Neuronal Plasticity in the Retina

描述（由申请人提供）：该研究项目是一项实验研究，旨在了解神经元网络如何由于内在昼夜节律振荡器的影响而改变或适应。在兔子视网膜中，初步证据表明昼夜节律（24小时）时钟调节视杆细胞和视锥细胞对神经节细胞和视锥细胞连接的水平细胞的输入，这是一种接受来自视锥细胞的突触接触的二级细胞。生物钟是一种生物振荡器，在没有外部计时提示（例如恒定黑暗）的情况下具有大约24小时的持续节律性。调节神经节细胞和视锥连接水平细胞的光反应的昼夜因素尚不清楚。初步证据表明，视网膜中的时钟调节内源性多巴胺和腺苷的释放，并且这些神经调质介导了内部和外部视网膜中的杆和锥通路上的时钟效应。 我们将使用电生理学，神经化学和解剖学技术来确定生物钟是否会影响哺乳动物视网膜（即水平，神经节和所有无长突细胞）的外部和内部视网膜神经元的光反应，以及生物钟是否以及如何利用多巴胺，腺苷和褪黑激素来实现其效果。我们还将确定哺乳动物视网膜中是否存在调节内源性多巴胺和腺苷释放以及细胞外pH的时钟，以及该时钟是否位于视网膜的外层或内层。最后，我们将描述哺乳动物生物钟调节多巴胺和腺苷释放的机制。将使用体外兔和小鼠视网膜制备物，在昼夜恒定黑暗条件下研究视锥连接水平细胞和All无长突细胞的光反应和示踪剂偶联，以及神经节细胞的光反应。 视网膜中的昼夜节律钟过程的破坏可介导感光细胞变性。因此，增加对生物钟过程和途径以及递质功能的理解将有助于理解人类视网膜过程和功能障碍，并为视网膜疾病的药物治疗提供基础。此外，增加多巴胺和腺苷在视网膜中作用的知识可能有助于理解和治疗帕金森病和精神分裂症。

DESCRIPTION (provided by applicant): This research project is an experimental study that seeks to understand how neuronal networks change or adapt due to the influence of an intrinsic circadian oscillator. In the rabbit retina, preliminary evidence indicates that a circadian (24-hour) clock regulates rod and cone input to ganglion cells and cone-connected horizontal cells, a type of second order cell that receives synaptic contact from cones. A circadian clock is a type of biological oscillator that has persistent rhythmicity with a period of approximately 24 hours in the absence of external timing cues (e.g. constant darkness). The circadian factors that regulate the light responses of ganglion cells and cone-connected horizontal cells are not known. Preliminary evidence suggests that a clock in the retina regulates the release of endogenous dopamine and adenosine and that these neuromodulators mediate the clock effects on rod and cone pathways in the inner and outer retina. We will use electrophysiological, neurochemical and anatomical techniques to determine whether a circadian clock affects the light responses of outer and inner retinal neurons in the mammalian retina (i.e. horizontal, ganglion and All amacrine cells) and whether and how the clock utilizes dopamine, adenosine, and melatonin to achieve its effects. We will also determine whether there is a clock in the mammalian retina that regulates endogenous dopamine and adenosine release and extracellular pH and whether this clock is in the outer or inner retina. Finally, we will characterize the mechanisms by which the mammalian clock regulates the release of dopamine and adenosine. The light responses and tracer coupling of cone-connected horizontal cells and All amacrine cells, as well as the light responses of ganglion cells will be studied under conditions of constant darkness in the day and night, using in vitro rabbit and mouse retinal preparations. Disruption of circadian clock processes in the retina may mediate photoreceptor cell degeneration. Thus, increased understanding of circadian clock processes and pathways and of transmitter function will aid in the understanding of human retinal processes and dysfunction, as well as provide the basis for drug therapy for retinal disorders. In addition, increased knowledge of the action of dopamine and adenosine in the retina may aid in the understanding and treatment of Parkinson's disease and schizophrenia.