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.

左旋多巴（L-DOPA）对早期帕金森病（PD）的治疗效果显着。然而，通过长期多巴胺替代疗法，运动障碍等运动副作用成为晚期帕金森病的一个严重问题。 PD 症状和治疗的潜在机制仍然知之甚少。我们最近在动物模型中的研究首次证明，低多巴胺条件下依赖于经验的异常运动学习（习得性运动抑制）可能在帕金森病运动症状中发挥重要作用，这一点得到了最近对帕金森病患者的研究和计算的支持。模型。 此外，我们还证明，谷氨酸能输入与通过 5 型腺苷酸环化酶 (AC5) 和 cAMP 通路的多巴胺信号传导相结合，有助于表达多巴胺 D2 受体的纹状体中型多刺中的皮质纹状体长时程增强和抑制（LTP 和 LTD）神经元（MSN）。更重要的是，我们发现异常的 LTP 与异常的运动学习相关，而预防这种异常的 LTP 与预防异常的运动学习相关。我们的行为和电生理学进展为识别和测试基于预防和/或逆转异常皮质纹状体 LTP 的潜在 PD 疗法奠定了基础。在此应用中，我们建议测试在表达 D2 的 MSN 中诱导皮质纹状体 LTP/LTD 的精确条件/参数。然后，我们的目标是建立异常皮质纹状体 LTP 和异常运动学习之间的因果关系，并测试可以预防这种异常皮质纹状体 LTP 和异常运动学习的治疗方法。 异常的运动学习。最后，我们将测试在 PD 模型中预防和逆转异常 LTP 的治疗效果。