The Functional Role of Inhibition in the Sound Evoked Goldfish Startle Behavior

描述(由申请人提供)： 许多神经疾病和精神疾病的原因仍然不明，尽管它们广泛流行，给家庭和社会造成了损失。来自人类和灵长类动物大脑的电子记录已经证明了单个神经元处理信息和做出决定的复杂能力，即计算机。有可能许多神经和精神疾病是由不正确执行计算的神经元引起的。这项拟议项目的长期目标是了解突触机制如何定义单个神经元的计算能力。为了解决这个问题，我研究了一个可识别的神经元，其活动与刻板印象行为相关。两个金鱼Mauthner(M-)细胞接收听觉输入，处理该输入，全有或全无的结果被转换为逃逸响应，即C-Start。因此，M细胞(S)必须从连续的感觉信息流中推断出刺激是否值得启动逃逸，逃逸的准确时间，逃逸的初始方向，这反映在左侧或右侧的M细胞是否被激活。由于M细胞胞体和外侧树突可以在体内获得细胞内的记录，我打算描述这些功能是如何通过声音诱发的突触兴奋和抑制之间的亚阈值相互作用来实现的。听觉传入在M细胞上产生兴奋性的化学突触和电突触，而甘氨酸能前馈抑制中间神经元则从化学和触觉上抑制M细胞。已发表的数据表明，声诱发兴奋性电紧张性突触后电位(PSPs)的时序与声刺激是锁相的。目的1将测试甘氨酸能抑制PSP的时序是否也是锁相的，并研究兴奋和抑制是如何整合的。目标2将确定声音诱发的突触活动的相位锁定是否对于明确确定水下声源的位置是必要的，目标3将确定M细胞甘氨酸能抑制的强度是否支配刺激将引发C-Start的概率。配对的细胞内记录将在空气中固定的鱼类中进行，这些结果将与利用高速视频、肌电和细胞外慢性电极监测鱼类行为的水下研究相关联。肌肉注射和局部电渗用士的宁将扰乱甘氨酸能抑制并模拟神经功能亢进，这是一种导致痉挛的遗传性疾病，与甘氨酸受体突变有关。这些实验的结果将阐明脊髓或脑干中甘氨酸能抑制被破坏是否会导致亢进，并确定可以减少痉挛的药物方法。

DESCRIPTION (provided by applicant): The causes of many neuorological and psychiatric illnesses remain unknown despite their widespread prevelance and cost to families and society. Electrical recordings from human and primate brains have demonstrated the sophisticated capacities of single neurons to process information and make decisions, i.e. compute. It is possible that many neurological and psychiatric diseases are caused by neurons that perform computations incorrectly. The long-term objective of the proposed project is to understand how synaptic mechanisms define the computational capacities of a single neuron. To address this question I study an identifiable neuron whose activity correlates with a stereotypic behavior. The two goldfish Mauthner (M-) cells receive auditory input, process this input, and the all-or-none result is translated in to an escape response, the C-start. Thus the M-cell(s) must deduce, from a continuous stream of sensory information, whether or not a stimulus merits the initiation of an escape, the precise timing of the escape, the initial direction of the escape, which is reflected in whether the left or right M-cell is activated. Since the M-cell soma and lateral dendrite are accessible to intracellular recordings in vivo I intend to describe how these functions are carried out by the sub-threshold interactions between sound evoked synaptic excitation and inhibition. Auditory afferents make excitatory chemical and electrical synapses on the M-cell while glycinergic feed-forward inhibitory interneurons chemically and ephaptically inhibit the M-cell. Published data indicates that the timing of sound evoked excitatory electrotonic postsynaptic potentials (PSPs) are phase locked to the sound stimulus. Aim 1 will test whether the timing of the glycinergic inhibitory PSPs are also phase locked and investigate how excitation and inhibition are integrated. Aim 2 will determine whether the phase locking of the sound evoked synaptic activity is necessary for unambiguously determining the location of a sound source underwater and Aim 3 will determine if the strength of glycinergic inhibition of the M-cell governs the probability that a stimulus will elicit a C-start. Paired intracellular recordings will be performed in immobilized fish in air, and these results will be correlated with underwater studies in behaving fish monitored with high speed video, EMG, and extracellular chronic electrodes. Strychnine applied by intramuscular injection and locally by electroporesis will disrupt glycinergic inhibition and simulate hyperekplexia, a hereditary disease resulting in spasticity and associated with mutations in the glycine receptor. The results of these experiments will clarify if glycinergic inhibition disrupted in the spinal cord or brain stem induces hyperekplexia and identify pharmacological approaches that can reduce spasticity.