Information flow in the limbic theta circuit revealed by Granger causality

描述（申请人提供）：海马的Theta行为可分为运动相关（类型1）、静止相关（类型2）和REM睡眠Theta等几类，具有不同的层特异性电流源分布、不同的药理特征和特征频率。不同频率θ波产生的机制尚不清楚，但它与行为的不同方面（感觉-运动整合、睡眠等）有很强的联系，这表明皮层下结构在其中起着重要作用。许多皮质下核表现出与海马振荡同步的θ节律性神经元活动，我们的目标是确定这些结构与海马节律性活动之间的功能关系。常用的对称信号分析方法在这方面的效用有限，因为它们不能提供因果影响的信息。因此，本R21的目的是测试一种新提出的称为格兰杰因果关系的方法对海马中产生θ波的两个皮质下结构的有效性：内侧隔（MS）和乳上核（SUM）。首先（具体目标1），我们将在两个实验中验证海马体网络背景下的方法；其中一种是因果方向已知（通过刺激输入通路和记录海马目标层的场电位），另一种是因果方向来自对经典海马“三突触回路”信息流的先验知识。然后，在具体目标2中，我们将通过皮层下θ波发生器（SUM和MS）解决海马θ波的因果影响和定向驱动问题，并检验格兰杰因果关系是否可以作为该系统假设驱动研究的工具。我们特别假设，SUM的参与仅限于特定的状态，因此我们期望在清醒探索和快速眼动睡眠的阶段性发作中发现SUM向海马的显著定向驱动，而在清醒不动和强直眼动睡眠的慢θ波中则没有。另一方面，我们假设MS为来自不同来源的上升驱动提供了最终的共同途径，将在所有θ波状态下显示出显著的海马定向驱动。

DESCRIPTION (provided by applicant): Theta behaviors in the hippocampus fall in several categories, e.g. movement related (Type 1), immobility related (Type 2), and REM sleep theta, with distinct layer specific current source distributions, different pharmacological features, and characteristic frequencies. The mechanism of the generation of theta at different frequencies is poorly understood but its strong association with different aspects of behavior (sensory-motor integration, sleep, etc.) indicates that subcortical structures play an essential role. A number of subcortical nuclei exhibit theta rhythmic neuronal activity synchronized with hippocampal oscillations and our goal is to identify the functional relationship among these structures and rhythmic activity in the hippocampus. The commonly used symmetrical methods of signal analysis have limited utilities in this regard as they could not provide information on causal influences. Thus the goal of the present R21 is to test the effectiveness of a newly proposed method called Granger causality on two subcortical structures generating theta in the hippocampus: medial septum (MS) and supramammillary nucleus (SUM). First (Specific Aim 1), we will validate the method in the context of the hippocampal network in two experiments; one in which the causal direction is known (using stimulation of input pathways and recording field potentials in their target layers of the hippocampus) and the other in which the causal direction comes from prior knowledge of the information flow along the classic hippocampal "three-synaptic circuit". Then, in Specific Aim 2, we will address the causal influence and directional driving of hippocampal theta by subcortical theta generators (SUM and MS) and test whether Granger causality can be a tool in hypothesis-driven investigation of this system. We hypothesize, in particular, that SUM involvement is limited to specific states, and thus expect to find significant directional drive from SUM to hippocampus associated with fast theta during waking exploration and phasic episodes of REM sleep but not during slow theta of waking immobility, and tonic REM sleep. On the other hand, we hypothesize that MS, providing a final common pathway for ascending drives from different sources, will show significant directional drive to the hippocampus in all theta states. PUBLIC HEALTH RELEVANCE: The mechanism of the generation of theta at different frequencies is poorly understood but its strong association with different aspects of behavior indicates that subcortical structures play an essential role. The goal of the present R21 is to test the effectiveness of a newly proposed method called Granger causality on two subcortical structures: medial septum (MS) and supramammillary nucleus (SUM).