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: 10454861
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454861
• 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 Health Services; 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; 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：认知缺陷是与严重残疾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）。这需要增加对VA的兴趣 研究社区，鉴于资深人口中精神病的较高实例， 在全国范围内，哪些占VA心理保健费用的40％。当前的治疗性 策略（第一代和第二代抗精神病药）并不能令人满意地解决与SZ相关的认知问题。 皮质脑电图模式的异常，最著名的自发性伽马频带活性（GBA） 在许多严重神经精神病学的临床研究中已经观察到了任务引起的GBA的减少 条件，并且已被指出是既是精神病的障碍，认知， 和社会功能领域。因此，通过 对电生理活性的模式进行更大的考虑和测试是否调节 模式可以改善功能。调节这种活动的一个关键变量是兴奋之间的平衡 和抑制性（E/I平衡）皮质神经活动。我们实验室的最近工作表明远距离 来自基础前脑白蛋白神经元（BF-PV）的GABA能投影能够双向 调节E/I平衡。这些研究有助于更好地了解E/I受损的作用 与SZ和其他精神疾病相关的认知和社会缺陷的出现平衡， 以及作为靶向恢复E/I平衡作为一种新型治疗方法的基本原理。 研究设计：在这项研究中，我们的总体假设假设BF-PV输出的调节 允许通过直接投影到皮质电路并通过投影来调整皮层E/I平衡 丘脑网状核（TRN）。 AIM 1将表征强大的系统级模型，以更好地定义 皮质活动的异常模式影响与精神病有关的认知和社会领域 疾病。 AIM 2试图对BF-PV调制背后的机制有更完整的了解 e/i的平衡。最后，AIM 3将测试对这种机制的操纵，以恢复新颖的治疗手段 皮质E/I平衡，并改善SZ的两种翻译相关模型中的认知。 方法论：在这里，我们将利用电生理，光遗传学和 行为范式。首先，直接检查E/I平衡和认知受损之间的关系， 我们将评估小鼠在与和和认知范式上的转化相关感官和认知范式上的表现和 没有BF-PV介导的皮质E/I的改变。使用，免疫组织化学和光学遗传学 方法，我们将尝试更好地表征E/I BF-PV调制涉及的电路路径 平衡。最后，我们将利用SZ的药理和转基因模型来确定抑制是否抑制 BF-PV输出能够恢复，E/I平衡，并且通过扩展提高了认知功能。 影响/意义：正常的大脑功能取决于神经网络保持稳定的能力，但 灵活的活动水平。这些实验将更好地理解协调的各个方面 神经活动对于感觉，认知和社会处理很重要。此外，它将表征 皮层途径能够调节E/i平衡并审问这一途径为一种新型治疗 挽救神经精神疾病障碍的目标。数以百万计的美国人目前遭受 导致异常E/I平衡和相关GBA损伤的条件以外（例如，阿尔茨海默氏症 疾病，自闭症，帕金森氏病），使得这种方法可能有益于研究 治疗其他神经精神疾病状态。这项工作是新颖的，将提供宝贵的见解 进入此类疾病的发病机理，并为治疗的发展奠定基础 有效预防和治疗的干预措施。