Neurophysiology of Receptor Actions in Prefrontal Cortex

前额皮质受体作用的神经生理学

• 批准号: 7127217
• 负责人: GRAHAM V WILLIAMS
• 金额: $ 17.19万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7127217
• 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质认知功能中的作用是神经生物学和临床研究的一个关键焦点，其动机是前额叶功能对多巴胺 D1 受体信号传导的显着依赖性，以及其在精神分裂症中的假设破坏。因此，对 D1 工作记忆神经机制调节的研究对精神分裂症中这一核心认知功能的损害产生了重要的见解。在非人类灵长类动物中，空间调节延迟活动或参与空间工作记忆任务的前额叶神经元的“记忆场”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反复激发对于记忆场的生成至关重要，并且是 D1 调制的战略位点。最近的体内研究发现了锥体神经元之间功能连接的证据，这些连接可能构成反复兴奋的基础，并且该电路元件突触功效的 D1 调节已在体外得到证实。 D 1 调制也与前额叶回路的前馈抑制机制有关，该机制已被纳入网络模型中，以提供对锥体细胞放电的空间和时间限制。因此，为了了解 D1 调节影响工作记忆的机制，有必要直接检查该受体对前额叶电路功能连接关键组成部分的选择性作用。为此，我们打算在执行空间工作记忆任务的非人类灵长类动物中，率先使用微离子电渗疗法的强大组合来分析选择性多巴胺受体功能，并使用多电极记录来分析前额神经元之间的功能连接。通过这些方法，我们的目标是 (i) 研究 D1 信号传导选择性调节假定锥体细胞之间的反复兴奋的假设，这取决于认知表现过程中时空处理的一致性程度，(ii) 表明通过修改假定的中间神经元和神经元之间的抑制连接，在这些微电路中存在 D 1 介导的前馈抑制的互补调节。 (iii) 显示 D 1 对假定的中间神经元的前馈激励的调制，这对于驱动其电路功能可能至关重要。这项工作的结果将有助于阐明多巴胺在前额叶功能中发挥作用的内在回路的要素，并查明精神分裂症中多巴胺失调的可能部位。