Neuronal Plasticity in the Retina

描述(申请人提供)：这项研究项目是一项实验研究，旨在了解神经元网络如何因内在昼夜节律振荡器的影响而改变或适应。在兔视网膜中，初步证据表明，昼夜节律(24小时)时钟调节杆状和视锥输入到神经节细胞和视锥连接的水平细胞，视锥连接的水平细胞是一种接受视锥细胞突触接触的二级细胞。生物钟是一种生物振荡器，在没有外部计时信号(例如，恒定的黑暗)的情况下，具有持续的节律性，周期约为24小时。调节神经节细胞和视锥连接水平细胞光反应的昼夜节律因素尚不清楚。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，这些神经调节剂在视网膜内外的视杆细胞和视锥细胞通路上介导时钟效应。 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影响哺乳动物视网膜内外神经元(即水平细胞、神经节细胞和所有无长突细胞)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，以及这个时钟是在视网膜外部还是内部。最后，我们将描述哺乳动物时钟调节多巴胺和腺苷释放的机制。采用兔和小鼠体外视网膜标本，研究视锥连接的水平细胞和所有无长突细胞以及神经节细胞在昼夜恒定黑暗条件下的光反应和示踪剂偶联。 视网膜生物钟过程的中断可能导致光感受器细胞的退化。因此，加深对生物钟过程和途径以及递质功能的了解将有助于了解人类视网膜的过程和功能障碍，并为视网膜疾病的药物治疗提供基础。此外，增加对多巴胺和腺苷在视网膜中作用的了解，可能有助于理解和治疗帕金森氏症和精神分裂症。

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.