Whole-Brain Light-Sheet Imaging Reveals Divergent Effects of Ketamine on the Dopamine System
Datta MS, Chen Y, Chauhan S, Zhang J, De La Cruz ED, Gong C, Tomer R. Whole-brain mapping reveals the divergent impact of ketamine on the dopamine system. Cell Rep 2023;42(12):113491. doi: 10.1016/j.celrep.2023.113491.
Background: Ketamine, a clinically relevant anesthetic and fast-acting antidepressant, has complex effects on the brain’s neurotransmitter systems. While acute ketamine effects on dopamine (DA) activity are well characterized, the long-term, brain-wide impact of chronic ketamine exposure remains poorly understood.
Hypothesis: This study tested the hypothesis that repeated ketamine exposure leads to dose-dependent and region-specific structural plasticity in the brain’s dopaminergic system.
Methods: The authors developed a high-resolution whole-brain phenotyping platform incorporating tissue clearing, immunolabeling and ClearScope light-sheet theta microscopy to map sub-cellular dopaminergic changes in male mice following chronic ketamine administration. The imaging was integrated with “suiteWB,” a computational pipeline enabling quantitative analysis of tyrosine hydroxylase positive (TH+) neuron counts and projections across annotated brain regions.
Results: Ten days of repeated ketamine exposure (30 or 100 mg/kg) resulted in divergent, dose-dependent alterations in TH+ neurons. Decreases were observed in midbrain regions linked to behavioral states (e.g., dorsal raphe, retrorubral area), while increases occurred in hypothalamic domains (e.g., arcuate nucleus, zona incerta). Additionally, projection density analyses revealed enhanced TH+ innervation of associative cortices (e.g., prefrontal cortex) and reduced projections to sensory and striatal regions. The study also identified previously untranslated TH mRNA+ neurons as a potential substrate for ketamine-induced plasticity, implicating post-transcriptional regulation.
Conclusions: Chronic ketamine induces complex and region-specific remodeling of the dopaminergic system, involving both gain and loss of TH+ neurons and their projections. These findings underscore the importance of unbiased, whole-brain analyses to understand the structural basis of ketamine’s therapeutic and adverse effects.
