Zhuang Xiaowen, Lemak Julia, Sridhar Sadhana, Nelson Alexandra B
Kavli Institute for Fundamental Neuroscience, UCSF, San Francisco, CA 94158, USA.
Weill Institute for Neurosciences, UCSF, San Francisco, CA 94158, USA.
bioRxiv. 2024 Nov 1:2024.02.19.581062. doi: 10.1101/2024.02.19.581062.
Healthy action selection relies on the coordinated activity of striatal direct and indirect pathway neurons. In Parkinson's disease (PD), in which loss of midbrain dopamine neurons is associated with progressive motor and cognitive deficits, this coordination is disrupted. Dopamine replacement therapy can remediate motor symptoms, but can also cause impulse control disorder (ICD), which is characterized by pathological gambling, hypersexuality, and/or compulsive shopping. The cellular and circuit mechanisms of ICD remain unknown. Here we developed a mouse model of PD/ICD, in which ICD-like behavior was assayed with a delay discounting task. We found that in parkinsonian mice, the dopamine agonist pramipexole drove more pronounced delay discounting, as well as disrupted firing in both direct and indirect pathway neurons. We found that chemogenetic inhibition of indirect pathway neurons in parkinsonian mice drove similar phenotypes. Together, these findings provide a new mouse model and insights into ICD pathophysiology.
健康的行为选择依赖于纹状体直接和间接通路神经元的协同活动。在帕金森病（PD）中，中脑多巴胺神经元的丧失与进行性运动和认知缺陷相关，这种协同作用被破坏。多巴胺替代疗法可以缓解运动症状，但也会导致冲动控制障碍（ICD），其特征为病理性赌博、性欲亢进和/或强迫性购物。ICD的细胞和神经回路机制仍然未知。在此，我们建立了一个PD/ICD小鼠模型，其中通过延迟折扣任务来检测类似ICD的行为。我们发现，在帕金森病小鼠中，多巴胺激动剂普拉克索导致更明显的延迟折扣，以及直接和间接通路神经元的放电紊乱。我们发现，对帕金森病小鼠间接通路神经元进行化学遗传学抑制会产生类似的表型。这些发现共同提供了一个新的小鼠模型，并为ICD的病理生理学提供了见解。
