Connecting objects to places: functional investigation of projections from lateral to medial entorhinal cortex

Our capacity for memory is critical for everyday life and is central to our sense of who we are. The brain's system for conscious memories is thought to use parallel streams of information in its early stages, with a brain region called the medial entorhinal cortex (MEC) processing information about where we are and an adjacent region called the later entorhinal cortex (LEC) processing information about features in our environment such as the location and identity of objects. According to this view, these distinct signals are then integrated by a downstream brain area called the hippocampus to generate complete memories. However, recent experiments suggest that the distinction between representations in the MEC and LEC of where we are and what objects are around us is not as clear cut as is often assumed. Consistent with this, our preliminary data show that the LEC directly connects to the MEC. This uncharted neural pathway could enable feature information and spatial information to be integrated prior to reaching the hippocampus. Our preliminary data also show that this pathway from the LEC to the MEC arises from 'fan cells' in LEC, a type of brain cell, or neuron, that is important for memory formation and is damaged in Alzheimer's disease. Our goal here is to establish when and how this pathway influences information processing in the MEC.

Our first aim will be to delineate the routes that signals from fan cells follow when they arrive in the MEC. Our preliminary data show that principal neurons in the MEC, a numerous type of neuron that relays signals to other brain areas, respond in complex ways to the activation of fan cells. We will use molecular-genetic tools to delineate roles in these complex responses of interneurons, a less numerous type of neuron that has extensive local connections, which our preliminary data suggest underlie the complex responses.

Our second aim will be to determine when fan cell projections are active and what effect they have on neurons in the MEC. We will use imaging technology to monitor the activity of fan cells as mice explore arenas and encounter objects. These experiments will tell us if fan cell projections are active during exploration in general or if their activity is specific to objects or to learning about an environment. We will then record the electrical activity of individual neurons in the MEC during similar behaviours and during direct activation of fan cell projections. In this way we will be able to associate the information that each neuron in the MEC represents during behaviour with its response to activation of the fan cell pathway.

Our third aim will be to evaluate what happens to representations of spatial and object-related information by individual neurons in the MEC when fan cells are inactivated, and what role local interneurons play in these representations. To do this, we will again record the electrical activity of neurons in the MEC during behaviour. We will then inactivate fan cell projections to the MEC and measure how this inactivation changes the representations of neurons in MEC. We will also delineate roles for local interneurons by applying the molecular-genetic tools that we validated in our first aim. These experiments will tell us whether spatial and object-related information in the MEC is supported by fan cells, and the underlying roles of local interneurons in processing fan cell signals.

Our results will impact our understanding of how the brain integrates signals that tell us where we are with signals that tell us about specific features of our environment. This will advance our fundamental understanding of how memories are formed and how we use spatial signals to navigate. Further, because fan cells in LEC are damaged in Alzheimer's disease, our data will help determine if symptoms of Alzheimer's disease, such as wandering behaviour and memory impairment, could be the result of damage to direct connections between LEC and MEC.

Current models of spatial cognition and memory assume that the medial and lateral entorhinal cortex (MEC/LEC) send parallel streams of information to the hippocampus. However, anatomical and functional studies suggest that MEC and LEC may also interact directly, but how these interactions are organised and what their functional consequences are has received little attention. Our preliminary data shows that fan cells in layer 2 of LEC send direct projections to principal neurons and interneurons in layers 1 and 2 of MEC. Fan cells are known to be critical for episodic-like memory and manifest early pathology in Alzheimer's Disease. Here, we propose to determine when and how fan cell projections influence neural representations in the MEC using chemogenetic, optogenetic and imaging tools in combination with electrophysiology and behaviour. We will use ex-vivo approaches to delineate roles of local inhibitory networks in complex responses of MEC principal cells to activation of fan cell inputs. We will determine when fan cell projections to MEC are active during behaviour and what their effect is on functionally identified neurons. Finally, we will test the contribution of fan cell projections to functional representations and evaluate roles of local inhibitory circuits. By delineating circuit mechanisms for functional interactions between two key brain areas our results will motivate new systems models for spatial cognition and memory. Further, they will establish candidate circuit mechanisms for symptoms of Alzheimer's Disease, such as wandering behaviour and episodic memory impairment, which could arise from degradation of LEC-MEC interactions.