Neural Basis of the Ontogeny of Eyeblink Conditioning

描述(申请人提供)：拟议的研究项目是对中枢神经系统发育变化的分析的继续，这些变化是大鼠眨眼经典条件作用的个体发生的基础。小脑及其与桥核和下橄榄的突触联系是眨眼条件作用神经回路的重要组成部分。从桥核到小脑的苔藓纤维投射形成条件性刺激(CS)的输入通路，从下橄榄到小脑的爬行纤维通路形成条件刺激(US)通路。该项目的初步发现表明，眨眼条件反射的个体发育与小脑中刺激诱导的和学习相关的神经元活动的发育变化有关。小脑的输入路径也经历了显著的发育变化。输入通路中最显著的发育变化之一是从小脑到下橄榄的神经反馈的发展。小脑反馈调节输入通路，从而调节小脑学习特异性可塑性的诱导。最初的研究表明，眨眼条件反射的个体发育是由于小脑、桥核和下橄榄之间的相互作用的发展。这个项目的初步实验结果是有希望的，但还需要更多的研究来确定上述小脑发育变化的起源和机制及其与脑干核团的相互作用。拟议项目的第一个具体目标将检查CS和US通路的解剖学发展。第二个具体目标将通过电刺激桥核、可逆性失活小脑和红核以及行为方法来研究CS通路发育变化的生理机制。第三个具体目标将通过电刺激下橄榄、下橄榄的药理操作和行为方法来研究US通路发展的潜在机制。第四个具体目标将使用体内和体外神经生理学技术来检测小脑内神经可塑性诱导的发育变化。阐明眨眼条件作用个体发生的神经机制可能有助于发现有关神经和行为发育之间关系的一般原理。除了该项目的基本研究目标外，拟议的研究结果可能有助于更好地了解与影响神经系统的各种发育障碍相关的功能病理学，包括胎儿酒精综合征、暴露于环境神经毒素、婴儿自闭症和唐氏综合症。

DESCRIPTION (provided by applicant): The proposed research project is the continuation of an analysis of developmental changes in the central nervous systems that underlie the ontogeny of eyeblink classical conditioning in rats. The cerebellum and its synaptic connections with the pontine nuclei and inferior olive are essential components of the eyeblink conditioning neural circuitry. The mossy fiber projection from the pontine nuclei to the cerebellum forms the input pathway for the conditioned stimulus (CS) and the climbing fiber pathway from the inferior olive to the cerebellum forms the unconditioned stimulus (US) pathway. The initial findings of this project demonstrate that the ontogeny of eyeblink conditioning is correlated with developmental changes in stimulus-elicited and learning-related neuronal activity in the cerebellum. The input pathways to the cerebellum also undergo significant developmental changes. One of the most striking developmental changes in the input pathways is the development of neural feedback from the cerebellum to the inferior olive. Cerebellar feedback regulates the input pathways and thereby regulates the induction of learning-specific plasticity in the cerebellum. The initial studies suggest that the ontogeny of eyeblink conditioning is due to the development of interactions between the cerebellum, pontine nuclei, and inferior olive. The findings of the initial experiments of this project are promising, but additional studies are required to determine the origins and mechanisms of the aforementioned developmental changes in the cerebellum and its interactions with brainstem nuclei. The first specific aim of the proposed project will examine the anatomical development of the CS and US pathways. The second specific aim will examine the physiological mechanisms underlying the developmental changes in the CS pathway using electrical stimulation of the pontine nuclei, reversible inactivation of the cerebellum and red nucleus, and behavioral methods. The third specific aim will examine the mechanisms underlying the development of the US pathway using electrical stimulation of the inferior olive, pharmacological manipulations of the inferior olive, and behavioral methods. The fourth specific aim will examine developmental changes in the induction of neural plasticity within the cerebellum using in vivo and in vitro neurophysiological techniques. Elucidating the neural mechanisms underlying the ontogeny of eyeblink conditioning may lead to the discovery of general principles concerning the relationship between neural and behavioral development. In addition to the basic research goals of this project, the results of the proposed studies may lead to a better understanding of the functional pathology associated with various developmental disorders that affect the nervous system including fetal alcohol syndrome, exposure to environmental neurotoxins, infantile autism, and Down's syndrome.