Synaptic and dendritic physiology in the prefrontal cortex

前额皮质的突触和树突生理学

• 批准号: 8990978
• 负责人: Adam G Carter
• 金额: $ 38.84万
• 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 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8990978
• 关键词: Amygdaloid structure; Animals; Apical; Axon; Biochemical; Brain; Cells; Cognition; Conflict (Psychology); Contralateral; Cyclic AMP-Dependent Protein Kinases; Data; Dendrites; Disease; Dopamine; Dopamine D1 Receptor; Electrophysiology (science); Emotions; Excitatory Synapse; Goals; Health; Hippocampus (Brain); Inhibitory Synapse; Interneurons; Memory; Mental Depression; Mental disorders; Microscopy; Mus; Neurons; Pathway interactions; Pharmacology; Physiology; Play; Positioning Attribute; Prefrontal Cortex; Primates; Process; Property; Publications; Resistance; Rodent; Role; Schizophrenia; Short-Term Memory; Signal Transduction; Synapses; Testing; Whole-Cell Recordings; cell growth regulation; cell type; cognitive function; hippocampal pyramidal neuron; insight; neuropsychiatric disorder; new therapeutic target; novel; optogenetics; postsynaptic; presynaptic; receptor; relating to nervous system; research study; response; selective expression; two-photon

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.

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动物的认知，情感和记忆很重要。在包括精神分裂症在内的多种神经精神疾病中强调了前额叶皮层的重要性 和抑郁。锥体神经元是前额叶皮层的主要细胞，并且可以处理多种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层下区域获得了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发射并支持认知功能，例如工作记忆。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反应的异质作用。我们最近发现，D1受体仅在5层锥体神经元（D1+神经元）的亚群中有选择地表达。与D1邻居相比，这些神经元具有紧凑的树突，高输入电阻，最小的H-电流和明显的爆发。重要的是，它们还通过D1受体选择性调节，D1受体通过蛋白激酶A（PKA）途径发出信号以提高兴奋性。该建议的目的是评估D1受体如何调节小鼠PFC中D1+神经元的兴奋性和抑制反应。我们首先使用全细胞记录，光遗传学和两光子显微镜的强大组合对D1+神经元的不同兴奋性输入进行表征。然后，我们使用这些方法来评估抑制性输入到D1+神经元上的特性，这些抑制性来自多种GABA能中间神经元。在这两种情况下，我们都会研究D1+神经元及其D1-邻骨的差异突触反应的基础的机制。定义了这些连接后，我们检验了我们的假设，即D1受体仅在D1+神经元下调节兴奋性和抑制突触。提出的实验将揭示这种锥体神经元的亚群如何与其长距离和局部电路相互作用。这些实验的结果将回答有关细胞和突触生理多巴胺调节的基本问题。他们还将帮助确定许多神经精神疾病的新型治疗靶标，这些疾病是由PFC中的多巴胺调节中断引起的。