Date of Award


Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)



First Advisor

Ronald S. Duman


Major depressive disorder is a common and debilitating illness for which there is a notable lack of efficient, effective treatment. While currently available pharmacotherapies typically take eight weeks to take effect and fail to do so at all for about a third of patients, the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown a much more favorable effectiveness profile, including improvements in symptoms within hours of administration, even for many patients who do not respond to typical antidepressants. Ketamine, as a modulator of glutamate signaling in the brain, has a distinct mechanism of action from the serotonin and norepinephrine modulators that are currently the mainstay of depression treatment. This dissertation seeks to contribute to the understanding of this unique mechanism, and particularly the brain circuits affected. Rodent studies have shown that ketamine induces a burst of glutamatergic activity in the medial prefrontal cortex (mPFC), which is necessary to produce its antidepressant effect. The downstream targets of this glutamatergic activity that are relevant to the ketamine antidepressant effect are unclear, but recent research has suggested a role for the dorsal raphe nucleus (DRN), which contains most of the brain’s serotonin-producing cells. In this thesis, I first provide a synthesis of the literature on the mechanism of ketamine’s antidepressant effect and the neural circuits that might underlie it. I then investigate the projection from the mPFC to the DRN using optogenetic stimulation of mPFC-originating axon terminals in the DRN, finding that activation of this pathway produces an antidepressant effect on the forced-swim test (FST), which measures “behavioral despair” induced by a stressful environment, but not on other measures of depression-like behavior. I also perform immunohistochemical studies of the DRN, which indicate that both serotonergic and non-serotonergic cells are activated by this stimulation. I then find additional support for this behavioral selectivity using a pharmacological approach: by inhibiting serotonin release during ketamine administration, I find that DRN activity is needed for the antidepressant effect of ketamine on the FST but not on other behavioral tests. Finally, I interrogate the projection from the mPFC to the nucleus accumbens using the same optogenetic approach as before. These experiments show that activation of the mPFC-to-DRN pathway produces an antidepressant effect on a particular subset of depression-like behavior and supports a role for serotonin signaling in the behavior measured by the FST.

Open Access

This Article is Open Access