Neuromodulation and Plasticity of the Visual System

我的NSERC计划是确定神经调质在视觉系统的可塑性和功能中的作用。在本论文中，我将专门研究内源性大麻素（endocannabinoid，eCB）系统在不同水平上对视觉神经元特性的贡献。 eCB在神经生物学功能如记忆、伤害感受、可塑性和许多细胞信号传导过程中起调节作用。eCB通常与神经元传递的调节和发育过程相关。这些作用在很大程度上取决于两种大麻素受体，CB1（CB1R）和CB2（CB2R）。这两种亚型都存在于中枢神经系统，包括视觉系统。例如，CBR存在于所有主要类型的视网膜神经元、外侧膝状体核（LGN）和视觉皮层（V1）的神经元中。虽然这些观察结果表明，eCB信号系统存在于视觉系统中，但关于大麻素对视觉神经元特性的功能影响的信息很少。鉴于eCBs广泛分布于视觉系统的大脑结构中，eCBs有可能影响视觉和视觉行为。在这项提案中，我计划使用补充方法（例如视网膜电图，单细胞记录和光学成像）继续研究大麻素在视觉中的功能作用。我提出三个具体目标： 第一个目的是通过研究CBRs的外源性激动剂和拮抗剂对成年啮齿动物的暗视和明视反应以及ON和OFF途径的影响来确定大麻素系统在视网膜功能中的贡献。结合这些实验，我们将使用其合成或降解酶的抑制剂评估eCB的作用。 第二个目的是使用视觉诱发电位、脑光学成像和单细胞记录来确定eCB介导的视网膜变化（在目的1中表征）对丘脑和皮质处理的后果。 第三个目的是调查eCB在LGN和V1中的直接和局部影响。因此，将CBR配体或酶抑制剂注射到两个结构中，以评估内源性大麻素对中枢水平视觉刺激的神经编码的影响。首先，将评估单独调节LGN活动对皮层处理的影响。然后，将研究在皮层水平施用eCBS对包含神经元的影响。 建议的实验是必不可少的更好地理解的基本作用的eCB系统在正常的视觉处理。这些独特的和创新的实验方法将解决不同层次的视觉系统功能与互补的方法学方法，我相信，他们代表了第一个必要的步骤，以揭示功能的作用，如感受野的形成和时间视觉编码的过程中，eCBs。

My NSERC program is to determine the role of neuromodulators in the plasticity and functioning of the visual system. In this proposal, I will specifically study the contribution of the endocannabinoid (eCB) system in properties of visual neurons at different levels. eCB plays a modulatory role in neurobiological functions such as memory, nociception, plasticity, and in a number of cellular signaling processes. eCBs are generally associated with the modulation of neuronal transmission and with developmental processes. These effects depend largely on two cannabinoid receptors, CB1 (CB1R) and CB2 (CB2R). Both subtypes have been found in the central nervous system, including the visual system. For example, CBRs are present in all major types of retinal neurons, in neurons of the lateral geniculate nucleus (LGN) and of the visual cortex (V1). While these observations indicate that an eCB signaling system exists in the visual system, there is little information, if any, about the functional impact of cannabinoids on visual neuron properties. Given the eCBs widespread distribution in cerebral structures of the visual system, eCBs have the potential to affect both vision and visual behavior. In this proposal, I plan to pursue my investigation on the functional role of cannabinoids in vision using complementary approaches (e.g. electroretinogram, single cell recording, and optical imaging). I propose three specific aims: The first aim is to determine the contribution of the cannabinoid system in the retinal function by studying the effects of exogenous agonists and antagonists of CBRs on the scotopic and photopic responses as well as on the ON and OFF pathways of adult rodents. In conjunction with these experiments, we will assess the effects of eCBs using inhibitors of their synthesis or degradation enzymes. The second aim is to determine the consequences of the eCB-mediated retinal changes (characterized in aim 1) on thalamic and cortical processing using visual evoked potentials, brain optical imaging and single-cell recordings. The third aim is to investigate the direct and local impact of eCBs in the LGN and V1. CBR ligands or enzyme inhibitors will thus be injected in the two structures to assess the influence of endocannabinoids on the neural coding of visual stimuli at central levels. First, the effects of solely modulating LGN activity on cortical processing will be assessed. Then, the effects of administrating eCBS at the cortical level on the comprising neurons will be studied. The proposed experiments are essential for a better understanding of the fundamental role of the eCB system in normal visual processing. These unique and innovative experimental approaches will address different levels of visual system functions with complementary methodological approaches, and I believe that they represent the first necessary step to reveal the functional role of eCBs on processes such as receptive field formation and temporal visual coding.