Synaptic and dendritic physiology in the prefrontal cortex

前额皮质的突触和树突生理学

• 批准号: 10532203
• 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/10532203
• 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; 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.

项目摘要 丘脑和额叶皮层（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范围。这些远程网络的重要性由多个 神经精神疾病，包括精神分裂症和多动症。但是，我们所知道的大多数 丘脑皮层电路来自感官系统，主要丘脑输入到达第4层（L4）。在 对比，小鼠PFC是缺乏L4的机构区域，而是接收高阶丘脑输入 直接到浅层层。我们最近发现，PFC都与 地中（MD）和腹侧（VM）丘脑。这些丘脑核支持不同的行为，但 对其与PFC相互作用的细胞，突触和电路机制知之甚少。我们找到了MD 强烈驱动层2/3（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，这两个输入都可以强大地参与抑制网络以驱动局部抑制 由GABA能中间神经元介导。该提案的目的是评估丘脑输入如何参与 浅表中间神经元的不同种群介导PFC中的抑制作用。在特定目标1中，我们使用 光遗传学和电生理学研究如何在丘脑输入中如何驱动多种类中间神经元 浅层层。我们的初步数据表明，MD和VM参与 中间神经元位于不同的子层中。在特定的目标2中，我们使用条件光遗传学研究 这些中间神经元如何接触层内和层次的抑制细胞。我们的初步数据 表明MD和VM联系的中间神经元参与不同的抑制和抑制回路 跨多层。最后，在特定的目标3中，我们将1光子光遗传学与2光子显微镜相结合 研究中间神经元的特定种群如何介导树突状Ca2+尖峰的抑制。我们的 初步数据表明，浅表中间神经元的亚群介导了强大的进料抑制 在树突中。我们实验的结果在一起将回答有关 PFC中丘脑 - 皮层电路和中间神经元的组织。他们还将帮助确定潜力 由PFC中的电路中断引起的许多神经精神疾病的治疗靶标。