Synaptic and dendritic physiology in the prefrontal cortex

描述(申请人提供)：前额叶皮质对控制从啮齿动物到灵长类动物的认知、情感和记忆非常重要。前额叶皮质的重要性在包括精神分裂症在内的多种神经精神疾病中得到强调。 和抑郁症。锥体神经元是前额叶皮质的主要细胞，处理不同的兴奋性和抑制性突触输入。这些神经元还从调节固有和突触生理的皮质下区域接受广泛的多巴胺能输入。多巴胺激活代谢性D1受体，以增强锥体神经元的激活，并支持工作记忆等认知功能。然而，先前的研究发现，D1受体对锥体神经元的兴奋性和抑制性反应具有异质性作用。我们最近发现，只有一小部分第5层锥体神经元(D1神经元)选择性地表达D1受体。这些神经元具有致密的树突、高的输入电阻、最小的h电流和明显的突发性放电。重要的是，它们还受到D1受体的选择性调节，这些受体通过蛋白激酶A(PKA)途径发出信号来增强兴奋性。本研究的目的是评估D1R是如何调节小鼠PFC中D1区神经元的兴奋和抑制反应的。我们首先利用全细胞记录、光遗传学和双光子显微镜的强大组合，表征了对D1神经元的不同兴奋输入。然后，我们使用这些方法来评估对D1神经元的抑制输入的性质，这些神经元来自各种GABA能中间神经元。在这两种情况下，我们研究了在d1神经元和它们的d1相邻神经元的不同突触反应的机制。在定义了这些联系之后，我们测试了我们的假设，即D1受体仅在D1神经元调节兴奋性和抑制性突触。拟议的实验将揭示这一锥体神经元亚群如何与它们的远程和局部电路相互作用。这些实验的结果将回答有关多巴胺对细胞和突触生理学的调节的基本问题。它们还将有助于确定许多神经精神疾病的新治疗靶点，这些疾病是由于前额叶中多巴胺调制中断而引起的。

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.