Time-restricted feeding entrains long-term behavioral changes through the IGF2-KCC2 pathway

Area of Science:

• Neuroscience
• Chronobiology
• Metabolic Signaling

Background:

• The suprachiasmatic nucleus (SCN) governs circadian rhythms, integrating light and peripheral signals.
• The precise role of nutrients and feeding patterns in SCN regulation is not fully understood.

Purpose of the Study:

• To investigate the impact of time-restricted feeding (TRF) on SCN function and associated behavioral rhythms.
• To identify molecular pathways in the SCN mediating TRF-induced effects.

Main Methods:

• Time-restricted feeding (ZT0-4) in mice.
• Intracellular calcium imaging in SCN GABAergic neurons.
• RNA-sequencing (RNA-seq) of the SCN.
• Genetic manipulation of KCC2 and IGF2 in SCN neurons.

Main Results:

• TRF (ZT0-4) induced sustained shifts in locomotor behavior and increased wakefulness.
• TRF activated Ca2+ signals in SCN GABAergic neurons.
• TRF upregulated IGF2 and downregulated KCC2 expression in the SCN.
• SCN-specific KCC2 loss-of-function amplified TRF aftereffects.
• IGF2 overexpression mimicked TRF-induced behavioral changes.

Conclusions:

• The IGF2-KCC2 pathway is a key mediator of behavioral adaptations to TRF.
• Nutrient timing influences SCN function and circadian behavior through specific molecular pathways.