Regulation of synaptic plasticity by eCBs in adult and aged mammalian cortex

描述(申请人提供)：与年龄相关的视觉功能退化包括空间敏锐度降低和刺激选择性丧失，这可能会损害视觉-运动协调。有趣的是，直接将GABA激动剂应用于衰老的视皮层可以立即导致刺激选择性的增加，这表明刺激选择性的下降可能是由于GABA能抑制的减少。在整个发育过程中，GABA能抑制增加，这可能会增加刺激的选择性，并降低成年人的眼优势可塑性。视觉皮质中可获得的突触可塑性水平的一个敏感测试是在单眼剥夺(MD)反应中观察到的双眼神经元中眼睛支配地位的变化。在青少年中，突触的可塑性很高，MD导致双眼神经元眼睛优势的转移。尽管成年人的眼球优势可塑性较低，但通过减少皮质抑制的手法可能会增强这种可塑性。老年人视皮层的眼优势可塑性水平尚不清楚。视觉剥夺可以增强成人视觉系统中突触的可塑性，部分是通过调节GABA能抑制来实现的。无论是视觉剥夺还是对抑制的药物阻断，都不适用于人类群体。在成年出生后150天(P150)和老年(P700)的大鼠中，所提出的实验通过使用1型大麻素受体(CBIR)间接操纵皮质抑制。CBIR定位于表达CCK的篮状细胞的突触前终末，是一类GABA能中间神经元。CB1Rs的激活减少了反馈抑制，促进了谷氨酸能传递。我的初步数据显示，CB1R拮抗剂重新激活了成年人的快速眼优势可塑性。在MD之后，从双眼视觉皮质收集的视觉诱发电位(VEP)显示，接受CB1R拮抗剂治疗的成年人的对侧偏见减少。本实验旨在探讨CB1R信号在成人和老年视觉系统的眼优势可塑性、视觉功能和形态突触可塑性中的作用。我们将使用硬膜下VEP、单单位记录以及树突棘分析来确定CB1R拮抗剂诱导的成年大鼠(PI50)和老年大鼠(P700)眼优势可塑性和形态可塑性的层状轨迹。CB1R通路的操作可能会增强成人的眼优势可塑性，为慢性MD后的功能恢复提供机会。在老年人群中，操纵CB1R通路可以恢复空间敏锐度和刺激选择性，从而改善老年视皮层的视觉功能。

DESCRIPTION (provided by applicant): Age-related degradation of visual functions includes decreased spatial acuity and a loss of stimulus selectivity, which can impair visuo-motor coordination. Interestingly, application of GABA agonists directly to the aged visual cortex induces an immediate increase in stimulus selectivity, suggesting the decline in stimulus selectivity may be due to a decrease in GABAergic inhibition. Throughout development GABAergic inhibition increases, which may increase stimulus selectivity and decrease ocular dominance plasticity in adults. A sensitive assay for the level of synaptic plasticity available in the visual cortex is the ocular dominance shift observed in binocular neurons in response to monocular deprivation (MD). In juveniles, synaptic plasticity is high and MD induces a shift in the ocular dominance of binocular neurons. Although ocular dominance plasticity is low in adults, it may be heightened by manipulations that reduce cortical inhibition. The level of ocular dominance plasticity in the aged visual cortex is unknown. Visual deprivation can enhance synaptic plasticity in the adult visual system, in part by regulation of GABAergic inhibition. Neither visual deprivation nor pharmacological blockade of inhibition is practical to translate to a human population. The proposed experiments manipulate cortical inhibition indirectly through use of type 1 cannabinoid receptors (CBIRs) in adult postnatal day 150 (P150) and aged (P700) rats. CBIRs are localized to presynaptic terminals of cholecystokinin-(CCK) expressing basket cells, a class of GABAergic interneurons. Activation of CB1 Rs decreases feedback inhibition and facilitates glutamatergic transmission. My preliminary data demonstrate CB1R antagonists reactivate rapid ocular dominance plasticity in adults. Following MD, visually evoked potentials (VEPs) collected from the binocular visual cortex reveal a decrease in the contralateral bias in adults treated with the CB1R antagonist. The proposed experiments explore CB1R signaling in ocular dominance plasticity, visual functions and morphological synaptic plasticity in the adult and aged visual system. Subdural VEPs, single-unit recordings as well as dendritic spine analyses will be used to identify the laminar locus of ocular dominance plasticity as well as morphological plasticity induced by CB1R antagonists in adult (PI 50) and aged (P700) rats. Manipulations of the CB1R pathway may enhance ocular dominance plasticity in adults, providing an opportunity for recovery of function following chronic MD. In the aged population, manipulations of the CB1R pathway may restore spatial acuity and stimulus selectivity and therefore improve visual function of the aged visual cortex.