Midbrain Tet1 dosage defines inter-individual binge-eating susceptibility.

Area of Science:

• Neuroscience
• Genetics
• Epigenetics

Background:

• Binge-eating disorder (BED) is a prevalent eating disorder with significant comorbidities.
• The underlying mechanisms of individual susceptibility to BED are not fully understood.
• Genetic and environmental factors are known risks, but individual differences remain unexplained.

Purpose of the Study:

• To investigate the role of DNA hydroxymethylase Tet1 in regulating binge-eating susceptibility.
• To elucidate the neural circuits and epigenetic mechanisms underlying inter-individual differences in BED.
• To explore the translational relevance of Tet1 in human binge-eating behavior.

Main Methods:

• Utilized a mouse model to study the impact of Tet1 dosage on binge-eating behavior.
• Investigated DNA hydroxymethylation remodeling in midbrain dopaminergic neurons (VTA DA).
• Examined the role of prelimbic medial prefrontal cortex (mPFC PL) to VTA projections and employed chemogenetics and gene re-activation.

Main Results:

• Tet1 dosage significantly influenced binge-eating susceptibility in mice, even in genetically identical individuals.
• Tet1 haplo-insufficiency led to reduced mPFC PL →VTA connectivity, correlating with altered binge-eating behavior.
• EGR1-guided re-activation of TET1 in VTA dopaminergic neurons restored binge-eating susceptibility.
• TET1 promoter methylation in human patients associated with binge-eating behavior and reward circuit function.

Conclusions:

• Tet1 dosage is a novel regulator of binge-eating susceptibility.
• The mPFC PL →VTA dopaminergic pathway, modulated by Tet1, is crucial for binge-eating behavior.
• This epigenetic regulatory network involving Tet1 is conserved in humans, suggesting potential therapeutic targets for BED.