Study of the entorhinal-hippocampal circuitry supporting spatial pattern separation in behaving animals
Human Cognitive and Systems Neuroscience
Final Report Abstract
The brain’s memory system faces an interesting challenge - it must somehow transform highly correlated inputs about the external world into distinct, specific memories. It is thought that the hippocampus, and in particular the dentate gyrus, overcomes this challenge by amplifying small differences in input, a process known as Pattern Separation. While convergent neural and behavioral evidence links this hippocampal population to pattern separation, the specific functional and circuit mechanisms mediating this function are not fully understood. In Aim 1, we start by assessing potential network mechanisms of pattern separation. Hypothesized mechanisms include the recruitment of unique populations, rate remapping, temporal decorrelation, and combinations of the three. To adjudicate between these possibilities, we combine a behavioral assay of pattern separation with the latest recording and analytic techniques to understand how small changes to the environment are decorrelated by hippocampal populations to support behavior. Our preliminary results point to two potential network mechanisms of pattern separation: a firing rate change induced by novelty, and a decorrelation of temporal co-activity patterns between neurons. In Aim 2, we address a major point of discussion in the field of hippocampal research. The vast majority of hippocampal behavioral and neural recording studies focus on the memory and encoding of space – from place cells and grid cells to standard behavioral assays including the Morris water maze, contextual fear conditioning, spatial alternation task, among others. Yet, memories are not just spatial, but must also integrate a myriad of non-spatial information. Thus, in Aim 2 we develop a non-spatial pattern separation task in which animals are tested on their ability to detect and remember small changes to an object. We propose the same recording and analysis techniques during this task to assess whether our preliminary network mechanisms generalize to non-spatial information processing. We expand our investigation upstream to the level of the inputs that contact mature granule cells in the dentate gyrus. Specifically, spatial and non-spatial information are hypothesized to arrive from the medial (MEC) and lateral (LEC) entorhinal cortex, respectively. Using a cre-transgenic mice line where entorhinal inputs to the dentate gyrus can be controlled, we propose to assess the engagement of these inputs in our modality-specific pattern separation tasks, and then assay the putative network mechanisms reported in Aim 1. Together, this research proposal aims to identify the biological mechanisms that support pattern separation which will help guide the development of targeted therapeutics to restore pattern separation and memory in disease.
