Striatal Acetylcholine and Behavioral Flexibility

描述（由申请人提供）：本提案的主要目的是更好地理解纹状体胆碱能系统如何促进行为灵活性。越来越多的证据表明，导致纹状体神经病理的神经和精神疾病，即帕金森病、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，帕金森病和亨廷顿病患者在尾状核和壳核的前部区域都表现出胆碱能标志物的减少。目前，纹状体回路或神经化学机制是认知灵活性的基础，尚不清楚。在阐明这些疾病的病因和开发有效的认知缺陷治疗方面的进展，部分依赖于识别纹状体内的基本神经化学机制，这些机制是帕金森病和亨廷顿病认知功能受损的基础。该建议的第一个目标是了解乙酰胆碱输出的背内侧和背外侧纹状体在视觉线索识别的习得和反转学习期间的动态变化，使用体内微透析高压液相色谱。帕金森氏症患者的最新研究表明，抗胆碱能治疗可导致认知灵活性缺陷。该建议的第二个目标是确定背内侧纹状体中特定的毒蕈碱受体亚型是否有助于行为灵活性。先前的研究发现，纹状体中的多巴胺活动也会影响认知灵活性。此外，现有研究表明，基底神经节中多巴胺能和胆碱能系统之间的相互作用与运动行为有关。该建议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排以影响行为灵活性。总的来说，这种方法采用了一种独特的方法来研究纹状体乙酰胆碱释放在实际学习和策略转移过程中的动态变化。拟议的研究还将提供有关特定毒蕈碱受体的补充信息，这些受体可能促进背内侧纹状体的行为灵活性。此外，所提出的研究可以帮助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有助于开发选择性和针对性的药物干预，以减轻帕金森病和亨廷顿病的认知症状，而不会产生不必要的运动副作用。

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.