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

研究丘脑团聚核在将前额叶皮层输入传递到海马体中的作用

• 批准号: BB/P001475/1
• 负责人: Michael Craig
• 金额: $ 41.16万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP001475%2F1
• 关键词: Investigating; role; thalamic; nucleus; reuniens

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.

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的电路的研究，但我们的大部分功能知识来自于在完整动物中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产生认知和复杂的行为，那么我们必须通过研究不同的大脑区域如何相互作用来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一个问题：我们的目标是研究允许大脑区域在远距离同步其活动的细胞电路。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）如何控制海马体的活动，海马体是记忆和空间导航所必需的结构。我们将通过使用尖端的遗传方法来研究回路功能，并结合现有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团聚核传递到海马体，我们将使用光遗传学方法研究其与海马体的联系。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团聚核，以允许蛋白质的表达，从而允许人们利用光控制神经元的活动。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收到来自团聚核的输入，以及该输入的功能是什么。这些实验中的大部分将使用减少的脑切片制剂进行，以便我们能够确定从团聚核接收连接的神经元的身份。在第二组实验中，我们还将记录完整麻醉动物的海马体活动，以便我们确定来自团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：导致其他神经元变得更加活跃的兴奋性细胞，以及降低其他神经元活动的抑制性细胞。团聚核位于丘脑，丘脑是大脑中的一种结构，通常将兴奋信息从一个大脑区域传递到另一个大脑区域。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，团聚核并不针对海马体中的兴奋性神经元。为了确定使用生理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组实验。这些狂犬病追踪方法使可视化单个神经元组接收的所有直接连接成为可能，因此我们将能够查看海马体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团聚核的直接输入。该项目有可能对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记忆非常重要。 目标导向的行为。在精神分裂症等精神疾病和帕金森病等神经退行性疾病中，前额皮质和海马体之间的通讯都会受到干扰。了解这些区域相互作用的电路是我们必须采取的重要一步，然后我们才能继续为这些情况设计有效、有针对性的治疗方法。

项目成果

No evidence from complementary data sources of a direct projection from the mouse anterior cingulate cortex to the hippocampal formation

• DOI: 10.1101/2022.01.25.477805
• 发表时间: 2022-01
• 期刊: bioRxiv
• 作者: L. Andrianova;Steliana Yanakieva;Gabriella Margetts-Smith;S. Kohli;Erica S Brady;J. Aggleton;Michael T Craig

Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal - medial prefrontal cortex circuit during natural sleep in AppNL-G-F/NL-G-F mice.

AppNL-G-F/NL-G-F 小鼠自然睡眠期间海马 - 内侧前额叶皮层回路中表达小白蛋白的中间神经元功能的改变和相关网络振荡。

• DOI: 10.1016/j.nbd.2023.106151
• 发表时间: 2023
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Brady ES

A cellular switchboard in memory circuits

存储电路中的蜂窝交换机

• DOI: 10.1126/science.add2681
• 发表时间: 2022
• 期刊: Science
• 影响因子: 56.9
• 作者: Craig M

Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal - medial prefrontal cortex circuit during natural sleep in App NL-G-F mice

App NL-G-F 小鼠自然睡眠期间海马 - 内侧前额叶皮层回路中表达小白蛋白的中间神经元功能的改变和相关网络振荡

• DOI: 10.1101/2022.02.08.479119
• 发表时间: 2022
• 作者: Brady E