Epigenetic dosage establishes individual vulnerability states in reward circuitry

No two individuals are alike. Organisms that share a genome and an environment still diverge into stable, reproducible differences in behavior, and for most behavioral and psychiatric traits a substantial fraction of this variation cannot be attributed to genetic or environmental differences alone. Yet, the molecular mechanisms that generate such individuality remain largely unknown. Here we identify developmental dosage of the DNA hydroxymethylase Tet1 as a regulator of individual vulnerability states in food reward circuitry, using reward-driven feeding as a quantitative behavioral lens [1]. Using a limited-access palatable-diet paradigm in mice, we show that ventral tegmental area dopaminergic (VTA-DA) neurons adopt a distinct, sustained activity state, which includes an anticipatory component that emerges across days and scales with the amount consumed. By acute, chemogenetic inhibition we demonstrate that this hyperactivity state of VTA-DA neurons is required for escalated binge feeding and is accompanied by rapid, locus-specific hydroxymethylation remodeling at plasticity genes, a signature dissociable from that of conventional overfeeding paradigms. Together, these results establish reward-driven feeding as a tractable behavioral readout in which dopaminergic engagement leaves a defined epigenetic imprint.

VTA-DA neurons express high levels of Tet1, and reducing Tet1 dosage does not shift mean feeding but instead unmasks pronounced inter-individual variance, splitting genetically identical mice into stable susceptible and resilient states. This hypervariability depends on disruption of Tet1 during development rather than in adulthood, and is specific to reward-driven feeding and not anxiety- or cocaine-related behaviors, indicating that Tet1 sets the reproducibility (canalization) of food reward-circuit assembly. Notably, we trace this divergence to developmentally established differences in prelimbic mPFC→VTA connectivity. Silencing this projection confers resilience, whereas EGR1-guided reinstatement of TET1 catalytic activity in adult VTA-DA neurons restores susceptibility, demonstrating that the developmental program that establishes these epigenetic states remains accessible to modulation in the mature brain.

In humans, a genetically anchored TET1 promoter methylation state is bimodally distributed across eating-disorder cohorts, tracks binge-eating behavior, and is associated with altered reward-circuit activation during a monetary incentive delay task using fMRI. Critically, these activation signatures parallels the circuit relationship defined in mice suggesting conservation of this vulnerability axis. Together, these findings place Tet1 within a class of dosage-sensitive epigenetic robustness factors (alongside regulators such as Trim28 and Nnat) and identify it as one of the first molecular regulators of behavioral individuality. Tet1 thus tunes the reproducibility of reward-circuit development, buffering circuit assembly while permitting probabilistic divergence. Thereby, Tet1 dosage provides a molecular entry point to how stable behavioral individuality — and vulnerability within it — arises from a shared developmental logic. More broadly, our results suggest that susceptibility to reward-related conditions, from compulsive feeding to addiction, may emerge not from cumulative genetic or environmental insult but from the same developmental mechanisms that normally constrain inter-individual variability.

References

1. Gruber, T. et al. Midbrain Tet1 dosage defines inter-individual binge-eating susceptibility. bioRxiv (2026). https://doi.org/10.64898/2026.03.14.711800