Synaptic and dendritic physiology in the prefrontal cortex

前额皮质的突触和树突生理学

• 批准号: 10063906
• 负责人: Adam G Carter
• 金额: $ 50.63万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-06 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063906
• 关键词: Animals; Apical; Area; Attention deficit hyperactivity disorder; Behavior; Cell Nucleus; Cells; Cognitive; Complex; Data; Dendrites; Distal; Electrophysiology (science); Functional disorder; Goals; Image; Interneurons; Mediating; Mental disorders; Mus; Photons; Physiology; Play; Population; Prefrontal Cortex; Primates; Property; Pyramidal Cells; Rodent; Role; Schizophrenia; Shapes; Signal Transduction; Synapses; Testing; Thalamic Nuclei; Thalamic structure; Transgenic Mice; Whole-Cell Recordings; Work; cell type; cognitive function; experimental study; insight; neural circuit; neuronal cell body; neuropsychiatric disorder; novel; optogenetics; sensory cortex; sensory system; therapeutic target; two photon microscopy; two-photon

PROJECT SUMMARY Interactions between the thalamus and prefrontal cortex (PFC) are important for cognitive function in animals ranging from rodents to primates. The importance of these long-range networks is highlighted by multiple neuropsychiatric diseases, including schizophrenia and ADHD. However, most of what we know about thalamo-cortical circuits comes from sensory systems, where primary thalamic inputs arrive in layer 4 (L4). In contrast, the mouse PFC is an agranular area that lacks L4, and instead receives higher-order thalamic inputs directly to superficial layers. We recently discovered that the PFC makes reciprocal connections with both the mediodorsal (MD) and ventromedial (VM) thalamus. These thalamic nuclei support distinct behaviors, but the cellular, synaptic and circuit mechanisms for their interactions with PFC are poorly understood. We found MD strongly drives layer 2/3 (L2/3) pyramidal cells, whereas VM inputs contact the dendrites of a subset of L5 pyramidal cells. Interestingly, both inputs also robustly engage inhibitory networks to drive local inhibition mediated by GABAergic interneurons. The goal of this proposal is to assess how thalamic inputs engage different populations of superficial interneurons to mediate inhibition in the PFC. In Specific Aim 1, we use optogenetics and electrophysiology to study how thalamic inputs drive multiple classes of interneurons in superficial layers. Our preliminary data suggests that MD and VM engage complementary populations of interneurons located in different sub-layers. In Specific Aim 2, we then use conditional optogenetics to study how these interneurons contact excitatory and inhibitory cells within and across layers. Our preliminary data indicate that the interneurons contacted by MD and VM participate in distinct inhibitory and disinhibitory circuits across multiple layers. Lastly, in Specific Aim 3, we combine 1-photon optogenetics with 2-photon microscopy to study how specific populations of interneurons mediate the suppression of dendritic Ca2+ spikes. Our preliminary data reveal that a sub-population of superficial interneurons mediates robust feed-forward inhibition in the dendrites. Together, the results from our experiments will answer fundamental questions about the organization of thalamo-cortical circuits and interneurons in the PFC. They will also help identify potential therapeutic targets for the many neuropsychiatric disorders that arise from disrupted circuitry within the PFC.

项目概要 丘脑和前额皮质 (PFC) 之间的相互作用对于动物的认知功能很重要 从啮齿动物到灵长类动物。多个方面都强调了这些远程网络的重要性 神经精神疾病，包括精神分裂症和多动症。然而，我们所知道的大部分 丘脑皮质回路来自感觉系统，主要丘脑输入到达第 4 层 (L4)。在 相比之下，小鼠 PFC 是一个缺乏 L4 的无颗粒区域，而是接收更高阶的丘脑输入 直接到达表层。我们最近发现 PFC 与 丘脑内侧 (MD) 和腹内侧 (VM)。这些丘脑核支持不同的行为，但是 人们对它们与 PFC 相互作用的细胞、突触和电路机制知之甚少。我们找到MD 强烈驱动第 2/3 层 (L2/3) 锥体细胞，而 VM 输入接触 L5 子集的树突 锥体细胞。有趣的是，这两种输入也强有力地参与抑制网络以驱动局部抑制 由 GABA 能中间神经元介导。该提案的目标是评估丘脑输入如何参与 不同群体的浅层中间神经元介导 PFC 的抑制作用。在具体目标 1 中，我们使用 光遗传学和电生理学研究丘脑输入如何驱动多种类型的中间神经元 表面层。我们的初步数据表明，MD 和 VM 涉及互补群体 中间神经元位于不同的子层。在具体目标 2 中，我们使用条件光遗传学来研究 这些中间神经元如何在层内和层间接触兴奋性和抑制性细胞。我们的初步数据 表明 MD 和 VM 接触的中间神经元参与不同的抑制和去抑制回路 跨越多个层。最后，在具体目标 3 中，我们将 1 光子光遗传学与 2 光子显微镜相结合 研究特定的中间神经元群体如何介导树突 Ca2+ 尖峰的抑制。我们的 初步数据表明，表面中间神经元的亚群介导强大的前馈抑制 在树突中。我们的实验结果将共同回答有关 前额皮质中丘脑皮质回路和中间神经元的组织。他们还将帮助识别潜在的 因 PFC 内的回路中断而引起的许多神经精神疾病的治疗靶点。