Theses Doctoral

Whole brain mapping reveals divergent changes in the dopaminergic system after chronic (R,S)-ketamine exposure

Datta, Malika Sen

The dopaminergic neurons form a brain-wide neuromodulatory system affecting reward, addiction, and motor behaviors. Alterations in dopamine signaling have been associated with many brain disorders, including schizophrenia and Parkinson’s disease. Over the last decade, it has been well-established that the dopaminergic system is capable of significant neurotransmitter phenotypic plasticity (NPP), which is defined as the activity-dependent loss or gain of a specific neurotransmitter usage by neurons. However, most of the related studies have focused on specific regions, providing important but limited insights into NPP. Attaining an unbiased mapping of brain-wide NPP and its relationship with behavioral changes has remained challenging. In this thesis, we first addressed the technical challenges by establishing a whole-brain phenotyping pipeline. Next, we utilized these tools to generate the first brain-wide map of NPP in response to chronic exposure to (R,S)-ketamine, revealing some of the underlying fundamental principles.

Here, we describe a whole brain NPP mapping pipeline for studying dopaminergic phenotypic plasticity following chronic (R,S)-ketamine exposure. The pipeline includes 1) an optimized whole brain tissue clearing/immunostaining method for labeling the dopaminergic neurons by utilizing rate-limiting marker tyrosine hydroxylase (TH), 2) high-resolution whole-brain imaging with CLARITY optimized light-sheet microscopy (COLM) and light sheet theta microscopy (LSTM), and 3) a custom python-based data analysis pipeline for quantitative mapping of the brain-wide NPP.

Our first key result is that chronic (R,S)-ketamine administration leads to divergent brain-wide changes in the dopaminergic system. Specifically, ten days (but not 1 or 5 days) of daily (R,S)-ketamine (100 mg/kg) administration resulted in a significant decrease in TH+ neurons in regions of the midbrain and a significant increase in areas of the hypothalamus. Second, chronic (R,S)-ketamine treatment also induced an increase in TH+ neuronal projections, including increases within associative cortical brain regions such as the prelimbic area, orbital area, and anterior cingulate area. Decreases in the density of TH+ neuronal projections were observed in the auditory (AUDd) and visual cortices (VISpl). Third, we performed mRNA expression mapping and before-after treatment comparison of the TH+ neuron population within the same animal to reveal that newly gained TH+ neurons are mainly recruited from the neuron pool that contained untranslated TH mRNA. Overall, this thesis provides a first brain-wide quantitative survey of the NPP caused by a specific drug (R,S)-ketamine, extending our fundamental understanding of the extent of adaptability of our brain in response to external stimuli.


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More About This Work

Academic Units
Neurobiology and Behavior
Thesis Advisors
Tomer, Raju
Ph.D., Columbia University
Published Here
January 4, 2023