Dendritic Integration and Direction Selectivity in Starburst Amacrine Cells

描述（由申请人提供）：在视网膜中，方向选择性神经节细胞响应于在优选方向上移动的光刺激而激发许多动作电位，并且响应于在相反方向上移动的光激发很少的动作电位。γ-氨基丁酸（GABA）从星爆无长突细胞树突的不对称释放被认为赋予方向选择性神经节细胞这种方向选择性调谐。与从远端树突向索马移动的光相比，在从其索马向远端树突移动的光刺激期间，星状无长突细胞在GABA释放位点附近的远端树突中表现出更大的Ca 2+增加。Ca 2+水平的这种不对称性的来源和后果还不清楚。 在这个提议中，我探讨了星爆无长突的假设， 细胞在单个树突中自主地计算方向。树突如何整合其输入具有广泛的重要性，因为它是所有具有多个输入的神经元中神经元信号传导的关键步骤之一。星爆型无长突细胞与其他类型的细胞不同，因为它们的整合点位于树突的远端而不是索马。此外，与许多其他类型的神经元不同，星爆型无长突细胞如何整合其输入的问题与细胞的已知生理功能有关，因为输入的顺序与移动光刺激的方向直接相关。因此，了解星爆细胞树突中的整合将直接有助于我们理解 星状无长突细胞在视网膜回路中的作用。 利用电生理学，谷氨酸 通过展开和成像技术，我将确定星爆细胞树突中固有的非线性是否有利于从索马向远端树突中的释放位点顺序到达的双极细胞输入，而不是以相反顺序到达的输入（Aim 1）。此外，我提出的实验，以确定是否先前观察到的Ca 2+在刺激过程中向远端树突的增加，导致抑制从星爆无长突细胞方向选择性神经节细胞（目标2）的增加。最后，我建议实验，以确定电压门控钙通道的作用，在建立不对称的钙离子内流和GABA释放星爆无长突细胞树突（目的3）。

DESCRIPTION (provided by applicant): In the retina, direction selective ganglion cells fire many action potentials in response to light stimuli moving in a preferred direction and few action potentials to light moving in the opposite direction. Asymmetric release of gamma-aminobutyric acid (GABA) from starburst amacrine cells dendrites is thought to confer this direction selective tuning to direction selective ganglion cells. Starburst amacrine cells have been shown to exhibit a larger increase in Ca2+ in their distal dendrites near GABA release sites during stimulation with light moving from their soma toward the distal dendrites compared with light moving from the distal dendrites toward the soma. The source and consequence of this asymmetry in Ca2+ levels are not well understood. In this proposal, I explore the hypothesis that starburst amacrine cells compute direction autonomously in individual dendrites. How a dendrite integrates its inputs is of broad importance because it is one of the key steps in neuronal signaling in all neurons with multiple inputs. Starburst amacrine cells are distinct from many other cell types because their integration point is located in the distal end of the dendrite rather than at the soma. In addition, in contrast to many other neuron types, the question of how the starburst amacrine cell integrates its inputs is relevant to the known physiological function of the cell sine the order of inputs is directly related to the direction of moving light stimuli. Therefore understanding integration in starburst cell dendrites will contribute directly to our understanding of the role of starburst amacrine cells in the retinal circuit. Using electrophysiology, glutamate uncaging and imaging techniques, I will determine whether an intrinsic non-linearity in the starburst cell dendrites favors bipolar cell inputs arriving sequentially from the soma toward the release sites in the distal dendrites over inputs arriving in the opposite order (Aim 1). In additin, I propose experiments to determine whether the previously observed increase in Ca2+ during stimulation toward distal dendrites leads to an increase in inhibition from starburst amacrine cells onto direction selective ganglion cells (Aim 2). Lastly, I propose experiments to determine the role of voltage-gated Ca2+ channels in establishing the asymmetry in Ca2+ influx and GABA release from starburst amacrine cell dendrites (Aim 3).