Optogenetic frequency scrambling of hippocampal theta oscillations dissociates working memory retrieval from hippocampal spatiotemporal codes

Abstract

The precise temporal coordination of activity in the brain is thought to be fundamental for memory encoding and retrieval. The medial septum (MS) provides the largest source of innervation to the hippocampus (HPC), and its inhibitory neurons play a major role in controlling HPC theta (~8 Hz) oscillations. While pharmacological inhibition of the MS is associated with memory impairment, the exact role of MS inhibitory neurons in HPC function and memory is not fully understood. While HPC place cells were previously reported to not depend on MS inputs, the exact role of MS inputs on HPC temporal codes is still a matter of debate. Moreover, pharmacological manipulations do not have the temporal resolution to distinguish the role of MS activity on working memory encoding, retention and retrieval. Here we stimulated the MS with optogenetics to either pace or ablate theta, while recording large hippocampal assemblies over time using calcium imaging along with local field potentials to monitor theta control. Using scrambled light stimulation, we could robustly ablate theta signals, which was associated with direct modulation of a subpopulation of neurons in the HPC. We found that such stimulation led to decreased working memory retrieval, but not encoding in both a delayed non-match to sample task and a novel place object recognition task. Strikingly, scrambled stimulations were not associated with disrupted spatiotemporal codes. Importantly, we show that our opsin did not transfect cholinergic cells and stimulation did not disrupt HPC ripple activity or running speed, suggesting a specific role for MS GABAergic cells in memory maintenance and retrieval that is independent from these other potential confounding mechanisms. Our study suggests that theta signals play a specific and essential role in supporting working memory retrieval and maintenance while not being necessary for hippocampal spatiotemporal codes.

Optogenetic reduction of theta oscillations reveals that a single reliable time cell sequence is not required for working memory

“…Stimulation of cholinergic neurons during the delay (Y. Zhang et al, 2021) , and inhibition or random rhythmic perturbation (Etter et al, 2021;Gemzik et al, 2021) of all septal cell types during the delay period led to behavioral impairments. In our study, despite switching to a partially remapped time cell sequence, selective inactivation of septal GABAergic neurons led to decreased firing rates and increased time information.…”