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

描述（由申请人提供）：多巴胺（DA）在前额叶皮层（PFC）的功能中起核心作用。虽然PFC中的大多数多巴胺受体都是D1型，但D2受体（D2Rs）在工作记忆中作为D1激活的平衡以及在设置转换任务期间调节行为方面都起着至关重要的作用。此外，D2R系统的功能障碍已被假设为许多精神疾病的基础，最显著的是精神分裂症，并且D2R是药物治疗的主要靶点。最近，我与Sohal实验室的合作者一起研究了小鼠PFC中表达D2R的神经元，发现了两个主要结果：（1）在第V层PFC中表达D2R的锥体细胞的群体与先前鉴定的厚簇状皮质下投射神经元的群体一致。(2)将D2R激动剂应用于这些细胞导致钙激活的非特异性离子通道介导的后去极化，其依赖于通过NMDR受体和树突状L型钙通道的钙进入。这些研究结果，与研究表明，厚簇PFC神经元形成一个高度经常性的网络在第五层的PFC建议以下假设：DA可以导致持久的网络活动的D2R表达细胞网络的时代类似的活动，已观察到与D1R激活，和DA刺激的量和类型可以调节这些细胞中的活动模式的稳定性。这一假设将通过实验和计算建模目标的组合进行测试。在实验上，我将测试D2R表达神经元对突触和多巴胺能刺激的精确反应，使用光遗传学技术刺激不同类型的轴突末梢。然后，这些数据将被整合到D2R表达神经元网络的生物物理模型中，以发现这些细胞中持续活动可能发生的精确条件，以及持续活动模式对不同类型的突触输入稳定的程度。这项研究将有助于阐明D2R表达细胞在PFC功能中的作用，通过提供这些细胞的明确模型。此外，该模型可用于深入了解正常D2R功能的扰动，这些扰动被假设为精神疾病（如精神分裂症）的基础。 公共卫生相关性：多巴胺在大脑皮层的正常功能中起着重要作用。多巴胺系统的功能障碍被认为是包括精神分裂症在内的许多精神疾病的基础。多巴胺对皮层网络影响的详细模型可能会对这些疾病的诊断和治疗产生新的见解。

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. PUBLIC HEALTH RELEVANCE: Dopamine has an important role in the normal function of the cortex. Dysfunction of the dopamine system is thought to underlie a number of psychiatric diseases including schizophrenia. A detailed model of dopamine's effect on cortical networks could lead to new insights into the diagnosis and treatment of these diseases.