Hippocampal CA1 state sequences: New insights into the relationship between Ripples and Theta

Abstract

The hippocampus has been extensively studied for its role in memory, navigation, spatial and temporal encoding. While hippocampal circuit activity is haled for its behavioral relevant state dependence, it remains unclear how internally driven hippocampal states are translated into organized behaviors across time. This dissertation tests the idea that CA1 does so through continuity between ripple and theta rich states, such that activity expressed in one state bias oscillatory dynamics, cell recruitment, and content in the following state. Using chronic recordings in freely behaving mice, Chapter-2 characterizes CA1 dynamics across a protocol designed to capture sleep before and after voluntary wheel running. Pre-run sleep, running and post-run sleep each carried distinct but related behavioral relevance. Pre-run ripple duration and the fraction of long ripples predicted later running performance and theta expression. Pyramidal cells and interneurons showed strong continuity between ripples and running-theta recruitment, but behavioral relevance was expressed most clearly in theta participation. Content analyses further revealed that pre and post run ripples preserved different forms of running theta information. Chapter-3 tested whether CA1 continuity is modifiable. Using global TrkB.T1 knockout mice and sub-anesthetic ketamine during virtual reality navigation these preliminary results showed that genotype and treatment selectively distorted ripple duration, early theta to late ripple relationships and cross state cell recruitment, suggesting that state continuity depends on local circuit conditions. Together this dissertation argues that CA1 circuitry carries structure across ripple and theta states to help organize anticipation, action and subsequent reorganization over time via CA1 state sequences.