UC San Diego

Rhythmic oscillations are prominent features of information processing in neuronal circuits that have been linked to cognitive processing. Neuronal oscillations, including theta oscillations (6-9 Hz), have been hypothesized to indicate accurate timing of neuronal activity within and across a system of brain regions including the hippocampus, medial entorhinal cortex, and prefrontal cortex. Disruption to oscillatory activity has been shown to cause severe disruptions in the ability to form and retrieve memories. This has led to the hypothesis that oscillatory activity and precisely timed neuronal activity is necessary for memory.

Theta (6-9 Hz) oscillations are generated by subcortical pacemaker cells in the medial septum that are GABAergic and express parvalbumin and exhibit rhythmic bursting that is phase-locked to theta. We used optogenetic techniques to target these GABAergic parvalbumin cells in the medial septum in order to precisely manipulate theta frequency. Using this technique, we thoroughly tested how the spike timing of individual cells within the entorhinal-hippocampal circuit is altered when oscillatory activity is modulated. We found that cells within the entorhinal-hippocampal became entrained to the altered theta frequency and also exhibited accelerated oscillatory frequencies that were not seen in baseline conditions.

Damage to the medial septum and its subsequent reduction in theta amplitude results in substantial impairments in hippocampal-dependent memory. However, reductions in theta amplitude by medial septal inactivation also cause large reductions in the firing rates of hippocampus and medial entorhinal cortex neurons. Therefore, it has been difficult to show whether theta oscillations themselves are critical for memory or whether effects on memory are due to other factors such as a reduction in firing rate. We therefore tested whether slightly offsetting the timing of theta oscillations is important for episodic memory and found that even a minor acceleration in theta frequency was sufficient to disrupt memory.

Overall, the results presented in this dissertation provide novel insights into the role of oscillations in controlling the spike timing of cells within the hippocampus and medial entorhinal cortex and directly show a role for oscillatory timing in spatial working memory.