Tuning cortical E/I balance for translational modeling of psychiatric disorders

调整皮质 E/I 平衡以建立精神疾病的转化模型

• 批准号: 10158430
• 负责人: JAMES M MCNALLY
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158430
• 关键词: Acute; Address; Alzheimer' s Disease; American; Animals; Antipsychotic Agents; Attention; Auditory; Behavior; Behavioral; Behavioral Paradigm; Brain; Cell Nucleus; Clinical; Clinical Research; Cognition; Cognitive; Cognitive deficits; Communities; Coupled; Data; Disease; Dorsal; Electroencephalography; Electrophysiology (science); Equilibrium; Exhibits; FOS gene; Generations; Genetic Models; Health Care Costs; Human; Impaired cognition; Impairment; Interneurons; Intervention; Investigation; Ketamine; Knockout Mice; Lead; Link; Medial; Mediating; Mental disorders; Modeling; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Output; Parkinson Disease; Parvalbumins; Pathogenesis; Pathologic Processes; Pathway interactions; Pattern; Performance; Pharmacology; Phenotype; Physiology; Play; Prefrontal Cortex; Prevention; Psyche structure; Psychoses; Research; Research Design; Role; Schizophrenia; Sensory; Social Functioning; Stream; Symptoms; Synapses; System; Techniques; Testing; Thalamic structure; Therapeutic; Therapeutic Intervention; Time; Transgenic Model; Translational Repression; Viral; Work; associated symptom; autism spectrum disorder; basal forebrain; behavioral phenotyping; cognitive function; disability; disabling symptom; effective intervention; equilibration disorder; experimental study; flexibility; habituation; improved; improved functioning; in vivo; innovation; insight; interest; military veteran; neural network; neuropsychiatric disorder; neuropsychiatry; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; object recognition; optogenetics; pre-clinical; relating to nervous system; response; restoration; sensory gating; serine racemase; social; social deficits; targeted treatment; therapeutic development; translational model

OBJECTIVE: Cognitive deficits are a major determinant of the long-term disability associated with severe neuropsychiatric disorders, including schizophrenia (Sz). This warrants increased interest in the VA research community, given the higher instance of psychiatric illness among the veteran population, treatment of which accounts for some 40% of VA mental healthcare costs nationally. Current therapeutic strategies (first and second-generation antipsychotics) do not satisfactorily address Sz-related cognitive issues. Abnormalities in the patterns of cortical EEG, most notably elevated spontaneous gamma band activity (GBA) and reduced task-evoked GBA, have been observed in a number of clinical studies of severe neuropsychiatric conditions, and have been indicated to underlie both the psychosis linked impairment of sensory, cognitive, and social domains of function. Thus, it may prove advantageous to address these symptom domains with a greater consideration to the patterns of electrophysiological activity and testing whether modulation of these patterns can improve function. One crucial variable regulating such activity is the balance between excitatory and inhibitory (E/I Balance) cortical neural activity. Recent work from our lab suggests that long range GABAergic projections from basal forebrain parvalbumin neurons (BF-PV) are capable of bi-directionally modulating E/I balance. These studies serve to provide a better understanding of the role of impaired E/I balance in the emergence of cognitive and social deficits associated with Sz, and other psychiatric disorders, as well as provide a rationale for targeting restoration of E/I balance as a novel therapeutic approach. RESEARCH DESIGN: In this study, our Overall Hypothesis postulates that modulation of BF-PV output allows tuning of cortical E/I balance, via direct projections to the cortical circuitry and through projections to the thalamic reticular nucleus (TRN). Aim 1 will characterize a powerful systems-level model to better define how abnormal patterns of cortical activity impact cognitive and social domains of function relevant to psychiatric disease. Aim 2 seeks to provide a more complete understanding of the mechanism behind BF-PV modulation of E/I balance. Finally, Aim 3 will test manipulations of this mechanism as a novel therapeutic means to restore cortical E/I balance, and improve cognition in two translationally relevant models of Sz. METHODOLOGY: Here we will utilize an innovative combination of electrophysiological, optogenetic, and behavioral paradigms. First, to directly examine the relationship between impaired E/I balance and cognition, we will assess performance of mice on translationally relevant sensory and cognitive paradigms both with and without BF-PV mediated alteration of cortical E/I. Using, both an immunohistochemical and optogenetic approach, we will attempt to better characterize the circuit pathway involved in BF-PV modulation of E/I balance. Finally, we will utilize both pharmacological and transgenic models of Sz, to determine if inhibition of BF-PV output is capable of restoring, E/I balance, and by extension improve cognitive function. IMPACT/SIGNIFICANCE: Normal brain function relies on the ability of neural networks to maintain stable, yet flexible, levels of activity. These experiments will provide a better understanding of aspects of coordinated neural activity that are important for sensory, cognitive, and social processing. Further, it will characterize a subcortical pathway capable of modulating E/I balance and interrogate this pathway as a novel therapeutic target to rescue impairments in neuropsychiatric disorders. Millions of Americans are currently suffering from conditions that lead to abnormal E/I balance, and associated GBA impairment, beyond Sz (e.g. Alzheimer's disease, Autism, Parkinson's disease), making it likely that this approach will benefit research into the treatment of other neuropsychiatric disease states as well. This work is novel and will provide valuable insight into the pathogenesis of such disorders, and also lay groundwork for the development of therapeutic interventions for effective prevention and treatment.

