Dopamine D2 Receptors in Prefrontal Function: An Optogenetic and Modeling Study

描述(申请人提供)：多巴胺(DA)在前额叶皮质(PFC)的功能中起着核心作用。虽然PFC中的大多数多巴胺受体是D1型的，但D2受体(D2Rs)在平衡工作记忆中的D1型激活和在集合转移任务中调节行为方面发挥着至关重要的作用。此外，D2R系统的功能障碍被认为是许多精神疾病的基础，最明显的是精神分裂症，D2R是药物治疗的主要靶点。最近，我与Sohal实验室的合作者研究了小鼠PFC中D2R表达的神经元，发现了两个主要结果：(1)在V层PFC中表达D2R的锥体细胞群与先前发现的粗簇状、皮质下投射神经元群一致。(2)应用D2R激动剂可引起钙激活的非特异性离子通道介导的后去极化，该通道依赖于钙离子通过NMDR受体和树突L型钙通道进入细胞内。这些发现，再加上PFC神经元在PFC的V层形成一个高度重复的网络的研究，提出了以下假设：DA可以在表达D2R的细胞网络中导致持续网络活动的时代，类似于D1R激活所观察到的活动，DA刺激的数量和类型可以调节这些细胞中活动模式的稳定性。这一假设将通过实验和计算建模目标的组合来检验。在实验上，我将使用光遗传学技术刺激不同类型的轴突终末，测试表达D2R的神经元对突触和多巴胺能刺激的准确反应。然后，这些数据将被整合到表达D2R的神经元网络的生物物理模型中，以发现这些细胞之间发生持续活动的确切条件，以及持续活动模式对不同类型突触输入的稳定程度。这项研究将通过提供一个明确的模型，帮助阐明D2R表达细胞在PFC功能中的作用。此外，这个模型可以用来洞察正常D2R功能的扰动，这些扰动被假设为精神分裂症等精神疾病的基础。

DESCRIPTION (provided by applicant): Dopamine (DA) plays a central role in the function of the prefrontal cortex (PFC). While the majority of dopamine receptors in PFC are D1-type, D2-receptors (D2Rs) play a vital role both as a counterbalance to D1 activation in working memory and in modulating behavior during set-shifting tasks. Additionally, dysfunction of the D2R system has been hypothesized to underlie a number of psychiatric diseases, most notably schizophrenia, and D2Rs are a major target of drug therapies. Recently, with collaborators in the Sohal laboratory, I have studied D2R-expressing neurons in mouse PFC and discovered two major results: (1) The population of D2R-expressing pyramidal cells in layer V PFC is coincident with a previously identified population of thick-tufted, subcortically projecting neuron. (2) Applying D2R agonists to these cells leads to a calcium-activated non-specific ion channel mediated afterdepolarization that is dependent on calcium entry through NMDR receptors and dendritic L-type calcium channels. These findings, taken together with studies showing that thick-tufted PFC neurons form a highly recurrent network in layer V of PFC suggest the following hypothesis: DA can lead to epochs of persistent network activity in D2R-expressing cell networks analogous to the activity that has been observed with D1R activation, and the amount and type of DA stimulation can modulate the stability of patterns of activity in these cells. This hypothesis will be tested through a combination of experimental and computational modeling aims. Experimentally, I will test the precise response of D2R-expressing neurons to synaptic and dopaminergic stimuli using optogenetic techniques to stimulate different types of axon terminals. This data will then be integrated into a biophysical model of networks of D2R-expressing neurons to discover the precise conditions under which persistent activity can occur among these cells and the extent to which patterns of persistent activity are stable against different types of synaptic input. This study will help to illuminate the role of D2R-expressing cells in the function of the PFC by providing an explicit model of these cells. In addition, this model may be used to gain insight into perturbations of normal D2R function that have been hypothesized to underlie psychiatric diseases such as schizophrenia.