Preventing Experience Dependent Aberrant Plasticity Under Dopamine Deficiency

预防多巴胺缺乏下的经验依赖性异常可塑性

• 批准号: 9188890
• 负责人: Daniel S McGehee
• 金额: $ 40.03万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188890
• 关键词: ADORA2A gene; Acute; Adverse effects; Affect; Agonist; Animal Model; Animals; Behavioral; Bradykinesia; Brain; Cells; Chronic; Computer Simulation; Confounding Factors (Epidemiology); Corpus striatum structure; Cyclic AMP; Data; Deterioration; Development; Disease model; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Dyskinetic syndrome; Electric Stimulation; Electrophysiology (science); Figs - dietary; Frequencies; Glutamates; Goals; Lead; Learning; Link; Long-Term Potentiation; Mental Depression; Methods; Motor; Motor output; Neurons; Neurotransmitters; Parkinson Disease; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Play; Preparation; Prevention; Protocols documentation; Psychological reinforcement; Publishing; Replacement Therapy; Role; Signal Transduction; Slice; Staging; Symptoms; Synapses; System; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Withholding Treatment; adenylyl cyclase type V; base; experience; in vivo; indicated prevention; inhibitor/antagonist; motor impairment; motor learning; motor symptom; novel; optogenetics; prevent; programs

The therapeutic effects of L-DOPA are remarkable in early stage Parkinson's disease (PD). However, with chronic dopamine replacement therapy, motor side effects such as dyskinesia become a severe problem in advanced PD. Mechanisms underlying PD symptoms and therapy are still poorly understood. Our recent studies in animal models have for the first time demonstrated that experience-dependent aberrant motor learning (learned motor inhibition) under low dopamine conditions may play a major role in PD motor symptoms, which was supported by recent studies on PD patients and by computational models. Moreover, we have demonstrated that glutamatergic inputs in combination with dopamine signaling through the adenylyl cyclase type 5 (AC5) and the cAMP pathway contributes to corticostriatal long-term potentiation and depression (LTP and LTD) in the dopamine D2 receptor-expressing striatal medium spiny neurons (MSNs). More importantly, we have found that aberrant LTP is associated with aberrant motor learning while prevention of such aberrant LTP is associated with prevention of aberrant motor learning. Our behavioral and electrophysiological advances have set the stage for identifying and testing potential PD therapies based on preventing and/or reversing aberrant corticostriatal LTP. In this application, we propose to test the precise conditions/parameters for induction of corticostriatal LTP/LTD in D2-expressing MSNs. We then aim to establish a causal link between aberrant corticostriatal LTP and aberrant motor learning as well as to test treatments that can prevent such aberrant corticostriatal LTP and aberrant motor learning. Finally, we will test the therapeutic effects of preventing and reversing aberrant LTP in PD models.

L-DOPA的治疗作用在帕金森氏病（PD）的早期阶段非常出色。然而，通过慢性多巴胺替代疗法，运动副作用（例如运动障碍）成为晚期PD的严重问题。 PD症状和治疗的机制仍然很少了解。我们最近在动物模型的研究首次证明，在低多巴胺条件下，经验依赖性的异常运动学习（学习的运动抑制）可能在PD运动症状中起主要作用，这得到了对PD患者和计算模型的最新研究的支持。 此外，我们已经证明，谷氨酸能输入与多巴胺信号通过5型（AC5）（AC5）结合使用，cAMP途径有助于皮质施加性长期增强和抑郁症（LTP和LTD）在多巴胺D2受体D2受体表达纹状体培养基中（MSSN）。更重要的是，我们发现异常LTP与异常运动学习有关，而预防这种异常LTP与预防异常运动学习有关。我们的行为和电生理学进步为基于预防和/或逆转异常皮质纹状体LTP而识别和测试潜在的PD疗法的阶段奠定了基础。在此应用程序中，我们建议测试D2表达MSN中皮质纹状体LTP/LTD诱导的精确条件/参数。然后，我们旨在建立异常皮质纹状体LTP与异常运动学习之间的因果关系，并测试可以防止这种异常皮质乳化性LTP和 异常运动学习。最后，我们将测试预防和逆转PD模型中异常LTP的治疗效果。