Synaptic and dendritic physiology in the prefrontal cortex

项目总结 丘脑和前额叶皮质(PFC)之间的相互作用对动物的认知功能很重要 从啮齿动物到灵长类动物。这些远程网络的重要性从多个方面突显出来 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关于 丘脑-皮质回路来自感觉系统，初级丘脑输入到达第四层(L4)。在……里面 相比之下，小鼠的PFC是一个缺乏L4的非颗粒区，而是接受更高阶的丘脑输入 直接延伸到表层。我们最近发现，PFC与两者之间存在相互联系 丘脑内侧背侧(MD)和腹内侧(Vm)。这些丘脑核团支持不同的行为，但 它们与PFC相互作用的细胞、突触和电路机制还知之甚少。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，这两个输入还强健地接触到抑制网络以驱动局部抑制 由GABA能中间神经元介导。这项提案的目标是评估丘脑的输入如何参与 不同群体的浅层中间神经元在PFC中起到调节抑制的作用。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类中间神经元 浅层。我们的初步数据表明，MD和VM参与了互补的人群 中间神经元位于不同的亚层。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 提示MD和Vm接触的中间神经元参与不同的抑制和去抑制环路 跨越多个层。最后，在具体目标3中，我们将单光子光遗传学与双光子显微镜相结合 研究特定的中间神经元群体如何介导树突状钙尖峰的抑制。我们的 初步数据显示，一个亚群的浅层中间神经元介导了强大的前馈抑制。 在树枝状突起中。总而言之，我们的实验结果将回答关于 前额叶丘脑皮质环路和中间神经元的组织。他们还将帮助确定潜在的 许多神经精神疾病的治疗目标，这些疾病是由PFC内的电路中断引起的。

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.