When studying for a doctoral degree (PhD), candidates submit a thesis that provides a critical review of the current state of knowledge of the thesis subject as well as the student’s own contributions to the subject. The distinguishing criterion of doctoral graduate research is a significant and original contribution to knowledge.
Once accepted, the candidate presents the thesis orally. This oral exam is open to the public.
The discovery that animals engage in intracranial self-stimulation (ICSS) provided a direct way to study the neural networks that direct motivation. In ICSS experiments, animals are implanted with electrodes terminating in reward-implicated substrates. The development of optogenetics advanced the study of the brain reward system by confirming a causal role of midbrain dopamine firing in reward seeking. Since then, the correspondence of optical stimulation parameters to the neural signal of dopamine neurons causing operant behavior has been studied. In parallel, attention was paid to the application of deep brain stimulation on refractory mental illness, including depression. This thesis describes two psychophysical experiments that use optogenetic ICSS of midbrain dopamine neurons. The first experiment shows that, for a substantial range of powers (~12.6 mW - 31.6 mW), the trade-off between power and pulse duration undergoes temporal summation, aligning with Bloch’s Law. Pulse duration can be used to control the volume of activated opsin-expressing dopamine neurons. The second experiment provides a psychophysical measurement of firing fidelity of midbrain dopamine neurons. This study supports that pulse frequencies higher than 40 Hz are ineffective or counter-productive at improving the vigor of operant behavior. Together these experiments highlight the benefit of using measurable outcomes (e.g., operant response) as the basis for making inferences about the effectiveness of optical stimulation. These experiments contribute to the hypothesis that, similarly to electrical ICSS, the variable determining the intensity of reward seeking is the induced aggregate firing rate. Such insights can aid the understanding of how deep brain stimulation functions to alleviate depression. It is suggested here that the antidepressant effects of deep brain stimulation of the medial forebrain bundle (MFB) may involve activation of non-dopaminergic neural pathways. The reward platform hypothesis is presented, which suggests that MFB stimulation may cause antidepressant effects by facilitating reward seeking. This hypothesis is developed in relation to motivation parameters that promote involvement with response-contingent rewarding activities. Ways to test this hypothesis in both pre-clinical and clinical models are proposed. This thesis provides practical guidelines for optogenetic experiment designs, and it outlines original, theory-driven hypotheses about the structural and functional underpinnings of antidepressant deep brain stimulation.