Striatal Acetylcholine and Behavioral Flexibility

描述(由申请人提供)：本提案的主要目标是更好地了解纹状体胆碱能系统如何有助于行为灵活性。越来越多的证据表明，导致纹状体神经病理的神经和精神障碍，即帕金森氏病、亨廷顿病和精神分裂症，会导致认知灵活性的严重缺陷。除了常见的认知症状外，帕金森氏病和亨廷顿病患者的尾状核和壳核前部的胆碱能标志物都有所减少。目前，尚不清楚是什么纹状体回路或神经化学机制支撑着认知灵活性。在阐明这些疾病的病因和开发有效的认知缺陷治疗方法方面的进展，在一定程度上取决于确定纹状体内的基本神经化学机制，这些机制是帕金森氏症和亨廷顿病认知功能受损的基础。该方案的第一个目标是了解在获得和逆转学习视觉线索辨别的过程中，背内侧和背外侧纹状体中乙酰胆碱输出的动态变化，使用体内高压液相色谱微透析。最近帕金森氏病患者的计时表明，抗胆碱能治疗会导致认知灵活性障碍。该提案的第二个目标是确定背内侧纹状体中特定的M受体亚型是否有助于行为灵活性。此前的研究发现，纹状体中的多巴胺活动也会影响认知灵活性。此外，现有的研究表明，与运动行为有关的基底神经节中的多巴胺能系统和胆碱能系统之间存在相互作用。该提案的第三个目标是确定多巴胺D1和/或D2受体是否调节背内侧纹状体的乙酰胆碱外流，以影响行为灵活性。总体而言，该方法采用了一种独特的方法来研究实际学习和策略转移过程中纹状体乙酰胆碱释放的动态变化。这项拟议的研究还将提供有关特定M受体的补充信息，该受体可能促进背内侧纹状体的行为灵活性。此外，拟议的研究还有助于解开特定纹状体回路中神经递质的复杂相互作用，因为它与行为灵活性有关。这些实验的发现可能使有选择和有针对性的药物干预措施的开发能够缓解帕金森氏症和亨廷顿病的认知症状，而不会产生不想要的运动副作用。

DESCRIPTION (provided by applicant): The main objective of this proposal is to build a greater understanding of how the striatal cholinergic system contributes to behavioral flexibility. There is accumulating evidence that neurological and psychiatric disorders that lead to striatal neuropathology, i.e. Parkinson's disease, Huntington's disease and schizophrenia, produce severe deficits in cognitive flexibility. In addition to the common cognitive symptomology, Parkinson's and Huntington's disease patients both exhibit decreases in cholinergic markers in the anterior regions of the caudate and putamen. At present, unknown is what striatal circuitry or neurochemical mechanisms underlie cognitive flexibility. Advances in elucidating the etiology of these disorders and development of effective treatments for the cognitive deficits relies, in part, on identifying the basic neurochemical mechanisms within the striatum that underlie the cognitive functions impaired in Parkinson's and Huntington's disease. The first goal of the proposal is to understand the dynamic changes in acetylcholine output in the dorsomedial and dorsolateral striatum during acquisition and reversal learning of a visual cue discrimination, using in vivo microdialysis with high pressure liquid chromatography. Recent timings in Parkinson's disease patients suggest that anti-cholinergic treatments lead to cognitive flexibility deficits. The second goal of the proposal is to determine whether specific muscarinic receptor subtypes in the dorsomedial striatum contribute to behavioral flexibility. Previous studies found that dopamine activity in the striatum also influences cognitive flexibility. Furthermore, extant research indicates an interaction between the dopaminergic and cholinergic systems in the basal ganglia related to motor behavior. The third goal of the proposal is to determine whether dopamine D1 and/or D2 receptors modulate acetylcholine efflux in the dorsomedial striatum to influence behavioral flexibility. Overall, this approach takes a unique approach in examining the dynamic changes in striatal acetylcholine release during the actual learning and shifting of strategies. The proposed studies will also provide complimentary information on the specific muscarinic receptors that may facilitate behavioral flexibility in the dorsomedial striatum. Moreover, the proposed studies can help unravel the complex interaction of neurotransmitters in specific striatal circuitry as it relates to behavioral flexibility. The findings from these experiments may enable the development of selective and targeted pharmacological interventions to alleviate the cognitive symptomology in Parkinson's and Huntington's disease without producing unwanted motoric side effects.