Temporally precise control of theta oscillations

描述(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质神经元的协调活动。大脑皮层细胞组件的同步神经元活动导致脑电记录和局部场电位的电振荡。精神、神经和神经退行性疾病，包括精神分裂症、癫痫和阿尔茨海默病，其特征是振荡时间和模式的变化。然而，目前尚不清楚哪些治疗干预可以恢复对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，但只有在theta振荡能够以高时间精度控制的情况下，才能测试这一点。因此，我们建议利用光遗传失活技术在神经回路中产生theta的时间精度来检验theta振荡在记忆编码和提取过程中为海马神经元提供时间协调的假设。我们将在两个目标上检验这一假设。第一个目标是实现对theta节律的时间精确控制，第二个目标是使用时间上精确的干扰来确定在记忆获得、保持或提取过程中是否需要通过theta振荡来协调海马峰电位计时。为了达到这两个目的，我们将AAV9-Arch3.0-EYFP或AAV9-ArchT3.0-EYFP注入大鼠的内侧隔区，并在大鼠的海马区和/或内侧内嗅皮层放置记录电极。AAV9因能广泛感染脑组织而被选为病毒载体，Arch3.0和ArchT3.0被选为视蛋白，因为它们是有效的光诱导神经元活动抑制因子。在手术后恢复后，将训练大鼠在目标1上连续在跑道上奔跑或随机觅食。行为相关的照明方案将被用来确定隔区振荡和离散光脉冲对海马theta振荡的影响。为所有人 协议，分析将集中在theta振荡的幅度和频率的变化，以及theta/Gamma耦合的影响。对于目标2，大鼠将接受八字延迟空间交替任务的训练，该任务具有不同的编码、提取和保持阶段。在不同的日子，光脉冲将在这些阶段中的一个阶段传递，以确定何时需要theta振荡。对于破坏行为表现的光刺激方案，我们将检查记忆表现下降期间海马细胞尖峰定时的变化。通过使用时间上精确的起搏器失活来进行振荡，所提出的目标将确定记忆任务的哪些阶段需要振荡的神经活动，以及记忆过程需要在多大程度上精确地控制海马区的神经活动。由于电刺激模式也可以通过抑制正在进行的神经元活动而有效，这些实验将为脑深部刺激的治疗应用提供新的见解。

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.