Neural Basis of the Ontogeny of Eyeblink Conditioning

描述（由申请人提供）：拟议的研究项目是对大鼠眨眼经典条件反射个体发生的中枢神经系统发育变化分析的继续。小脑及其与脑桥核和下橄榄核的突触连接是眨眼条件神经回路的重要组成部分。从脑桥核到小脑的苔藓纤维投射形成条件刺激（CS）的输入通路，从下橄榄核到小脑的攀爬纤维投射形成非条件刺激（US）通路。该项目的初步研究结果表明，眨眼条件反射的个体发育与小脑中刺激引起的和学习相关的神经元活动的发育变化相关。小脑的输入通路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核的神经反馈的发展。小脑反馈调节输入通路，从而调节小脑中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生是由于小脑，脑桥核和下橄榄核之间的相互作用的发展。该项目的初步实验结果是有希望的，但需要更多的研究来确定小脑中上述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。第二个具体的目标将检查的生理机制的发展变化的CS通路使用电刺激的脑桥核，可逆性失活的小脑和红核，和行为的方法。第三个具体目标将检查使用下橄榄的电刺激，下橄榄的药理学操作和行为方法的US通路的发展的机制。第四个具体的目标将检查在小脑内使用在体内和体外神经生理学技术的神经可塑性的诱导的发育变化。阐明眨眼条件反射的个体发生背后的神经机制可能会导致发现神经和行为发育之间的关系的一般原则。除了该项目的基本研究目标外，拟议研究的结果可能会导致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征。

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.