CA CHANNELS IN THALAMIC & HIPPOCAMPAL RHYTHMIC ACTIVITY

描述（申请人摘要）：在从清醒到清醒的过渡期间， 在睡眠状态下，新皮层的神经元活动会发生显著变化， 以前混乱的活动变得有节奏和全球同步。这 所谓的慢波睡眠，包括睡眠纺锤波和δ节律， 需要丘脑通过丘脑皮层细胞向新皮层输入信息。的 丘脑皮层细胞本身含有专门的离子通道， 电压门控特性允许有节奏的膜电位振荡。EEG 海马体的记录显示，行为探索是 以θ节律为标志，而慢波睡眠和清醒不动则以θ节律为标志， 被称为尖波/涟漪活动的同步节奏爆发。个人 海马CA 1和CA 3区神经元也产生膜电位 振荡和动作电位的节律性爆发。同步这些 丘脑和海马体中的单个神经元振荡器被认为发生在 通过GABA能中间神经元。目前的模型表明，这些膜 潜在的振荡和它们的夹带由中间神经元需要T型 钙通道然而，由于缺乏特异性T型钙通道阻滞剂， 阻止了对这一假设的直接检验。靶向基因新技术 T型钙通道的敲除和最近的克隆，现在使这种工作 可能我们的实验室已经开发出基因破坏技术， 小鼠脑中有丝分裂后神经元的有限群体。该方法 允许删除NR 1，NMDA受体的一个组成部分，只在 海马CA 1区锥体神经元。由此产生的条件性敲除 小鼠海马长时程增强、海马区 细胞同步和空间学习记忆。结果表明 CA 1区突触可塑性在空间学习中的重要作用。我们 我建议采用类似的方法来检验T型钙 海马神经元的固有振荡需要通道 和丘脑神经元进行切片电生理学研究。因此，我们建议审查 这些振荡在产生丘脑皮层睡眠中的作用 节律、海马theta节律和海马尖波/涟漪活动 使用总体多电极记录技术。最后，我们将开始 探索这些神经元活动的节律模式在睡眠/觉醒中的作用 周期、注意力、动机、基本感觉和运动技能，以及 学习和记忆。这样的工作也可能开始解释细胞和 颞叶癫痫等神经精神疾病的分子基础， 这些生理节律变成病理性的失神发作。

DESCRIPTION (applicant's abstract): During the transition from the awake to the sleep state, neuronal activity in the neocortex is dramatically altered, previously chaotic activity becomes rhythmic and globally synchronous. This so-called slow-wave sleep, which includes sleep spindles and delta rhythms, requires thalamic input to the neocortex via thalamocortical cells. The thalamocortical cells themselves contain specialized ion channels whose voltage-gating properties allow rhythmic membrane potential oscillations. EEG recordings of the hippocampus have revealed that behavioral exploration is marked by theta rhythm, while slow wave sleep and awake immobility are marked by synchronous rhythmic bursts called sharp wave/ripple activity. Individual neurons of hippocampal areas CA1 and CA3 also generate membrane potential oscillations and rhythmic bursts of action potentials. Synchronization of these single neuronal oscillators in the thalamus and hippocampus is thought to occur through GABAergic interneurons. Current models suggest that these membrane potential oscillations and their entrainment by interneurons requires T-type calcium channels. Yet, the lack of specific T-type calcium channel blockers has prevented direct tests of this hypothesis. New technologies for targeted gene knockout and recent cloning of T-type calcium channels now make such work possible. Our laboratory has developed technologies for gene disruption in restricted populations of postmitotic neurons in the murine brain. This method permitted the deletion of NR1, a component of the NMDA receptor, exclusively in pyramidal neurons of hippocampal area CA1. The resulting conditional knockout mice were deficient in hippocampal long term potentiation, hippocampal place cell synchronization, and spatial learning and memory. The results demonstrated a critical role for synaptic plasticity in area CA1 in spatial learning. We propose to employ similar methods to test the hypothesis that T-type calcium channels are required for intrinsic neuronal oscillations in the hippocampal and thalamic neurons using slice electrophysiology. We then propose to examine the role of these oscillations in the production of thalamocortical sleep rhythms, hippocampal theta rhythm, and hippocampal sharp wave/ripple activity using ensemble multielectrode recording techniques. Lastly, we will begin to explore the role of these rhythmic modes of neuronal activity in sleep/wake cycles, attention, motivation, elementary sensory and motor skills, and learning and memory. Such work may also begin to explain the cellular and molecular basis for neuropsychiatric disorders like temporal lobe epilepsy and absence seizures where these physiologic rhythms become pathologic.