Research Projects

The scientific goal presented in this proposal is to uncover fundamental neurophysiological principles that govern learning and memory as an organism experiences a new spatial environment. Understanding these principles is critical for improving learning and its expression in memory in conditions where it is impaired, such as during aging and associated neurodegenerative diseases. Our approach will focus on uncovering distinct neurophysiological signatures within the hippocampus, a brain region critical for learning and memory linked to improved behavioral outcomes. Specifically, we will leverage a targeted optogenetic manipulation strategy to precisely stimulate the long-range projecting GABAergic theta-coordinator neurons in the medial septum (MS) using carefully designed closed-loop manipulation algorithms. Optogenetic experiments provide essential tools to determine causality in systems neuroscience, and a central goal of our lab is to discover nodes in the nervous system that enable the flexible binding of cross-region synchronization at fast timescales. Using these powerful tools, we want to test the hypothesis that manipulating the frequency and content of hippocampal spatial representations will improve learning in complex behavioural tasks. We will conduct large-scale electrophysiological recordings in rats' hippocampus with hybrid implants with an optic fiber targeted to the MS. We will need a two-step approach to develop these tests. Aim 1: Develop closed-loop optogenetic manipulation protocols that specifically alter hippocampal representations during movement We will use a closed-loop optogenetic stimulation protocol to rhythmically stimulate medial septal PV neurons at 4 Hz and 12 Hz briefly as animals approach a choice point. Prior work in mice and rats (including ours) has shown that such a manipulation entrains hippocampal theta at the requested frequency. However, the specific impact of this entrained hippocampal EEG has yet to be evaluated in the context of hippocampal representations. The development of this manipulation can allow us to test whether the septo-hippocampal pathway can be used to “change” the content of spatial computations in the hippocampus. Aim 2: Test the hypothesis that precise optogenetic stimulation during cognitively challenging tasks will improve learning We will build on the prior observations and develop tasks with varying degrees of cognitive flexibility, such as a. multi-arm sequence learning task, and test the protocols developed in AIM 1, which can either increase the length of spatial representations or increase their frequency. We would expect to see better learning performance when one increases the length early during learning, as longer hippocampal representations may be more efficacious in binding far-away spatial interrelationships. Later in learning, we might find that more frequent non-local representations help the animal to evaluate path-value pairs in a complex environment.