目的：认知缺陷是与严重疾病相关的长期残疾的主要决定因素。 神经精神疾病，包括精神分裂症（Sz）。这增加了人们对 VA 的兴趣 研究界，鉴于退伍军人中精神疾病的发生率较高， 其治疗费用约占退伍军人管理局全国精神保健费用的 40%。目前治疗 策略（第一代和第二代抗精神病药）不能令人满意地解决与 Sz 相关的认知问题。 皮质脑电图模式异常，最明显的是自发伽马带活动（GBA）升高 在许多严重神经精神疾病的临床研究中都观察到了任务诱发的 GBA 的减少 条件，并已被表明是与精神病相关的感觉、认知、 和社会功能领域。因此，通过以下方法解决这些症状领域可能会被证明是有利的： 更多地考虑电生理活动的模式并测试这些活动是否受到调节 模式可以改善功能。调节这种活动的一个关键变量是兴奋性之间的平衡 和抑制（E/I 平衡）皮质神经活动。我们实验室最近的工作表明，长距离 来自基底前脑小白蛋白神经元 (BF-PV) 的 GABA 能投射能够双向 调节 E/I 平衡。这些研究有助于更好地理解 E/I 受损的作用 与 Sz 和其他精神疾病相关的认知和社交缺陷的出现的平衡， 并为恢复 E/I 平衡作为一种新的治疗方法提供了理论基础。 研究设计：在这项研究中，我们的总体假设假设 BF-PV 输出的调制 允许通过直接投射到皮质电路以及通过投射到大脑皮层 E/I 平衡来调节 丘脑网状核（TRN）。目标 1 将描述一个强大的系统级模型，以更好地定义如何 皮质活动的异常模式影响与精神病相关的认知和社会功能领域 疾病。目标 2 旨在更全面地了解 BF-PV 调制背后的机制 E/I 平衡。最后，目标 3 将测试对该机制的操作，作为一种新颖的治疗手段来恢复 皮质 E/I 平衡，并改善两个 Sz 翻译相关模型的认知。 方法：在这里，我们将利用电生理学、光遗传学和 行为范式。首先，直接检查 E/I 平衡受损与认知之间的关系， 我们将使用 和 来评估小鼠在翻译相关的感觉和认知范式上的表现 无 BF-PV 介导的皮质 E/I 改变。使用免疫组织化学和光遗传学 方法，我们将尝试更好地表征 E/I 的 BF-PV 调制所涉及的电路路径 平衡。最后，我们将利用 Sz 的药理学和转基因模型来确定是否抑制 BF-PV 输出能够恢复 E/I 平衡，进而改善认知功能。 影响/意义：正常的大脑功能依赖于神经网络保持稳定的能力，但 灵活的活动水平。这些实验将有助于更好地理解协调的各个方面 对于感觉、认知和社会处理很重要的神经活动。此外，它将表征 皮层下通路能够调节 E/I 平衡并质疑该通路作为一种新型治疗方法 目标是挽救神经精神疾病的损伤。目前，数以百万计的美国人正遭受着 导致 E/I 平衡异常以及相关 GBA 损伤（超出 Sz 范围）的疾病（例如阿尔茨海默病） 疾病、自闭症、帕金森病），使得这种方法可能有利于对 其他神经精神疾病的治疗也是如此。这项工作很新颖，将提供有价值的见解 深入了解此类疾病的发病机制，并为治疗药物的开发奠定基础 有效预防和治疗的干预措施。