Neural circuit mechanisms of the Fronto-Parietal Network

额顶网络的神经回路机制

• 批准号: 10554165
• 负责人: Houman Qadir
• 金额: $ 4.08万
• 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/10554165
• 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; Link; Long-Term Potentiation; Maps; Mediating; Mental Depression; Methods; Motor Cortex; Mus; N-Methyl-D-Aspartate Receptors; Neuroanatomy; 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 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; skills; 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.

项目总结