Precisely timed theta oscillations are selectively required during the encoding phase of memory

Nat Neurosci. 2021 Nov;24(11):1614-1627. doi: 10.1038/s41593-021-00919-0. Epub 2021 Oct 4.


Brain oscillations have been hypothesized to support cognitive function by coordinating spike timing within and across brain regions, yet it is often not known when timing is either critical for neural computations or an epiphenomenon. The entorhinal cortex and hippocampus are necessary for learning and memory and exhibit prominent theta oscillations (6-9 Hz), which are controlled by pacemaker cells in the medial septal area. Here we show that entorhinal and hippocampal neuronal activity patterns were strongly entrained by rhythmic optical stimulation of parvalbumin-positive medial septal area neurons in mice. Despite strong entrainment, memory impairments in a spatial working memory task were not observed with pacing frequencies at or below the endogenous theta frequency and only emerged at frequencies ≥10 Hz, and specifically when pacing was targeted to maze segments where encoding occurs. Neural computations during the encoding phase were therefore selectively disrupted by perturbations of the timing of neuronal firing patterns.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Entorhinal Cortex / chemistry
  • Entorhinal Cortex / physiology*
  • Hippocampus / chemistry
  • Hippocampus / physiology*
  • Male
  • Memory / physiology*
  • Mice
  • Mice, 129 Strain
  • Mice, Transgenic
  • Optogenetics / methods
  • Spatial Behavior / physiology*
  • Theta Rhythm / physiology*
  • Time Factors