Nucleus reuniens of the thalamus as a target for driving network-wide memory states - The primary goal of the present proposal is to explore the role of pathway-specific RE neurons in the synchronized activity of the prefrontal-hippocampal circuit (mPFC-HC) and memory-related rhythms in wake (episodic-like sequence memory) and in sleep states (REM/NREM). To accomplish this, Aim 1 focused on determining if and how excitation of RE neurons could drive memory-related mPFC-HC coherent states. The K99 phase experiments tested a range of relevant frequencies in RE pathway-specific neurons to identify stimulation capable of driving mPFC-HC coherent modes in freely behaving rats. It was found that activating RE neurons elicited a beta-driven coherence between the prefrontal cortex and hippocampus, similar to that of memory-driven brain states, and this effect was independent of frequency or optogenetic stimulation type (pulse or sinewave) delivered in RE. As I transition to my independent career (R00), Aim 2 will explore the role of pathway-specific RE neurons in driving theta- and delta-related sleep oscillations (REM/NREM) using a closed-loop setup. During the K99 training phase, I learned to run a sophisticated rodent sequence memory task capable of testing multiple RE-dependent memory dimensions and developed a cutting-edge closed-loop optogenetic control system capable of detecting neurophysiological modes (NREM/REM) between the hippocampus and medial prefrontal cortex in real time to trigger RE optogenetic stimulations at relevant behavioral states (wake/sleep). My scientific training in anatomy, optogenetics, multisite electrophysiological recordings, closed-loop approaches, and my theoretical background on RE-related mnemonic processes and arousal provide me with the foundation and technical skills necessary to pursue the goals of the R00 phase of this award. The training received during the K99 phase has prepared me to enter the independent stage of my career with the theoretical, technical, methodological, networking, and laboratory management skills necessary to answer scientific questions at the circuit and network level, establish my own laboratory, and independently pursue future scientific directions. Overall, this research will shed new light on the mechanisms of mPFC-HC circuit interactions that support memory and are modulated by the midline thalamus, specifically RE. This fundamental understanding will advance knowledge of RE function in relation to pathophysiological issues such as memory and sleep symptoms observed in many psychiatric and neurological disorders.
