Project Summary/Abstract. Theta rhythms are ~4-12 Hz neuronal oscillations that occur in various brain re- gions and have been linked to specific behaviors and cognitive processes. Aberrant theta rhythms have been observed in several cognitive disorders including schizophrenia, autism spectrum disorders, and Alzheimer’s disease and may contribute to cognitive deficits in these disorders. Therefore, circuit-level interventions aimed at promoting theta rhythms may be effective treatments for cognitive impairments in brain disorders associated with aberrant theta rhythms. A large body of rigorous research supports the premise that successful learning and memory require theta rhythms in the hippocampus, a key brain region for memory storage. Theta rhythms occur prominently in the hippocampus of rats during active exploratory behaviors. In behaving rats, theta-coor- dinated ensembles of hippocampal neurons that code spatial trajectories develop with learning and are thought to be a key mechanism underlying spatial memory storage. Theta-coordinated neuronal ensembles are acti- vated in sequences that provide temporally compressed representations of learned paths, with cells that represent earlier and later locations firing on earlier and later phases of theta cycles, respectively. Recent work from our lab showed that theta-coordinated sequences of neurons recorded in hippocampal subfield CA1 differed between correct and error trials in rats performing a spatial memory task (Zheng et al., 2021). Theta-coordinated sequences were less temporally compressed and began at a significantly delayed phase of the theta cycle during error trials compared to correct trials. These results suggest new and exciting hypotheses about network mech- anisms underlying errors in memory. However, it remains largely unknown which inputs to CA1 neurons drive temporal compression of theta-coordinated sequences and which inputs trigger neuronal firing at the start of a sequence. The proposed work is expected to fill these gaps in knowledge through behavioral neurophysiology experiments in rats that employ state-of-the-art multisite recording, optogenetic manipulation, and neuronal en- semble decoding techniques. Specific Aim 1 will test whether theta rhythmic stimulation of inputs to CA1 from the medial entorhinal cortex (MEC), a region that transmits processed sensory information about an animal’s current position in space, triggers sequence activation. Specific Aim 1 will also test whether theta rhythmic stimulation of MEC inputs reduces memory errors on a spatial delayed match-to-sample memory task. Specific Aim 2 will test whether theta rhythmic stimulation of subfield CA3, a region where memories are thought to be stored, increases temporal compression of sequences and improves performance on a spatial delayed match- to-sample memory task. The work is expected to reveal new mechanisms underlying successful memory en- coding. The work is also expected to suggest novel treatm...