Lateral Entorhinal Cortex (LEC) and episodic memory: examining LEC's impact on pattern separation and neurogenesis

Episodic memory is a fundamental cognitive process. Our episodic memories include details of specific objects or people, spatial locations and contextual details that allow us to differentiate between one event and another. A key feature of episodic memory is that it integrates the features of events to help guide future behaviour. For example, an episodic memory of where we parked our car this morning will allow us to accurately locate the car when we need to go home. Damage to an area of the brain called the hippocampus produces an inability to form new episodic memories. Our own recent work has shown that one of the main inputs to the hippocampus from lateral entorhinal cortex (LEC) is also necessary to integrate the features of an event pointing towards a key role for this LEC-hippocampus network in episodic memory. However, the circuit mechanisms within this network that integrate this information are unknown. One of the main targets for LEC input to hippocampus is the dentate gyrus (DG) subfield. DG is one of a small number of regions in the brain where newborn neurons are generated every day in a process called neurogenesis. These newborn neurons have been shown to be important for simple forms of memory such as fear conditioning, specifically for a process called pattern separation which allows us to discriminate between similar stimuli. However, the role of these newborn neurons and pattern separation in distinguishing between different episodic memories for very similar events is unknown. As a critical next step we will test the hypothesis that neurogenesis mediates pattern separation of similar episodic memories in the hippocampus supported by input from LEC. We will test predictions from this hypothesis through 3 specific aims:

Aim 1: To determine whether newborn neurons facilitate pattern separation in tests requiring integration of the features of episodic memory.
Aim 2: To determine whether LEC inputs to DG mediate the number of newborn neurons and pattern separation in tests requiring integration of EM features.
Aim 3: To determine whether neurogenesis affects pattern separation in hippocampal place cells during tests requiring integration of episodic memory features.

We anticipate wide reaching impact of this research. Episodic memory is affected by lifestyle factors such as diet, exercise and cognitive stimulation and decline in episodic memory is the first symptom of Alzheimer's disease. Understanding the neural mechanisms that support episodic memory will give specific targets to researchers interested in maintaining healthy cognitive function through the lifespan as well as those attempting to develop therapeutic strategies for disorders of memory. We also anticipate impact in the reduction of the number of laboratory animals needed in memory studies. In the last 5 years an estimated 43000 animals were used in studies of object recognition, the basis of all of the behavioural tasks in the current application. The proposed research will examine how enriched environments could improve memory performance in these animals. Improved performance would increase statistical power and mean that fewer animals would be needed to study these types of memory. Given the number of animals involved uptake by only 5% of the research community could mean thousands fewer animals being used in research.

Lateral entorhinal cortex (LEC) and its input to hippocampus are important neural targets for understanding episodic memory (EM). However, the circuit mechanisms within this LEC-hippocampal network that support EM are unknown. We will use new and established behavioural tests of EM in mice combined with state-of-the-art genetic manipulations and in vivo recording to probe the role of LEC input to the hippocampus focussing specifically on hippocampal newborn neurons and pattern separation. Our results will provide valuable insight into healthy ageing as well as having clinical relevance to Alzheimer's disease.
We will examine pattern separation in tests that require the integration of features of EM including objects, places and contexts. We have adapted existing tests of EM to examine similar and dissimilar sets of integrated features. We will test the hypothesis that increased numbers of newborn neurons within the dentate gyrus region of hippocampus will facilitate pattern separation; specifically by improving discrimination of similar events in memory. We will go on to test whether this is mediated by input from LEC. We will use environmental enrichment to upregulate numbers of newborn neurons and the GFAP-TK mouse which allows temporary downregulation of newborn neurons. We will also make use of the Sim1:Cre mouse that we have previously shown gives genetic access to the pathway from LEC to DG. This will allow us to permanently inactivate this pathway using TeLC, which blocks synaptic output. We will also use the Sim1:Cre mouse combined with DREADDs to allow acute, time controlled inactivation of the LEC-DG pathway. Finally, we will examine how increased numbers of newborn neurons affect cellular mechanisms by recording place cells as mice carry out the pattern separation tasks. This is a powerful approach where numbers of newborn neurons can be correlated with pattern separation at both a behavioural and cellular (place cells) level in individual mice.