Synaptic circuit mechanisms of rhythmic oscillatory dynamics in the cerebral cortex

有节奏的大脑活动通过大脑特定区域内和区域间大量神经细胞的协调来控制行为。特别重要的是日常记忆的形成或回忆，这需要颞叶数以百万计的神经细胞在十分之一秒内同步行动。在包括人类在内的哺乳动物中，这种同步是通过脑电图（EEG）测量的“缓慢”振荡电节律观察到的。在慢脑电图信号的每个周期中，出现了与认知过程相关的高频振荡。包括痴呆和与年龄相关的记忆障碍在内的脑部疾病都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，以及数百种神经细胞的具体作用，这些神经细胞合作提供了这样一个壮举的功能，仍然有待确定。大脑节律性创造了大量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以不同振荡周期表示的现实生活事件的实际序列。在该项目中，我们将利用我们发现的三种新型神经细胞来确定它们在节律性振荡神经元活动和记忆处理中的作用。这种新型的神经细胞是在大脑深处的皮层下被称为内侧隔的区域发现的，每一种类型的神经细胞都向大脑皮层的一个或多个特定区域发送平行的投影，每一个区域在记忆的形成和回忆中起着不同的作用。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变性影响的区域。利用一种新的技术对这些和其他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类大脑中细胞类型的全面定义。基于我们最近的发现，我们将在阿尔茨海默病的小鼠模型中确定这些类型的神经细胞的功能是如何变化的。然后，我们将使用外部调制这些特定通路的活动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有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.