Synaptic and Dendritic Physiology in the Prefrontal Cortex

描述(申请人提供)：前额叶皮质对控制从啮齿动物到灵长类动物的认知、情感和记忆非常重要。前额叶皮质的重要性在包括精神分裂症和药物成瘾在内的多种神经疾病中都得到了强调。锥体神经元是前额叶皮质的主要细胞，整合了来自多个脑区的谷氨酸能输入。这些兴奋性神经元还从调节锥体神经元的皮质下脑区接受广泛的多巴胺能输入。谷氨酸和多巴胺能共同帮助调节锥体神经元的生理特性，并决定前额叶皮质的功能。这项研究的主要目标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。一种机械的方法将揭示突触传递和整合过程中产生的电和钙信号。钙信号控制这些神经元突触可塑性的诱导、基因表达和形态稳定性。我们将结合使用双光子显微镜和双光子激光技术来研究单个树突和棘突上的这些信号。计划中的实验将揭示不同的电压敏感离子通道和谷氨酸受体在产生钙信号方面的重要性。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，以影响局部钙信号。这些实验的结果将回答关于前额锥体神经元如何整合它们的突触输入的基本问题。此外，他们将为这些神经元功能障碍引起的衰弱神经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.