Neuromodulation and Plasticity of the Visual System

我的NSERC项目是为了确定神经调节剂在视觉系统的可塑性和功能中的作用。在这项建议中，我将具体研究内源性大麻素(ECB)系统在不同水平的视神经元特性中的贡献。 ECB在记忆、伤害性、可塑性等神经生物学功能以及一些细胞信号过程中起着调节作用。ECB通常与神经元传递的调节和发育过程有关。这些作用在很大程度上依赖于两种大麻素受体，CB1(CB1R)和CB2(CB2R)。这两种亚型都在中枢神经系统中发现，包括视觉系统。例如，CBRs存在于所有主要类型的视网膜神经元、外侧膝状核(LGN)和视皮层(V1)的神经元中。虽然这些观察表明视觉系统中存在ECB信号系统，但关于大麻类化合物对视觉神经元特性的功能影响的信息很少，如果有的话。鉴于ECB广泛分布在视觉系统的大脑结构中，ECB有可能同时影响视觉和视觉行为。在这项提案中，我计划使用互补的方法(例如视网膜电图、单细胞记录和光学成像)来继续我对大麻类物质在视觉中的功能作用的研究。我提出三个具体目标： 第一个目的是通过研究外源性CBRS激动剂和拮抗剂对成年啮齿动物的暗视和明视反应以及对On和Off通路的影响，来确定大麻素系统在视网膜功能中的作用。结合这些实验，我们将使用合成或降解酶的抑制剂来评估ECB的影响。 第二个目标是利用视觉诱发电位、大脑光学成像和单细胞记录来确定欧洲央行介导的视网膜变化(在目标1中描述)对丘脑和皮质处理的影响。 第三个目标是调查ECB在LGN和V1中的直接和局部影响。因此，将在这两个结构中注入CBR配体或酶抑制剂，以评估内源性大麻素对中枢水平视觉刺激神经编码的影响。首先，将评估单独调节LGN活动对大脑皮层处理的影响。然后，我们将研究在大脑皮层水平给予ECBS对组成神经元的影响。 拟议的实验对于更好地理解欧洲央行系统在正常视觉处理中的基础作用至关重要。这些独特和创新的实验方法将以互补的方法处理不同水平的视觉系统功能，我认为它们是揭示ECB在感受野形成和时间视觉编码等过程中的功能作用的第一步。

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.