Over 50 million people worldwide suffer from epilepsy. Of these, nearly a third will be refractory to medical therapy, and many will be poor candidates for surgical resection. Thus there is a need for novel targets and therapies, the former of which will require a greater understanding of neural networks involved in epilepsy, and the latter of which demands the development of novel therapeutic techniques. Seizures are less frequent during periods where theta – a 3-12Hz oscillatory rhythm in the hippocampal local field potential – is present. Theta is thought to originate in the medial septum, a basal forebrain structure that projects to the site of origin for the most common form of intractable epilepsy, the hippocampus. As has been demonstrated with pharmacologic and electrical stimulation, theta generation via the medial septum is consequently an ideal target for intervention. However, of the three neuron populations within the medial septum – cholinergic, GABAergic, and glutamatergic – it is unclear which is responsible for theta, or indeed if a single population is driving the oscillation. Optogenetics, a novel technique that enables activation and inhibition of genetically-defined neurons on a millisecond time-scale, provides the means to functionally dissect this septohippocampal axis and leverage the results for seizure therapy. In this thesis, I detail the current state of deep brain stimulation for epilepsy, and describe our motivation for targeting the medial septum and the importance of the hippocampal theta rhythm. I describe new technologies, software, and adaptations to our electrophysiology platform, NeuroRighter, to enable concurrent optogenetic neuromodulation and electrophysiology in awake and behaving animals, and demonstrate how these technologies and techniques can be used in several experimental approaches. I next use this system to show that both the GABAergic and glutamatergic neurons of the medial septum can drive and pace hippocampal oscillatory rhythms, but only the glutamatergic neurons are necessary to maintain phase relationships between successive theta cycles. I also demonstrate that activating and inhibiting the cholinergic neurons of the medial septum does not alter hippocampal local field potential activity, but does alter single-unit firing rates. These results shed light on the function of the medial septum in generating and modulating theta, and provide clear targets for optogenetic modulation of epilepsy.

Afhandling--Copenhagen.

Afhandling--Copenhagen.

Thèse (M.Sc.)--Université Laval, 2003. / Texte en français ou en anglais. Bibliogr. Publié aussi en version électronique.

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The effect of the dopaminergic drugs amphetamine and pimozide on reinforced and non-reinforced species-typical responding was observed in normal mice and mice with lesions of the septal area. In Experiment 1 amphetamine increased wheel running in the reinforced groups with septal lesioned subjects showing greater enhancement than normal animals. Amphetamine depressed wheel running in non-reinforced septal animals and had no effect on non-reinforced normals. Pimozide decreased wheel running in all groups. In Experiment 2, amphetamine increased string pulling in reinforced normal and septal lesioned mice, but this increase was not dose dependent. Non-reinforced septal and normal animals exhibited amphetamine induced decreases in response rate. Again pimozide decreased string pulling in all groups.

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