Advanced Medical Scientist-Programm 2019

Thema: "A novel pathway links caffeine effects with the circadian CLOCK system and mediates antidepressant action"

Zusammenfassung:
Circadian rhythm changes, reduced wakefulness and feelings of helplessness are symptoms of depression, the most common mental illness worldwide. Caffeine alters wakefulness and depression­symptoms, but the underlying mechanisms are poorly understood. We are presenting a novel pathway, which links caffeine with the circadian CLOCK pathway via the dopaminergic phosphoprotein DARPP-32 in the mouse striatum. Phospho-T75-DARPP-32 disrupts binding of the circadian regulators CLOCK and BMAL 1 to chromatin and thereby regulates gene expression. T75A-DARPP-32 mutant mice show diminished caffeine-induced antidepressant effects in the awake phase. Furthermore, T75A-mutants are more light-dependent in their activity. We propose to study gene expression changes, which underlie altered depression-like behaviors in T75A-DARPP-32 mutants: 1. Through RNA-sequencing we will determine global gene expression changes induced by the DARPP-32:CLOCK pathway. 2. Using virus-mediated gene transfer, we will establish causality between gene products and their antidepressant effects. 3. We will characterize molecular and behavioral consequences of changed light cycles on the T75-DARPP-32 pathway. 4. Viral constructs will be used to improve light-cycle adaptations in vivo. This study may identify novel antidepressant targets and help to understand how circadian and depression-like behaviors are connected.