The endocannabinoid system in the monkey visual brain.

在最后一个任期内的补助金，我们产生了新的和突破性的结果的表达，本地化和功能的内源性大麻素系统在猴子视网膜。猴子的视觉系统与人类非常相似，这使得它成为研究视觉的一个非常有趣的物种，因此可以将数据推断给人类。我们已经明确表明，大麻素受体在特定的视网膜成分中表达，可能有助于多种视觉功能。大麻素受体1（CB 1）主要在视网膜中央的视锥细胞中表达，而大麻素受体2（CB 2 R）主要在视网膜神经胶质细胞（Müller细胞）中发现。第三种推定的内源性大麻素GPR 55在视杆细胞光感受器中表达。这些受体类型对视网膜功能的贡献通过它们对视网膜电图波（ERG）的作用来评估。通过玻璃体内注射受体激动剂或阻断剂，我们能够显示它们对明视和暗视ERG波的不同调节作用。然而，问题仍然是这些大麻素受体在视网膜受体结构的上游表达的位置，主要是初级（丘脑的背侧外侧膝状体核）和次级（上级丘-枕）皮质下中继和相关的皮质受体区域，如纹状体皮质（区域V1）和纹状体外皮质（V2和V3）。我们还将研究这些受体在传出背侧（如hMT+区）和腹侧（如下颞叶）皮质视觉流中的表达。 大麻素受体的表达和定位将用我们实验室目前使用的免疫组织化学方法进行测量。大麻素受体对更高视觉功能的功能将使用电生理学技术如视觉诱发皮层电位（VECP）和图形视网膜电图反应（PERG）进行研究，这些技术是视觉敏锐度和对比敏感度的良好测量方法，其附加优势是这些技术完全无创，可以在麻醉制剂上获得。内源性大麻素受体的选择性激动剂或阻断剂将通过其对视觉诱发反应模式的调节作用来突出其对M（大细胞）和P（小细胞）通路的相对贡献。最后，将使用不需要长时间训练的行为技术（如目前用于人类婴儿的行为技术，如优先注视）评估视觉功能（例如，视敏度、对比敏感度、视动性眼球震颤、运动）的体内测量。拟议项目的结果对于理解大麻对视觉系统发挥作用的机制以及因此对视觉的作用具有重要意义。

During the last tenure of the grant, we produced novel and groundbreaking results on the expression, localization and function of the endocannabinoid system in the monkey retina. Monkeys have a very similar visual system to humans and this makes it a rather interesting species to study vision and hence extrapolate data to humans. We have shown unequivocally that the cannabinoid receptors are expressed in specific retinal components and might contribute to diverse visual functions. The cannabinoid receptor 1 (CB1) is mainly expressed in the cone photoreceptors of the central retinal whereas the cannabinoid receptor 2 (CB2R) is mainly found in the retinal glia (Müller cells). The third putative endocannabinoid, GPR55, is expressed in the rod photoreceptors. The contribution of these receptors types to retinal function was assessed through their action on the electroretinographic waves (ERG). Through intravitreous injections of agonists or blockers of the receptors, we were able to show their different modulatory influences on the photopic and scotopic ERG waves. The question remains however on where these cannabinoid receptors are expressed upstream in the retino-recipient structures mainly the primary (dorsal Lateral geniculate nucleus of the thalamus) and the secondary (Superior colliculus-Pulvinar) subcortical relays and the associated cortical recipient areas such the striate cortex (area V1) and the extrastriate cortices (V2 and V3). We will also investigate the expression of these receptors in the efferent dorsal (e.g. area hMT+) and ventral (e.g. inferotemporal) cortical visual streams. The expression and localization of the cannabinoid receptors will be measured with immunohistochemical methods that are currently used in our laboratory. The functions of the cannabinoid receptors on higher visual functions will be investigated using electrophysiological techniques like the Visually Evoked Cortical Potentials (VECP) and pattern electroretinographic responses (PERG) that are good measures of visual acuity and contrast sensitivity with the added advantage that these techniques are totally non-invasive and can be obtained on anesthetized preparations. Selective agonists or blockers of the endocannabinoid receptors will highlight their relative contribution to the M (magnocellular) and P (parvocellular) pathways through their modulatory effects on the visually evoked response patterns. Finally, in vivo measures of visual functions (e.g. visual acuity, contrast sensitivity, optokinetic nystagmus, motion) will be assessed using behavioral techniques that do not require lengthy training such as those currently used in human infants like preferential looking. The results of the proposed project are of great importance for the understanding of the mechanisms by which cannabis sativa exerts its function on the visual system and hence on vision.