Midbrain dopamine (mDA) neurons are required for the formation of reward-associated memories, a vital mechanism allowing animals to adapt to their environment. On the flipside, dopaminergic dysfunction caused by repeated exposure to strong reinforcers such as drugs of abuse or hyperpalatable foods can potentially trigger addiction and compulsive, ‘binge’-style eating behaviors, respectively. Intriguingly, humans as well as other animals display striking inter-individual differences in their vulnerability to develop such maladaptive behaviors, which can even be observed despite identical genetics and environment. Thus, we here sought out to explore the role of epigenetic modifications as potential drivers of stochastic variation in the susceptibility to develop binge-eating behavior. To accomplish this, we first performed fluorescence-assisted nuclei sorting (FANS) specifically of mDA neurons from control mice versus mice trained to binge-feed on a hyperpalatable, high-fat diet. When analyzing the DNA methylation landscape of this purified cell type by means of the Infinium Mouse Methylation BeadChip (Mm285), we found that binge-feeding induces a dramatic reorganization of the mDA methylome (2,674 DMR with increased methylation versus 9,799 DMR with decreased methylation; p-value 0.05 and effect size 0.1). The marked loss of methyl marks across multiple genomic regions suggests a prominent role of demethylating enzymes such as Ten-Eleven Translocation 1 (TET-1) dioxygenase, which we interestingly found to be highly enriched in mDA neurons. Consistently,
Tet1 haploinsufficient mice (
Tet1 +/-) exhibited marked differences in motivated, reward-related behaviors including reduced sucrose preference and attenuated binge-feeding. Notably, bistable segregation into either binge-prone versus binge-resistant animals was significantly amplified in
Tet1+/- mice hinting at a potential role in the stochasticity of behavioral variation towards calorie rewards. To reverse already established binge-feeding phenotypes, we started leveraging virus-based approaches to rewire the mDA methylome in a locus-specific, temporally controlled and TET1-mediated fashion
in-vivo. In sum, we provide evidence for TET1-mediated DNA demethylation in mDA neurons as an important non-genetic, non-environmental regulator determining flexibility in motivated behaviors and susceptibility to binge-eating disorders.
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