Synaptic and Dendritic Physiology in the Prefrontal Cortex

描述（由申请人提供）：从啮齿类动物到灵长类动物，前额叶皮层对控制认知、情感和记忆非常重要。前额叶皮层在多种神经系统疾病，包括精神分裂症和药物成瘾中的重要性得到了强调。锥体神经元是前额叶皮层的主要细胞，整合来自大脑多个区域的谷氨酸输入。这些兴奋性神经元也接受来自皮质下脑区调节锥体神经元的广泛多巴胺能输入。谷氨酸能和多巴胺能的输入共同帮助控制锥体神经元的生理特性，并决定前额皮质的功能。本研究的主要目的是了解这些输入如何在锥体神经元的亚细胞水平上相互作用。一个机制的方法将揭示在突触传递和整合过程中产生的电和钙（Ca）信号。Ca信号控制着这些神经元突触可塑性的诱导、基因表达和形态稳定性。结合双光子显微镜和双光子激光脱模将用于研究这些信号在单个树突和棘。计划中的实验将揭示不同电压敏感离子通道和谷氨酸受体在产生Ca信号中的重要性。此外，他们将确定多巴胺受体激活如何调节这些通道和受体来影响局部Ca信号。这些实验的结果将回答有关前额叶锥体神经元如何整合其突触输入的基本问题。此外，他们将为由这些神经元功能障碍引起的衰弱性神经系统疾病确定新的治疗靶点。

DESCRIPTION (provided by applicant): The prefrontal cortex is important for controlling cognition, emotion and memory in animals ranging from rodents to primates. The importance of the prefrontal cortex is highlighted in multiple neurological diseases, including schizophrenia and drug addiction. Pyramidal neurons are the principal cells of the prefrontal cortex and integrate glutamatergic inputs from multiple brain regions. These excitatory neurons also receive extensive dopaminergic inputs from sub-cortical brain areas that modulate pyramidal neurons. Together, glutamatergic and dopaminergic inputs help to govern the physiological properties of pyramidal neurons and determine the function of the prefrontal cortex. The primary goal of this study is to understand how these inputs interact at the sub-cellular level in pyramidal neurons. A mechanistic approach will reveal the electrical and calcium (Ca) signals generated during synaptic transmission and integration. Ca signals control the induction of synaptic plasticity, gene expression and morphological stability of these neurons. A combination of 2-photon microscopy and 2-photon laser uncaging will be used to study these signals at individual dendrites and spines. The planned experiments will reveal the importance of different voltage-sensitive ion channels and glutamate receptors in generating Ca signals. Moreover, they will determine how dopamine receptor activation modulates these channels and receptors to influence local Ca signals. The results from these experiments will answer fundamental questions about how prefrontal pyramidal neurons integrate their synaptic inputs. Moreover, they will identify novel therapeutic targets for the debilitating neurological diseases that arise from dysfunction of these neurons.