Temporally precise control of theta oscillations

描述（由申请人提供）：高级神经功能，包括感知、认知和记忆，依赖于至少数千个皮层神经元的协调活动。大型皮层细胞集合体的同步神经元活动导致脑电图记录和局部场电位中的电振荡。精神病学、神经学和神经退行性疾病，包括精神分裂症、癫痫和阿尔茨海默病，其特征在于振荡时间和模式的变化。然而，目前还不知道哪些治疗干预可以恢复神经回路的时间控制，以实现认知功能的改善。有人认为，海马theta节律为支持记忆过程的神经元放电模式提供了时间控制，但这只能在theta振荡可以以高时间精度控制的情况下进行测试。因此，我们建议使用的时间精度的光遗传失活技术在神经回路中的θ生成测试的假设，θ振荡提供海马神经元在记忆编码和检索的时间协调。我们将从两个方面来检验这一假设。第一个目标是实现精确的时间控制的θ节律和第二个目标是使用时间上精确的中断，以确定是否协调海马棘波定时θ振荡是需要在记忆的获取，保留，或检索。为了这两个目的，我们将AAV 9-Arch3.0-EYFP或AAV 9-ArchT3.0-EYFP输注到内侧隔中，并将记录电极放置在大鼠的海马和/或内侧内嗅皮质中。选择AAV 9作为病毒载体，因为它提供脑组织的广泛感染，并且选择Arch3.0和ArchT3.0作为视蛋白，因为它们是神经元活性的有效光诱导抑制剂。从手术中恢复后，为了目标1，将训练大鼠在轨道上连续奔跑或随机觅食。行为相关的照明协议将被用来确定振荡和离散的光脉冲在隔区海马θ振荡的影响。为所有 协议，分析将集中在θ振荡的振幅和频率的变化，也对θ/γ耦合的影响。对于目标2，大鼠将在具有不同编码、提取和保持阶段的数字8延迟空间交替任务上训练。在不同的日子里，光脉冲将在其中一个阶段被发送，以确定何时需要θ振荡。对于破坏行为表现的光刺激方案，我们将检查在记忆表现下降期间海马细胞的尖峰时间的变化。通过使用时间上精确失活的起搏器振荡，所提出的目标将确定哪些阶段的记忆任务需要振荡的神经活动，以及在何种程度上精确定时的神经活动在海马体中所需要的记忆过程。由于电刺激范例也可以通过抑制正在进行的神经元活动而有效，因此这些实验将为脑深部电刺激的治疗用途提供新的见解。

DESCRIPTION (provided by applicant): High-level neural functions, including perception, cognition, and memory, rely on the coordinated activity of at least thousands of cortical neurons. The synchronized neuronal activity of large cortical cell assemblies results in electrical oscillations in electroencephalographic records and in local field potentials. Psychiatric, neurological, and neurodegenerative diseases, including schizophrenia, epilepsy, and Alzheimer's disease are characterized by a change in oscillatory timing and patterns. However, it is currently not known which therapeutic interventions could restore temporal control of neural circuits to achieve improvements in cognitive function. It has been suggested that the hippocampal theta rhythm provides temporal control for neuronal firing patterns that support memory processes, but this can only be tested if theta oscillations can be controlled with high temporal precision. We therefore propose to use the temporal precision of optogenetic inactivation techniques in neural circuits for theta generation to test the hypothesis that theta oscillations provide temporal coordination for hippocampal neurons during memory encoding and retrieval. We will test this hypothesis in two aims. The first aim is to attain precise tempora control of the theta rhythm and the second aim is to use temporally precise disruption to determine whether the coordination of hippocampal spike timing by theta oscillations is required during memory acquisition, retention, or retrieval. For both aims, we will infuse AAV9-Arch3.0-EYFP or AAV9-ArchT3.0-EYFP into medial septum and place recording electrodes in the hippocampus and/or the medial entorhinal cortex of rats. AAV9 was selected as a viral vector because it provides widespread infection of brain tissue, and Arch3.0 and ArchT3.0 were selected as opsins because they are effective light-induced inhibitors of neuronal activity. After recovery from surgery, rats will, for aim 1, be trained to continuously run on a track or randomly forage. Behaviorally relevant illumination protocols will be used to determine the effects of oscillating and discrete light pulses in the septal area on hippocampal theta oscillations. For all protocols, the analysis will focus on changes in the amplitude and frequency of theta oscillations and also on the effect of theta/gamma coupling. For aim 2, rats will be trained on a figure-eight delayed spatial alternation task with distinct encoding, retrieval, and retention phases. On separate days, light pulses will be delivered during one of these phases to determine when theta oscillations are required. For light- stimulation protocols that disrupt behavioral performance, we will examine the changes in the spike timing of hippocampal cells during decreased memory performance. By using temporally precise inactivation of a pacemaker for oscillations, the proposed aims will determine which phases of a memory task require oscillatory neural activity and to what extent the precisely timed neural activity in hippocampus is required for memory processes. Because electrical stimulation paradigms can also be effective by inhibiting ongoing neuronal activity, these experiments will provide new insight for the therapeutic use of deep brain stimulation.