Neurophysiology of Receptor Actions in Prefrontal Cortex

前额皮质受体作用的神经生理学

• 批准号: 6951064
• 负责人: GRAHAM V WILLIAMS
• 金额: $ 17.41万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951064
• 关键词: Primates; biological signal transduction; brain electrical activity; cognition; dopamine; dopamine receptor; electrodes; electrophysiology; intercellular connection; interneurons; magnetic resonance imaging; neural information processing; neuroanatomy; neurophysiology; neuroregulation; neurotransmitter transport; prefrontal lobe /cortex; pyramidal cells; receptor expression; short term memory

DESCRIPTION (provided by applicant): Dopamine's role in regulating cognitive functions of prefrontal cortex is a pivotal focus of neurobiological and clinical research, motivated by the striking dependence of prefrontal function on dopamine D1 receptor signaling, and its hypothesized disruption in schizophrenia. Thus, studies on D1 modulation of the neural mechanisms of working memory have generated important insights into the impairment of this core cognitive function in schizophrenia. In nonhuman primates, the spatially tuned delay activity, or "memory fields" of prefrontal neurons engaged by spatial working memory tasks are highly dependent on the prevailing level of D1 receptor stimulation. Computational models predict that recurrent excitation between pyramidal cells is essential for the generation of memory fields, and a strategic site for D1 modulation. Recent studies in vivo have found evidence of functional connections between pyramidal neurons that may form the basis of recurrent excitation, and D1 modulation of the synaptic efficacy of this circuit element has been demonstrated in vitro. D 1 modulation has also been implicated in the feedforward inhibitory mechanisms of prefrontal circuits, which have been incorporated into network models to provide for spatial and temporal constraints on pyramidal cell firing. Therefore, in order to understand the mechanisms by which D1 modulation impinges on working memory, it is necessary to directly examine the selective actions of this receptor on the key components of functional connectivity in prefrontal circuitry. For this purpose, we intend to pioneer the use of a powerful combination of microiontophoresis for analysis of selective dopamine receptor function, with multielectrode recording for analysis of the functional connectivity between prefrontal neurons, in nonhuman primates performing spatial working memory tasks. By these means, we aim (i) to investigate the hypothesis hat D1 signaling selectively regulates recurrent excitation between putative pyramidal cells, dependent on the degree of concordance in their spatiotemporal processing during cognitive performance, (ii) to show that there is a complementary D 1-mediated regulation of feed forward inhibition in these microcircuits via modification of inhibitory connections between putative interneurons and pyramidal cells, and (iii) to show D 1 modulation of feed forward excitation onto putative interneurons that may be essential for driving their circuit functions. Findings from this work will help to elucidate the elements of intrinsic circuitry by which dopamine exerts its role in prefrontal function and pinpoint the probable sites of dopamine dysregulation in schizophrenia.

描述（由申请人提供）：多巴胺在调节前额叶皮层认知功能中的作用是神经生物学和临床研究的关键焦点，其动机是前额叶功能对多巴胺D1受体信号传导的显著依赖性及其在精神分裂症中的假设中断。因此，D1调制的神经机制的工作记忆的研究产生了重要的见解精神分裂症的核心认知功能的损害。在非人灵长类动物中，空间调谐延迟活动，或“记忆领域”的前额叶神经元从事空间工作记忆任务是高度依赖于D1受体刺激的普遍水平。计算模型预测，锥体细胞之间的经常性兴奋是必不可少的记忆领域的产生，和D1调制的战略网站。最近的研究在体内发现的证据，锥体神经元之间的功能连接，可能形成的基础上，经常性的兴奋，和D1调制的突触功效的这个电路元件已被证明在体外。D1调制也与前额叶回路的前馈抑制机制有关，前额叶回路已被纳入网络模型，以提供对锥体细胞放电的空间和时间约束。因此，为了了解D1调制影响工作记忆的机制，有必要直接检查该受体对前额叶回路功能连接的关键组成部分的选择性作用。为此，我们打算开拓使用一个强大的组合，微离子电渗法的选择性多巴胺受体功能的分析，与多电极记录的功能连接分析前额叶神经元之间，在非人灵长类动物执行空间工作记忆任务。通过这些手段，我们的目的是（i）调查假设D1信号选择性地调节假定的锥体细胞之间的反复兴奋，依赖于认知表现过程中时空处理的一致性程度，（ii）显示存在一个互补的D1-在这些微回路中通过修饰假定的中间神经元和锥体细胞之间的抑制性连接介导前馈抑制的调节，以及（iii）显示对推定的中间神经元的前馈激励的D1调制，这可能是驱动它们的电路功能所必需的。这项工作的结果将有助于阐明多巴胺发挥其在前额叶功能中的作用的内在电路的元素，并查明精神分裂症中多巴胺失调的可能位点。