Investigating the role of the thalamic nucleus reuniens in relaying prefrontal cortex input to the hippocampus

从基础神经科学研究中获得的大量知识来自于对特定大脑区域回路的研究，而我们的大部分功能知识来自于在完整动物身上进行的行为研究和功能成像实验。如果神经科学的总体目标是了解神经元水平的生理过程如何引起认知和复杂行为，那么我们必须通过研究不同的大脑区域如何相互作用，弥合细胞神经科学和行为之间的差距。这是当前项目寻求解决的问题：我们的目标是研究允许大脑区域长距离同步活动的细胞回路。具体来说，我们将研究前额叶皮层（一个与执行控制和计划相关的区域）如何控制海马体（一个对记忆和空间导航至关重要的结构）的活动。我们将通过使用尖端遗传学方法研究电路功能，结合已建立的神经生理学方法来解决这个问题。来自前额叶皮层的输入通过丘脑核团传递到海马，我们将使用光遗传学方法研究它与海马的联系。对于我们的项目，光遗传学方法将涉及使用病毒将基因传递到核reuniens，以允许蛋白质的表达，从而允许人们使用光来控制神经元的活动。这将使我们能够记录海马体中单个神经元的活动，然后使用光脉冲来确定这些神经元是否接受来自联合核的输入，以及这种输入的功能是什么。这些实验中的大多数将使用简化的脑切片制备来进行，以使我们能够确定从神经元连接的神经元的身份。在第二组实验中，我们还将记录完整的麻醉动物海马体的活动，以确定来自重聚核的输入如何影响海马体网络的活动。神经元可以分为两大类：兴奋性细胞，使另一个神经元变得更加活跃，抑制性细胞，减少其他神经元的活动。联合核位于丘脑，丘脑是大脑中的一个结构，通常将兴奋信息从一个大脑区域传递到另一个区域。在我们的试验数据中，我们发现证据表明，非常出乎意料的是，核reuniens不针对海马体中的兴奋性神经元。为了确定这种使用生理学方法进行的观察是否确实准确，我们将使用先进的狂犬病追踪方法进行一系列实验。这些狂犬病追踪方法使我们能够可视化单个神经元组接收的所有直接连接，因此我们将能够查看海马中兴奋性细胞的所有直接输入，以确认它们是否确实接收到来自重聚核的直接输入。该项目有可能为神经科学做出及时而重大的贡献：前额叶皮层和海马体之间的相互作用对于工作记忆和目标导向行为是重要的。前额叶皮层和海马体之间的交流在精神疾病（如精神分裂症）和神经退行性疾病（如帕金森病）中都会被破坏。了解这些区域相互作用的电路是我们为这些疾病设计有效的、有针对性的治疗方法之前必须采取的重要步骤。

A great deal of knowledge gained from fundamental neuroscience research has come from studying the circuitry of specific brain regions, yet most of our functional knowledge comes from behavioural studies and functional imaging experiments carried out in intact animals. If the overall aim of neuroscience is to understand how physiological processes at the level of the neuron give rise to cognition and complex behaviours, then we must bridge the gap between cellular neuroscience and behaviour, by studying how different brain regions interact. This is a problem that the current project seeks to address: we aim to study the cellular circuitry that allows brain regions to synchronise their activity across long distances. Specifically, we will study how the prefrontal cortex, a region linked to executive control and planning, can control activity in the hippocampus, a structure that is essential for memory and spatial navigation.We will address this problem through use of cutting edge genetic approaches for studying circuit function, combined with established neurophysiological methods. Input from the prefrontal cortex is relayed to the hippocampus via the thalamic nucleus reuniens, and we will study its connections to the hippocampus using optogenetic methods. For our project, the optogenetic methods will involve using viruses to deliver genes to the nucleus reuniens to allow the expression of proteins that allow one to control the activity of neurons using light. This will enable us to record the activity of individual neurons in the hippocampus and then use light pulses to determine whether these neurons receive input from the nucleus reuniens, and what the function of this input will be. The majority of these experiments will be carried out using reduced brain slice preparations to allow us to determine the identity of neurons that receive connections from the nucleus reuniens. In a second set of experiments, we will also record the activity of the hippocampus in intact, anaesthetised animals to allow us to determine how inputs from the nucleus reuniens can affect activity in the hippocampal network. Neurons can be split into two broad categories: excitatory cells that cause another neurons to become more active, and inhibitory cells that reduce the activity of other neurons. The nucleus reuniens is located in the thalamus, a structure in the brain that generally relays excitatory information from one brain region to another. In our pilot data, we found evidence to suggest that, very unexpectedly, the nucleus reuniens does not target excitatory neurons in the hippocampus. To determine whether this observation, made using physiological methods, is indeed accurate, we will carry out a set of experiments using advanced rabies tracing methods. These rabies tracing methods make it possible to visualise all direct connections that an individual group of neurons receive, so we will be able to view all direct inputs to excitatory cells in the hippocampus to confirm whether or not they do receive direct input from the nucleus reuniens.This project has the potential to make a timely and significant contribution to neuroscience: interactions between the prefrontal cortex and hippocampus are important for working memory and goal-directed behaviour. Communication between the prefrontal cortex and the hippocampus is disrupted in both psychiatric conditions such as schizophrenia, and neurodegenerative disorders such as Parkinson's disease. Understanding the circuitry through which these regions interact is an important step that must be taken before we can move on to design effective, focused treatments for these conditions.