Synaptic circuit mechanisms of rhythmic oscillatory dynamics in the cerebral cortex

有节奏的大脑活动通过在专门的大脑区域内和之间协调大量神经细胞来控制行为。特别重要的是日常记忆的形成或回忆，这需要在大约十分之一秒的时间内，颞叶数百万个神经细胞同步行动。在哺乳动物中，包括人类，这种同步性被观察到是一种由脑电(EEG)测量的缓慢的振荡电节律。嵌入在缓慢脑电信号的每个周期中，与认知过程相关的更高频率的振荡出现。包括痴呆症和与年龄相关的记忆障碍在内的大脑疾病伴随着这些大脑节律的扰动，从而突出了它们的生物学重要性。在不同的时间尺度上建立和维持这种有节奏的大脑活动的机制，以及为实现这种功能的壮举而合作的数百种神经细胞的具体作用仍有待确定。大脑节律性创造了大群神经细胞活动水平增加和减少的连续“窗口”，这使得大脑皮层能够编码和连接真实生活事件的实际序列，这些事件在不同的振荡周期中表现出来。在拟议的项目中，我们将利用我们发现的三种新的神经细胞来确定它们在节律振荡神经元活动和记忆处理中的作用。这种新类型的神经细胞位于大脑深处的皮质下区域，称为内侧隔区，每种类型的神经细胞都向大脑皮层的一个或多个选定区域发送平行投射，每个区域在记忆的形成和回忆中都扮演着不同的角色。这些合作的大脑区域，包括海马体和内嗅皮层，是阿尔茨海默病中最先受到神经退化影响的区域。使用一种新的技术对这些和其他内侧隔区神经细胞的基因表达谱进行分子解剖，我们将提供小鼠和人脑中细胞类型的全面定义。在我们最新发现的基础上，我们将确定这些类型的神经细胞在阿尔茨海默病小鼠模型中的功能是如何变化的。然后，我们将使用这些特定通路中的一些活动的外部调制来测试如何改善记忆处理。因此，这个项目将促进我们对哺乳动物大脑与记忆处理相关的功能组织的理解。

Rhythmic brain activity governs behaviour through the coordination of large numbers of nerve cells within and amongst specialised brain regions. Of particular importance is the formation or recall of everyday memories, which requires the synchronised action of millions of nerve cells of the temporal lobe within about a tenth of a second. In mammals, including humans, such synchronisation is observed as a 'slow' oscillating electrical rhythm measured by electroencephalography (EEG). Embedded within each cycle of the slow EEG signal, higher frequency oscillations emerge in relation to cognitive processes. Brain disorders including dementia and age-related memory impairments are accompanied by perturbation of these brain rhythms, thus highlighting their biological importance. The mechanisms for establishing and maintaining such rhythmic brain activity at various time scales, and the specific roles of the hundreds of nerve cell varieties that cooperate to deliver such a feat of function, remain to be defined. Brain rhythmicity creates sequential "windows" of increased and decreased activity levels of large groups of nerve cells, which enables the cerebral cortex to encode and link actual sequences of real-life events that are represented on distinct oscillatory cycles. In the proposed project, we will exploit our discovery of three novel varieties of nerve cells for establishing their roles in rhythmic oscillatory neuronal activity and memory processing. The novel types of nerve cell are found in a subcortical area deep within the brain called the medial septum, and each type sends parallel projections to a select area or areas of the cerebral cortex that each plays a distinct role in the formation and recall of memories. These cooperative brain areas, including the hippocampus and entorhinal cortex, are the ones first affected by neurodegeneration in Alzheimer's disease. Using a novel technology for the molecular dissection of gene expression profiles of these and other nerve cells in the medial septum, we will provide a comprehensive definition of cell types in both the mouse and the human brain. Building on our recent discoveries, we will establish how the function of these types of nerve cells changes in a mouse model of Alzheimer's disease. We will then use external modulation of the activity of some of these specific pathways to test how to improve memory processing. This project will thus advance our understanding of the functional organisation of the mammalian brain in relation to memory processing.