Synaptic and Dendritic Physiology in the Prefrontal Cortex

前额皮质的突触和树突生理学

• 批准号: 8402157
• 负责人: Adam G Carter
• 金额: $ 35.91万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-06 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8402157
• 关键词: Action Potentials; Animals; Area; Back; Behavior; Brain; Brain region; Calcium Channel; Calcium Signaling; Cells; Cognition; Complex; Dendrites; Dendritic Spines; Disease; Disease Attributes; Dopamine; Dopamine Receptor; Drug Addiction; Emotional; Emotions; Event; Functional disorder; Gene Expression; Glutamate Receptor; Glutamates; Goals; Health; Human; Image; Individual; Ion Channel; Kinetics; Laser Scanning Microscopy; Lasers; Location; Magnesium; Mediating; Membrane; Memory; Microscopy; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Pattern; Pharmacology; Photons; Physiological; Physiology; Play; Prefrontal Cortex; Primates; Property; Receptor Activation; Rodent; Schizophrenia; Shapes; Short-Term Memory; Signal Transduction; Slice; Sodium; Synapses; Synaptic Transmission; Synaptic plasticity; System; Technology; Testing; Ventral Tegmental Area; Vertebral column; cognitive control; dopamine D4 receptor; excitatory neuron; hippocampal pyramidal neuron; human disease; nervous system disorder; neuronal cell body; new therapeutic target; novel; receptor; research study; response; voltage

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.

描述（由申请人提供）：前额叶皮层对于控制从啮齿动物到灵长类动物的认知、情绪和记忆非常重要。前额皮质的重要性在多种神经系统疾病中凸显出来，包括精神分裂症和毒瘾。锥体神经元是前额皮质的主要细胞，整合来自多个大脑区域的谷氨酸能输入。这些兴奋性神经元还接收来自调节锥体神经元的皮层下大脑区域的大量多巴胺能输入。谷氨酸能和多巴胺能输入共同帮助控制锥体神经元的生理特性并确定前额皮质的功能。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。机械方法将揭示突触传递和整合过程中产生的电信号和钙 (Ca) 信号。 Ca 信号控制这些神经元突触可塑性、基因表达和形态稳定性的诱导。 2 光子显微镜和 2 光子激光解笼的组合将用于研究单个树突和棘的这些信号。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，他们还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 Ca 信号。这些实验的结果将回答有关前额锥体神经元如何整合其突触输入的基本问题。此外，他们还将确定新的治疗靶点，用于治疗因这些神经元功能障碍而引起的衰弱性神经系统疾病。