Neurophysiology of Receptor Actions in Prefrontal Cortex

描述(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关键焦点，其动机是前额叶功能对多巴胺D1受体信号的显著依赖，以及它在精神分裂症中的假想破坏。因此，对工作记忆神经机制的D1调控的研究对精神分裂症患者这一核心认知功能的损害具有重要的意义。在非人类灵长类动物中，参与空间工作记忆任务的前额叶神经元的空间调节延迟活动或“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兴奋对于记忆场的产生是必不可少的，也是D1调制的战略位置。最近的体内研究发现，锥体神经元之间存在功能性联系，这可能是反复兴奋的基础，并且在体外已经证实了该回路元件对突触效能的调节作用。前额叶电路的前馈抑制机制也涉及到D1调制，这些机制已被纳入网络模型，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调制影响工作记忆的机制，有必要直接检测该受体对前额叶功能连接的关键成分的选择性作用。为此，我们打算在执行空间工作记忆任务的非人灵长类动物中，率先使用微离子导入和多电极记录的强大组合来分析选择性多巴胺受体功能，并分析前额神经元之间的功能连接。通过这些手段，我们的目的是(I)研究假设的D_1信号选择性地调节假定的锥体细胞之间的重复兴奋，依赖于它们在认知操作过程中时空加工的协调程度，(Ii)证明在这些微电路中存在互补的D_1介导的前馈抑制调节，通过改变假定的中间神经元和锥体细胞之间的抑制连接，以及(Iii)显示前馈兴奋对假定的中间神经元的D_1调制，这可能是驱动它们的电路功能所必需的。这项工作的发现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元素，并准确定位精神分裂症中多巴胺失调的可能部位。

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.