Intrinsic Cornu Ammonis Area 1 Theta-Nested Gamma Oscillations Induced by Optogenetic Theta Frequency Stimulation

摘要

Gamma oscillations (30–120 Hz) are thought to be important for various cognitive functions, including perception and working memory, and disruption of these oscillations has been implicated in brain disorders, such as schizophrenia and Alzheimer's disease. The cornu ammonis area 1 (CA1) of the hippocampus receives gamma frequency inputs from upstream regions (cornu ammonis area 3 and medial entorhinal cortex) and generates itself a faster gamma oscillation. The exact nature and origin of the intrinsic CA1 gamma oscillation is still under debate. Here, we expressed channelrhodopsin-2 under the CaMKIIα promoter in mice and prepared hippocampal slices to produce a model of intrinsic CA1 gamma oscillations. Sinusoidal optical stimulation of CA1 at theta frequency was found to induce robust theta-nested gamma oscillations with a temporal and spatial profile similar to CA1 gamma in vivo. The results suggest the presence of a single gamma rhythm generator with a frequency range of 65–75 Hz at 32°C. Pharmacological analysis found that the oscillations depended on both AMPA and GABAA receptors. Cell-attached and whole-cell recordings revealed that excitatory neuron firing slightly preceded interneuron firing within each gamma cycle, suggesting that this intrinsic CA1 gamma oscillation is generated with a pyramidal–interneuron circuit mechanism.>SIGNIFICANCE STATEMENT This study demonstrates that the cornu ammonis area 1 (CA1) is capable of generating intrinsic gamma oscillations in response to theta input. This gamma generator is independent of activity in the upstream regions, highlighting that CA1 can produce its own gamma oscillation in addition to inheriting activity from the upstream regions. This supports the theory that gamma oscillations predominantly function to achieve local synchrony, and that a local gamma generated in each area conducts the signal to the downstream region.