Thalamic Regulation of Striatal Dendritic Morphology in Parkinsonism

描述（由申请人提供）：帕金森病（PD）的直接原因是黑质（SN）多巴胺神经元变性以及由此产生的纹状体多巴胺不足。然而，PD的病理学并不限于SN多巴胺神经元的丢失。在显示PD退行性变化的其他部位中，丘脑中央核-束旁复合体是其中之一。来自这些丘脑神经元的谷氨酸能传出投射到纹状体，在那里它们靶向中等多刺神经元（MSN）树突。先前已经表明，纹状体多巴胺投射的中断导致MSN的营养不良性变化，包括树突长度和棘密度的减少。然而，MSN树突状结构的可能调控丘脑纹状体神经元尚未探讨。来自束旁核（PF）的轴突突触到MSN的树突轴上。我们推测，从PF纹状体投射中断的结果在纹状体MSN树突的营养不良的变化。我们将评估丘脑和黑质多巴胺病变如何影响MSN树突形态在体内和体外。PD的主要治疗是多巴胺替代疗法，其靶向定位于MSN树突棘的多巴胺受体。MSN树突（多巴胺受体位于其上）的改变可能是晚期PD对多巴胺替代治疗反应性丧失的基础。了解丘脑如何促进PD病理学对于开发改善的疾病治疗方法非常重要，特别是在治疗选择有限的PD后期。

DESCRIPTION (provided by applicant): The proximate cause of Parkinson's disease (PD) is degeneration of substantia nigra (SN) dopamine neurons and the resultant striatal dopamine insufficiency. However, the pathology in PD is not limited to the loss of SN dopamine neurons. Among other sites showing degenerative changes in PD is the thalamic centromedian-parafasicular complex. Glutamatergic efferents from these thalamic neurons project to the striatum, where they target medium spiny neuron (MSN) dendrites. It has previously been shown that disruption of the striatal dopamine projection results in dystrophic changes in MSNs, including a decrease in dendritic length and spine density. However, the possible regulation of MSN dendritic structures by thalamostriatal neurons has not been explored. Axons from the parafascicular nucleus (PF) synapse onto the dendritic shaft of MSNs. We hypothesize that disruption of the striatal projection from the PF results in dystrophic changes in striatal MSN dendrites. We will assess how thalamic and nigral dopamine lesions affect MSN dendritic morphology both in vivo and in vitro. The primary treatment for PD is dopamine replacement therapy, which targets dopamine receptors that are localized to the spines of MSN dendrites. Alterations in MSN dendrites, on which dopamine receptors are localized, may underlie the loss of responsiveness to dopamine replacement therapy in late-stage PD. Understanding how the thalamus contributes to PD pathology is important for the development of improved treatments for the disorder, particularly late in the course of PD when treatment options are limited.