Functional Organization Of The Basal Ganglia

基底神经节的功能组织

• 批准号: 7136234
• 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/7136234
• 关键词: Parkinson' s disease; basal ganglia; biological signal transduction; brain mapping; central neural pathway /tract; dopamine; dopamine receptor; gene expression; neural information processing; neural plasticity; neuroanatomy; neurophysiology; protein kinase; receptor expression

Research in the Section on Neuroanatomy is concerned with the function of the basal ganglia. This forebrain neural system 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 uses neuroanatomical methods to study the connectional organization of the basal ganglia to study the regulation of gene expression responsible for neuronal plasticity within the striatum. 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. The purpose of these studies is to better establish how disorders of the basal ganglia, such as Parkinson's disease, result in clinical movement disorders, and 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.

关于神经解剖学的部分研究与基底神经节的功能有关。该前脑神经系统从所有皮质区域，通过纹状体输入的过程接收输入，其输出途径通过丘脑提供了反馈，以向参与行为选择和控制的皮质区域提供反馈。我们的工作使用神经解剖学方法来研究基底神经节的连接组织，以研究负责纹状体内神经元可塑性的基因表达的调节。当前的工作重点是扩展我们先前的发现，即通过在“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，调节纹状体输出途径的平衡功能。神经调节剂（例如多巴胺）可以改变神经元对突触输入的长期反应，例如皮质的谷氨酸能兴奋性输入。这种神经塑性是通过神经递质受体介导的蛋白激酶信号转导途径激活的激活来介导的，蛋白激酶信号转导途径的激活导致转录因子的激活和诱导负责改变突触反应的特定基因。我们证明，在纹状体中，“直接”和“间接”纹状体投影神经元通过不同形式的神经元可塑性，通过不同的蛋白激酶信号途径的差异激活影响对皮质输入的反应，多巴胺维持这些不同形式的反应。帕金森氏病动物模型中多巴胺病变后纹状体的功能障碍似乎是由于一种特别异常的神经元可塑性，这是由于调节特定蛋白激酶信号转导途径的调节所致。这些研究的目的是更好地确定基底神经节的疾病，例如帕金森氏病，导致临床运动障碍，以及基底神经节是否也可能参与此类精神障碍，例如注意力缺陷多功能过度活跃障碍，或滥用精神药物。