Cellular and synaptic mechanisms for dopaminergic modulation of prefrontal cortex

描述（由申请人提供）：前额叶皮层（PFC）在认知方面起着关键作用，包括工作记忆、行为灵活性和决策。相反，这个大脑区域的功能障碍会导致认知缺陷，包括精神障碍的主要方面，如精神分裂症。在这里，我们将阐明神经调节剂多巴胺如何调节PFC内特定类别神经元的活动。这是很重要的，因为多巴胺被认为是调节PFC的正常和病理功能。事实上，精神分裂症研究中的一个主要假设是，异常的多巴胺能调节导致PFC功能障碍和精神分裂症的一些症状。然而，前额叶多巴胺受体发挥其正常和病理作用的具体机制仍然是未知的。我们最近在《神经科学杂志》上发表的文章描述了多巴胺受体对PFC中特定神经元群体的新影响。这项提议将集中在前额叶神经元的这一亚群上，我们称之为“A型神经元”。“我们提出，不同类别的多巴胺受体对这些神经元的兴奋性产生相反的影响，并且这些神经元中的异常活动可能由某些多巴胺受体的过度激活驱动，可以在小鼠中产生类似精神分裂症的行为。首先，我们将确定特定的离子通道和其他机制，介导多巴胺受体对A型神经元的影响。然后，我们将确定多巴胺受体如何通过改变A型神经元的兴奋性来改变它们对突触输入的反应。我们将特别确定多巴胺受体是否对来自不同来源的突触输入产生不同的影响。最后，我们将向PFC中释放多巴胺的纤维提供各种模式的刺激。这些实验将测试这些纤维中不同的活动模式将激活不同的多巴胺受体，产生不同的多巴胺受体的假设。 对A型神经元的影响我们的许多实验将利用新的光遗传学技术，这使得用光刺激特定的神经元或神经连接成为可能。这项提案将集中在多巴胺受体如何调节A型神经元的活动。我们的长期目标是将A型神经元活动的这些变化与PFC依赖行为的影响联系起来，包括精神分裂症和其他精神疾病中发生的病理行为。

DESCRIPTION (provided by applicant): The prefrontal cortex (PFC) plays a key role in aspects of cognition including working memory, behavioral flexibility, and decision making. Conversely, dysfunction of this brain region causes cognitive deficits, including major aspects of psychiatric disorders such as schizophrenia. Here, we will elucidate how the neuromodulator dopamine regulates activity in a specific class of neurons within the PFC. This is important because dopamine is believed to regulate both the normal and pathological function of the PFC. In fact, a major hypothesis in schizophrenia research is that abnormal dopaminergic modulation causes PFC dysfunction and some symptoms of schizophrenia. However, specific mechanisms through which prefrontal dopamine receptors exert their normal and pathological effects remain largely unknown. Our recent publication in the Journal of Neuroscience describes new effects of dopamine receptors on a specific population of neurons in the PFC. This proposal will focus on this subpopulation of prefrontal neurons, which we refer to as "type A neurons." We propose that different classes of dopamine receptors produce opposing effects on the excitability of these neurons, and that aberrant activity in these neurons, which may be driven by excessive activation of certain dopamine receptors, can produce schizophrenia-like behaviors in mice. First, we will identify specific ion channels and other mechanisms that mediate the effects of dopamine receptors on type A neurons. Then, we will determine how, by altering the excitability of type A neurons, dopamine receptors can alter their responses to synaptic input. We will specifically determine whether dopamine receptors produce distinct effects on synaptic inputs that arise from different sources. Finally, we will deliver various patterns of stimulation to fibes that release dopamine in the PFC. These experiments will test the hypothesis that different patterns of activity in these fibers will activate different dopamine receptors, producing distinct effects on type A neurons. Many of our experiments will utilize new optogenetic technologies, which make it possible to stimulate specific neurons or neural connections, with light. This proposal will focus on how dopamine receptors modulate the activity of type A neurons. Our long-term goal is to relate these changes in type A neuron activity to effects on PFC-dependent behaviors, including pathological behaviors that occur in schizophrenia and other psychiatric disorders.