Neural circuit mechanisms of the Fronto-Parietal Network

项目摘要 认知功能障碍导致生活质量下降，社会和职业结果更差 许多神经精神疾病，包括成瘾、抑郁、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不足；补救这一问题需要更好的理解 认知的潜在神经回路。最佳认知功能是由稳定的涌现支持的 由共同激活的大脑皮层区域组成的认知网络。始终如一的认知网络 在认知任务中激活的是额顶网络(FPN)。这个网络涉及到共同激活 前额叶和更多后顶叶皮质。FPN失稳发生在几种神经精神障碍中 以功能障碍为特征的。因此，了解允许FPN稳定的神经电路机制 填补了设计以认知为目标的新治疗策略所需的知识的主要空白 功能障碍。屏状核是一种皮质下结构，一旦激活，就会同步遥远的皮质区域。 这是由屏核到皮质的广泛的直接兴奋性投射实现的，其中包括FPN皮质 地区。此外，根据人类功能评估，屏蔽体在功能上与FPN相连 成像。我们在小鼠身上的初步数据表明，存在将前额叶皮质连接到 顶叶后皮质通过屏蔽区，这一回路能够通过增强而稳定 前额-屏区突触的突触强度。因此，我们假设屏蔽门自适应地 稳定FPN皮质成分。为了验证这一新的假设，在目标1中，我们使用了病毒途径的组合- 追踪、光遗传学和全细胞电生理学，以测试突触连接的存在和强度 前额叶传入和屏蔽区投射神经元以顶叶后皮质为靶点。在《目标2》中，我会 确定前额-屏区突触内潜在增强的突触机制以及如何 这种增强可以驱动电路稳定。这将使用全细胞膜片钳来实现 电生理学，这是本提案中技术培训的主要方法。结果是 这项研究旨在介绍FPN出现的第一个候选回路机制，从而推动 我们对FPN病理的了解，并最终导致认知功能障碍。综上所述，这项创新的提案 将提供大量的概念和技术培训机会，这些培训机会对于PI最终 获得研究独立性。

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.