Dendritic Ca signals in striatal medium spiny neurons

描述（由申请人提供）：纹状体是一个关键的大脑区域，在自主运动的启动和执行中起着核心作用。中棘神经元（MSNs）是纹状体中最常见的细胞类型，它们引起纹状体向参与运动协调的其他脑区发送的抑制性投射。MSN的退化或功能紊乱发生在几种人类运动障碍中，包括亨廷顿氏病和帕金森氏病以及某些精神疾病和药物成瘾。在大多数神经元中，刺激诱发的钙进入MSN调节许多过程，包括神经元兴奋性，电路连接和基因转录。最近，在亨廷顿病患者以及该疾病的小鼠模型中已经确定了钙处理的扰动。有趣的是，这种缺陷在出现任何运动症状之前就可以检测到，并且可能暗示钙调节的改变直接导致疾病后期出现的神经元功能障碍。尽管存在用于研究神经元中的钙处理的成熟技术，但MSN树突中的钙信号传导的性质仍然相对未被探索。拟议的工作将使用双光子激光扫描显微镜，双光子激光uncaging和全细胞电生理学的组合来分析MSN如何整合许多突触的活动。我们的研究将探讨如何在MSNs和突触活动中发现的许多类型的电压门控离子通道之间的非线性相互作用决定膜去极化和钙信号。一种新的技术将被用来确定树突上的活性突触的空间排列是否决定了突触活动对膜去极化的净效应。此外，我们将研究这些非线性是否在突触可塑性的诱导中发挥作用。最后，将检查多巴胺对突触整合和钙处理的影响。最终，我们希望了解MSNs的特殊电生理和形态学特性如何影响纹状体功能，以及这些过程的扰动如何导致人类疾病。

DESCRIPTION (provided by applicant): The striatum is a key brain area that plays a central role in the initiation and execution of voluntary movements. Medium spiny neurons (MSNs) are the most common cell type in the striatum and they give rise to the inhibitory projection that striatum sends to other brain areas involved in motor coordination. Degeneration or perturbed function of MSNs occurs in several human movement disorders including Huntington's and Parkinson's as well as in certain psychiatric illnesses and drug addiction. As in most neurons, stimulus-evoked calcium entry into MSNs regulates many processes including neuronal excitability, circuit connectivity, and gene transcription. Recently, perturbed calcium handling has been identified in patients with Huntington's disease as well as in mouse models of the disease. Interestingly this defect is detectable before the appearance of any motor symptoms and may hint that altered calcium regulation directly leads to the neuronal dysfunction seen in later stages of the disease. Despite the existence of well-established techniques for the study of calcium handling in neurons, the properties of calcium signaling in dendrites of MSNs remain relatively unexplored. The proposed work will use a combination of 2-photon laser scanning microscopy, 2-photon laser uncaging, and whole-cell electrophysiology to analyze how MSNs integrate the activity of many synapses. Our study will examine how nonlinear interactions between the many types of voltage-gated ion channels found in MSNs and synaptic activity dictate both membrane depolarization and calcium signaling. A novel technique will be used to determine if the spatial arrangement of active synapses on the dendrite determines the net effect of synaptic activity on membrane depolarization. Furthermore we will examine whether these nonlinearities play a role in the induction of synaptic plasticity. Lastly, the effect of dopamine on synaptic integration and calcium handling will be examined. Ultimately, we hope to understand how the specialized electrophysiological and morphological properties of MSNs influence striatal function and how perturbation of these processes contributes to human disease.