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

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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.