。我们针对的神经元表达了三个转录因子通过遗传和死后研究，失眠和其他在退伍军人中常见的神经精神疾病。帮助退伍军人的路线图是：我们将根据他们的发展起源（AIM 1）。我们将使用转基因小鼠，使其活性操纵确定它们如何影响睡眠效果行为和皮质振荡（AIM 2）。最后，我们将最先进识别控制成人活性的转录因子的遗传技术（AIM 3），使我们纠正神经精神疾病中的异常睡眠觉醒行为和皮质电活动设计基于病毒载体的疗法，该疗法对这些转录因子作用（长期目标）。前脑GABA能神经元是在发育中的大脑区域中产生的涉及发展影响退伍军人的多种神经精神疾病的风险。在尾巴，内侧和外侧神经节透性和胚胎前区域。在每个区域，不同的转录因子指定独特的神经元组。我们将使用表达酶，CRE的转基因小鼠重组酶（CRE），在这些转录因子的控制下，以识别它们并操纵其活动。将这些小鼠菌株与另一种小鼠菌株交叉，该菌株表达红色荧光蛋白 CRE的存在，结合免疫染色将使我们能够绘制其位置和表型（目标1）。在AIM 2中，我们将通过使用病毒注射来增加其活性或消融它们来研究它们的功能在CRE存在下表达蛋白质的载体。这些实验将揭示这些神经元的作用在睡眠效果行为和首次对皮质电活动的控制中，并为翻译研究以改变其活性。最后，在AIM 3中，我们将开始迈向翻译的第一步通过使用最先进的遗传技术来调节其中一种转录的活性因素，LHX6，其表达在与精神分裂症有关的GABA能细胞类型中发生了变化。我们将使用一个最先进的基因编辑技术，称为群集定期散布的短圆锥体重复序列（CRISPR），目前正在临床试验中针对各种疾病进行测试。如果成功，正如我们强大的初步数据所建议的那样，该项目将允许新颖的翻译通过操纵基础的活性来研究和纠正退伍军人中与疾病相关异常的方法前脑神经元和基因，这些神经元和基因调节睡眠效果行为和皮质电活动。