Cellular and synaptic mechanisms of theta-nested gamma oscillations in the medial entorhinal cortex
OA Version
Citation
Abstract
Neural oscillations play a central role in organizing brain activity across space and time. In the medial entorhinal cortex (mEC), a region critical for spatial navigation and memory, gamma oscillations (30 to 140 Hz) coordinate neuronal firing and structure information flow. These fast rhythms are often nested within slower theta oscillations (4 to 12 Hz), forming a temporal framework that supports the encoding of spatial and episodic memories. Despite their importance, the circuit mechanisms underlying theta-nested gamma oscillations in the mEC remain incompletely understood, particularly regarding the roles of specific excitatory and inhibitory cell types and the balance between excitation-driven and inhibition-driven dynamics. By integrating whole-cell patch-clamp recordings, optogenetic stimulation, pharmacological blockers, local field potential recordings, and targeted-illumination confocal voltage imaging, this dissertation establishes a detailed framework for identifying the cellular and circuit interactions that generate gamma oscillations in superficial layers of the mEC. Using transgenic mice with cell-type-specific optogenetic expression, I demonstrate that parvalbumin-expressing fast-spiking interneurons can autonomously generate gamma-frequency inhibition, even without fast excitatory input, supporting an interneuron network gamma (ING) mechanism. In contrast, stimulation of excitatory CaMKII+ neurons recruits a pyramidal-interneuron network gamma (PING) circuit, in which excitation of interneurons precedes monosynaptic inhibition. Voltage imaging reveals network-wide gamma synchrony among excitatory neurons despite sparse individual firing and gamma cycle skipping. Finally, spatial correlation analyses show little evidence of anatomical clustering, suggesting that gamma synchrony emerges from functional rather than spatial organization. These findings clarify how distinct cell types contribute to gamma oscillations in the mEC and support a hybrid ING and PING framework. This work refines models of spatial computation in the cortex and has broader implications for understanding memory deficits in neurological conditions such as Alzheimer disease and epilepsy, where the temporal structure of neural activity is frequently disrupted.
Description
2025