Firstly, kudos to excellent graduate students Malika Datta and Yannan Chen, who led this highly inter-disciplinary project with contributions from many others in the lab. And we are very grateful to generous help and crucial advice we received from Prof. Christine Ann Denny Chalifoux throughout the project, and also grateful to advice from Prof. Rae Silver and Prof. Darcy Kelley over the years.

Ketamine has been in clinical use as a dissociative anesthetic for more than 50 years and has found several other uses in many clinical contexts (e.g., as pain management medication). Most recently, ketamine has emerged as a transformative anti-depressant (FDA approved) of great promise, especially for treatment-resistant depression patients. (e.g., see this NY Times story: https://www.nytimes.com/2021/05/30/opinion/ketamine-treatment-depression.html ).

However, like many drugs, ketamine's antidepressant impact is known to be transient, lasting only a week or so. This necessitates long-term maintenance continuous treatment for several years, with significant risks for side-effects. And, ketamine is also being increasingly abused as a recreational drug, often at high doses, and is known to cause cognitive (e.g., reduced executive function and memory) and sensory (e.g., auditory and visual hallucinations) impairments. Ex: https://www.nytimes.com/2023/02/20/us/ketamine-telemedicine.html

(1) Firstly, we developed an entire pipeline for high-resolution phenotyping of whole mouse brains, including high-resolution whole brain imaging and large-data (~100 Terabytes) analysis tools (suiteWB) for comparative analyses. These methodological advances were critical for performing an unbiased whole-brain investigation of the ketamine's impact on brain, not only at the level of neuronal cell bodies but also brain-wide neuronal projections.

(2) We specially focused on phenotyping the modulatory dopamine system. Several prior studies have shown that ketamine greatly impacts the dopamine system, leading to activation of dopamine neurons in VTA and increased dopamine release in frontal cortex, striatum and nucleus acumbens. Therefore, we hypothesized that repeated ketamine exposure over time may lead to persistent changes in the dopamine system.

Indeed, we found that Ketamine exposure for 10 days results in broad and divergent brain-wide changes in the dopamine system i.e. affecting some brain regions positively and others negatively, which is quite a surprising finding as until now the understanding was of the activating impact of ketamine. Specifically, we found decreases in dopamine neurons within behavioral state related mid-brain regions (dorsal raphe, retrorubral area etc) and increases in hypothalamic domains (ARH, PVp etc).