Information flow in the limbic theta circuit revealed by Granger causality

描述(由申请人提供)：海马体中的theta行为分为几类，例如运动相关(类型1)、静止相关(类型2)和REM睡眠theta，具有不同的层特定电流源分布、不同的药理学特征和特征频率。不同频率的theta的产生机制知之甚少，但它与行为的不同方面(感觉-运动整合、睡眠等)有很强的关联。表明皮质下结构起着至关重要的作用。许多皮质下核团表现出与海马振荡同步的theta节律性神经元活动，我们的目标是确定这些结构之间的功能关系和海马区的节律性活动。通常使用的对称信号分析方法在这方面的作用有限，因为它们不能提供关于因果影响的信息。因此，目前的R21的目标是测试一种名为格兰杰因果关系的新提出的方法在两个皮质下结构上的有效性，这两个结构在海马体中产生theta：内侧隔(MS)和乳头上核(SUM)。首先(特定目标1)，我们将在海马网的背景下通过两个实验验证该方法；一个实验中，因果方向已知(使用刺激输入路径和记录海马体靶层中的场电位)，另一个实验中，因果方向来自对沿着经典海马体“三突触回路”的信息流的先验知识。然后，在特定的目标2中，我们将讨论皮层下theta发生器(SUM和MS)对海马theta的因果影响和定向驱动，并测试Granger因果关系是否可以作为假设驱动的研究系统的工具。我们特别假设，总和参与仅限于特定的状态，因此预计在清醒探索和快速眼动睡眠的相位性发作期间，将发现从总和到海马体的显著方向性驱动，与快速theta有关，但在清醒不动和紧张性REM睡眠的慢theta中不会。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路径，将在所有theta状态下向海马体显示显著的方向性驱动。 与公共健康相关：不同频率的theta的产生机制还知之甚少，但它与行为的不同方面之间的强烈关联表明，皮质下结构发挥着至关重要的作用。目前R21的目标是测试一种新提出的名为Granger因果关系的方法在两个皮质下结构上的有效性：内侧隔(MS)和乳头上核(SUM)。

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).