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学的神经和精神障碍，即帕金森病、亨廷顿病和精神分裂症，会产生认知灵活性的严重缺陷。除了常见的认知障碍，帕金森病和亨廷顿病患者都表现出尾状核和壳核前部区域的胆碱能标记物减少。目前，认知灵活性背后的纹状体回路或神经化学机制尚不清楚。阐明这些疾病的病因学和开发有效的认知缺陷治疗方法的进展部分依赖于确定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中认知功能受损的基础。建议的第一个目标是了解乙酰胆碱输出的动态变化，在背内侧和背外侧纹状体在收购和逆转学习的视觉线索的歧视，在体内微透析与高压液相色谱。最近帕金森病患者的时间表明，抗胆碱能治疗导致认知灵活性缺陷。该提案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，现有的研究表明，多巴胺和胆碱能系统之间的相互作用，在基底神经节有关的运动行为。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中的乙酰胆碱流出以影响行为灵活性。总的来说，这种方法在研究实际学习和策略转换过程中纹状体乙酰胆碱释放的动态变化方面采取了独特的方法。拟议的研究还将提供有关可能促进背内侧纹状体行为灵活性的特定毒蕈碱受体的补充信息。此外，拟议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靶向的药物干预，以减轻帕金森病和亨廷顿病的认知障碍，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.