Functional Organization Of The Basal Ganglia

基底神经节的功能组织

• 批准号: 6671562
• 负责人: CHARLES R GERFEN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6671562
• 关键词: Parkinson's disease; basal ganglia; brain mapping; central neural pathway /tract; cerebral cortex; corpus striatum; dopamine; dopamine receptor; neuroanatomy; neuropharmacology; neurotransmitter receptor; receptor expression; regulatory gene

Resesarch in the Section on Neuroanatomy is concerned with the role of the basal ganglia in behavior. The basal ganglia receives inputs from all cortical areas, processes that input through the striatum, whose output pathways provide feedback, through the thalamus, to cortical areas involved in the selection and control of behavior. Our work focuses on two general questions of basal ganglia function. First, the organization of cortical input to the striatum, in order to understand what information the cortex provides to the basal ganglia? Second, to determine what the basal ganglia does with information from the cortex, which is essential to understand how the basal ganglia affects frontal cortical function. We address these questions in order to better establish how disorders of the basal ganglia, such as Parkinson?s disease, result in clinical movement disorders, or whether the basal ganglia might also be involved in such mental disorders, such as Attention Deficit Hyperactivity Disorder, or in the abuse of psychoactive drugs. Work done in this past year addressed primarily the second question. Current work is focused on extending our prior findings that dopamine, through the segregation of the D1 and D2 dopamine receptor subtypes in the "direct" and "indirect" striatal output neurons, regulates the balanced function of striatal output pathways. Neuromodulators such as dopamine act to alter the long term response of neurons to synaptic input, such as the glutamatergic excitatory input from the cortex. Such neuroplasticity is mediated by the activation of neurotransmitter receptor-mediated activation of protein kinase signal transduction pathways, which result in the activation of transcription factors and induction of specific genes that are responsible for altering synaptic responses. We demonstrated that in the striatum, the ?direct? and ?indirect? striatal projection neurons support distinct forms of neuronal plasticity that affect responses to cortical input, through the differential activation of distinct protein kinase signaling pathways, and dopamine maintains these different forms of response. Dysfunction of the striatum following dopamine lesions in animal models of Parkinson?s disease, appear to be due to a particularly aberrant form of neuronal plasticity that is due to a switch in the regulation of a particular protein kinase signal transduction pathway.

神经解剖学部分的研究关注基底神经节在行为中的作用。基底神经节接收来自所有皮质区域的输入，处理通过纹状体的输入，纹状体的输出路径通过丘脑向涉及行为选择和控制的皮质区域提供反馈。我们的工作重点是基底神经节功能的两个一般问题。首先，组织皮层向纹状体的输入，以了解皮层向基底节提供哪些信息？其次，确定基底神经节如何处理来自皮质的信息，这对于了解基底神经节如何影响额叶皮质功能至关重要。我们解决这些问题是为了更好地确定基底神经节疾病（例如帕金森病）如何导致临床运动障碍，或者基底神经节是否也可能与此类精神疾病（例如注意力缺陷多动障碍）有关。或滥用精神药物。去年所做的工作主要解决第二个问题。目前的工作重点是扩展我们之前的发现，即多巴胺通过“直接”和“间接”纹状体输出神经元中 D1 和 D2 多巴胺受体亚型的分离，调节纹状体输出通路的平衡功能。多巴胺等神经调节剂可改变神经元对突触输入（例如来自皮层的谷氨酸兴奋性输入）的长期反应。这种神经可塑性是通过神经递质受体介导的蛋白激酶信号转导途径的激活来介导的，从而导致转录因子的激活和负责改变突触反应的特定基因的诱导。我们证明，在纹状体中，“直接”和？间接？纹状体投射神经元支持不同形式的神经元可塑性，通过不同蛋白激酶信号通路的差异激活影响对皮质输入的反应，而多巴胺维持这些不同形式的反应。帕金森病动物模型中多巴胺损伤后纹状体的功能障碍似乎是由于神经元可塑性的特别异常形式引起的，而神经元可塑性是由于特定蛋白激酶信号转导途径的调节转换所致。