Optogenetic investigation of normal and pathological rhythms in the hippocampal formation

My dissertation work focuses on the mechanisms and properties of two oscillatory patterns, the high frequency sharp-wave ripple oscillation thought to be involved in the long term storage of memories, and the high amplitude pathological oscillations associated with epileptic seizure. Hippocampal sharp-wave ripples are observed in CA1 during inactivity and slow-wave sleep, and thought to be important for memory reconsolidation. Using optogenetic light ramp stimuli in transgenic mice, I found that gradual depolarization of CA1 pyramidal cells (mimicking CA3 sharp-wave input) is sufficient to induce fast gamma and sharp-wave ripple-like high frequency oscillations. I further demonstrate that the frequency of the oscillation is tightly correlated with the amplitude of the depolarizing input and is reduced by potentiation of GABAa. These results provide new insights into the mechanism and function of fast gamma and sharp-wave ripples. In separate experiments I have demonstrated that the same networks, when driven to super-physiological synchrony via optogenetic activation produce population discharges, after-discharge activity, pathological high-frequency oscillations, and behavioral seizure. Although optogenetic methods replicate the essential features of traditional electrical kindling, there are distinct advantages to this approach. These experiments depend critically upon the development of novel methods for optogenetic stimulation and multi-site recording in freely moving animals. Toward this end, I have developed and fully characterized a novel magnetic rotary fiber optic connector for optogenetic experiments. Collectively my dissertation work provides important insight into the mechanisms of normal and pathological oscillations in the hippocampus, previously unavailable using traditional methodologies.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2014

Author dc:creator

• Klorig, David C.

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/39336

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/39336