Synaptic and dendritic physiology in the prefrontal cortex

描述（由申请人提供）：前额叶皮层对于控制从啮齿动物到灵长类动物的认知、情感和记忆是重要的。前额叶皮层的重要性在包括精神分裂症在内的多种神经精神疾病中凸显出来 和抑郁症锥体神经元是前额叶皮层的主要细胞，处理各种兴奋性和抑制性突触输入。这些神经元还从调节内在和突触生理的皮层下区域接收广泛的多巴胺能输入。多巴胺激活代谢型D1受体，增强锥体神经元放电，支持工作记忆等认知功能。然而，以前的研究发现，在锥体神经元的兴奋性和抑制性反应的D1受体的异质性影响。我们最近发现，D1受体的选择性表达，只有一个亚群的第5层锥体神经元（D1+神经元）。这些神经元具有紧凑的树突，高输入电阻，最小的h-电流和显着的突发放电相比，他们的D1-邻居。重要的是，它们也被D1受体选择性地调节，D1受体通过蛋白激酶A（PKA）途径发出信号以增强兴奋性。该建议的目标是评估D1受体如何调节小鼠PFC中D1+神经元的兴奋性和抑制性反应。我们首先使用全细胞记录，光遗传学和双光子显微镜的强大组合来表征D1+神经元的不同兴奋性输入。然后，我们使用这些方法来评估D1+神经元的抑制性输入的特性，这些神经元来自各种GABA能中间神经元。在这两种情况下，我们研究的机制，在D1+神经元和他们的D1-邻居的差异突触反应的基础。定义了这些连接，我们测试我们的假设，D1受体调节兴奋性和抑制性突触只在D1+神经元。拟议的实验将揭示锥体神经元的这一亚群如何与它们的长程和局部回路相互作用。这些实验的结果将回答关于多巴胺调节细胞和突触生理学的基本问题。他们还将有助于确定新的治疗靶点，用于许多神经精神疾病，这些疾病是由PFC中的多巴胺调节中断引起的。

DESCRIPTION (provided by applicant): The prefrontal cortex is important for controlling cognition, emotion and memory in animals ranging from rodents to primates. The importance of the prefrontal cortex is highlighted in multiple neuropsychiatric diseases, including schizophrenia and depression. Pyramidal neurons are the principal cells of the prefrontal cortex, and process diverse excitatory and inhibitory synaptic inputs. These neurons also receive extensive dopaminergic inputs from subcortical regions that modulate intrinsic and synaptic physiology. Dopamine activates metabotropic D1 receptors to enhance pyramidal neuron firing and support cognitive functions like working memory. However, previous studies have found heterogeneous effects of D1 receptors on excitatory and inhibitory responses at pyramidal neurons. We recently discovered that D1 receptors are selectively expressed in only a subpopulation of layer 5 pyramidal neurons (D1+ neurons). These neurons have compact dendrites, high input resistance, minimal h-current and pronounced burst firing compared to their D1- neighbors. Importantly, they are also selectively modulated by D1 receptors, which signal through the protein kinase A (PKA) pathway to boost excitability. The goal of this proposal is to assess how D1 receptors modulate excitatory and inhibitory responses at D1+ neurons in the mouse PFC. We first characterize the different excitatory inputs onto D1+ neurons, using a powerful combination of whole-cell recordings, optogenetics and two-photon microscopy. We then use these approaches to assess the properties of inhibitory inputs onto D1+ neurons, which derive from a variety of GABAergic interneurons. In both cases, we examine the mechanisms that underlie differential synaptic responses at D1+ neurons and their D1-neighbors. Having defined these connections, we test our hypothesis that D1 receptors regulate excitatory and inhibitory synapses only at D1+ neurons. The proposed experiments will reveal how this subpopulation of pyramidal neurons interacts with their long-range and local circuits. The results from these experiments will answer fundamental questions about dopamine regulation of cellular and synaptic physiology. They will also help to identify novel therapeutic targets for the many neuropsychiatric diseases that arise from disrupted dopamine modulation in the PFC.