Neural circuit mechanisms of the Fronto-Parietal Network

额顶网络的神经回路机制

• 批准号: 10228340
• 负责人: Houman Qadir
• 金额: $ 3.84万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-14 至 2024-02-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228340
• 关键词: AMPA Receptors; Address; Anatomy; Attention; Back; Brain; Cell Nucleus; Cells; Chemosensitization; Claustral structure; Cognition; Cognitive; Data; Development; Distant; Electrophysiology (science); Frequencies; Functional Imaging; Functional disorder; Glutamates; Human; Impaired cognition; Investigation; Knowledge; Lead; Link; Long-Term Potentiation; Mediating; Mental Depression; Methods; Motor Cortex; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Occupational; Outcome; Output; Parietal; Parietal Lobe; Pathology; Postsynaptic Membrane; Prefrontal Cortex; Publishing; Quality of life; Rattus; Research; Rest; Role; Schizophrenia; Short-Term Memory; Structure; Study models; Synapses; Testing; Therapeutic; Training; Viral; Visual Cortex; addiction; association cortex; autism spectrum disorder; cognitive development; cognitive function; cognitive task; disabling symptom; flexibility; frontal lobe; human subject; imaging study; innovation; neural circuit; neuropsychiatric disorder; nonhuman primate; novel; novel therapeutic intervention; optogenetics; patch clamp; postsynaptic; recruit; social; training opportunity; treatment strategy

Project Summary Cognitive dysfunction results in a diminished quality of life and poorer social and occupational outcomes across many neuropsychiatric diseases, including addiction, depression, autism, and schizophrenia. Currently, therapeutic coverage for cognitive dysfunction is severely lacking; remedying this requires a better understanding of the underlying neural circuitry of cognition. Optimal cognitive function is supported by the stable emergence of cognitive networks, which are composed of co-activating cortical regions. A cognitive network that consistently activates across cognitive tasks is the Fronto-Parietal Network (FPN). This network involves co-activation of prefrontal and more posterior parietal cortices. FPN destabilization occurs in several neuropsychiatric disorders characterized by dysfunction. Thus, understanding the neural circuit mechanisms allowing for FPN stabilization stands to fill a major gap in knowledge necessary for devising novel treatment strategies targeting cognitive dysfunction. The claustrum is a subcortical structure that upon activation synchronizes distant cortical regions. This is enabled by widespread direct excitatory projections from claustrum to cortex, including FPN cortical regions. Furthermore, the claustrum is functionally connected to the FPN as assessed by human functional imaging. Our preliminary data in mice indicates the presence of a functional circuit linking prefrontal cortex to posterior parietal cortices through the claustrum and that this circuit is capable of stabilizing through potentiation of synaptic strength at prefrontal-to-claustrum synapses. Thus, we hypothesize that the claustrum adaptively stabilizes FPN cortical components. To test this novel hypothesis, in Aim 1 we use a combination of viral tract- tracing, optogenetics, and whole-cell electrophysiology to test the presence and strength of synaptic connectivity of prefrontal afferents with claustrum projection neurons targeting posterior parietal cortices. In Aim 2, I will determine the synaptic mechanisms underlying potentiation within the prefrontal-to-claustrum synapse and how this potentiation drives circuit stabilization. This will be performed using whole-cell patch clamp electrophysiology, which represents the primary approach for technical training in this proposal. The results of this study stand to introduce the first candidate circuit mechanism for FPN emergence and, therefore, advance our knowledge of FPN pathology, and ultimately, cognitive dysfunction. Taken together, this innovative proposal will provide substantial conceptual and technical training opportunities that are necessary for the PI to ultimately gain research independence.

项目摘要 认知功能障碍导致生活质量下降，社会和职业结果较差， 许多神经精神疾病，包括成瘾、抑郁症、自闭症和精神分裂症。目前， 认知功能障碍的治疗覆盖面严重缺乏;补救这一点需要更好地了解 潜在的认知神经回路。最佳认知功能的支持是稳定的涌现 认知网络，由共同激活的皮层区域组成。一个认知网络， 额顶叶网络（FPN）。该网络涉及以下物质的共激活： 前额叶和后顶叶皮层FPN不稳定发生在几种神经精神疾病中 以机能障碍为特点。因此，理解FPN稳定的神经回路机制 站在填补知识的主要空白，必要的设计新的治疗策略，针对认知 功能障碍屏状核是一种皮层下结构，激活后可使远距离皮层区域活动。 这是通过从屏状核到皮质的广泛的直接兴奋性投射实现的，包括FPN皮质 地区此外，屏状体在功能上与FPN连接，如通过人类功能测定所评估的。 显像我们在小鼠身上的初步数据表明，存在一个功能回路， 后顶叶皮层通过屏状核，这一电路能够通过增强稳定 突触强度的变化。因此，我们假设屏状体适应性地 稳定FPN皮质成分。为了验证这一新的假设，在目标1中，我们使用了病毒道- 追踪、光遗传学和全细胞电生理学来测试突触连接的存在和强度 前额叶传入与屏状核投射神经元靶向后顶叶皮质。在目标2中，我将 确定前额叶-屏状核突触内潜在的增强作用的突触机制，以及如何 这种增强驱动电路稳定。这将使用全细胞膜片钳进行 电生理学，这是本提案中技术培训的主要方法。的结果 本研究旨在介绍FPN出现的第一个候选电路机制，因此， 我们对FPN病理学的了解，最终，认知功能障碍。总的来说，这一创新建议 将为PI提供必要的大量概念和技术培训机会， 获得研究独立性。