Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Neuroscience

Supervisor

Dr. Stan Leung

Abstract

The medial septum (MS) is the main source of acetylcholine to the hippocampus, a structure involved in memory and Alzheimer’s disease (AD). Learning and memory involve long-term changes in synaptic strengths, and are suggested to be facilitated by a brain wave, theta rhythm in the hippocampus. Since medial septal neurons influence hippocampal neural activity, lesion of two neuronal populations in the MS, cholinergic and GABAergic, was performed by intraseptal infusion of 192 IgG-saporin and orexin-saporin, respectively. I hypothesized that 1) activation of cholinergic cells by vestibular stimulation induces an atropine-sensitive theta rhythm, modulates synaptic transmission and enhances long-term potentiation (LTP), a model of synaptic plasticity, in the hippocampus and 2) GABAergic neurons regulate granule cell activity by inhibiting interneurons in the dentate gyrus (DG).

Vestibular stimulation by passive whole-body rotation induced an atropine-sensitive theta rhythm that was not present in awake immobility. Following systemic cholinergic blockade, septal 192 IgG-saporin or bilateral vestibular lesion, rotation-induced theta and rotation-induced modulation of evoked potential were attenuated. LTP was enhanced when tetanus was delivered during rotation as compared to during immobility. Systemic cholinergic blockade or 192 IgG-saporin lesion abolished LTP enhancement by rotation.

I provided the first report investigating the role of septal GABAergic neurons on dentate neuronal unit activity in vivo. In urethane-anesthetized sham-lesion rats, pontis nucleus oralis (PNO) stimulation induced a theta rhythm, increased spontaneous granule cell activity, facilitated DG population spike and increased paired-pulse depression (PPD) of population spikes. In freely moving rats, PPD was larger during walking as compared to during immobility. Orexin-saporin lesion attenuated theta, and blocked PNO-induced population spike facilitation and PPD in anesthetized rats. Spontaneous granule cell activity decreased while spontaneous interneuronal activity increased in orexin-saporin lesion rats as compared to sham-lesion rats. It is inferred that tonic interneuronal inhibition is increased and granule cells are less likely to be activated in orexin-saporin lesion rats, as compared to sham-lesion rats.

Therefore, vestibular stimulation provides a physiological method to activate septal cholinergic neurons, consistent with improvement of cognition in humans. Vestibular stimulation may ameliorate cholinergic dysfunction deficits and targeting septal GABAergic neurons may improve behavioral functions in AD.

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