The early ticking of the central circadian pacemaker: when and how

Introduction

The 24-h (circadian) timing system develops during the perinatal period and rules our physiology later in life. It has the essential task of anticipating daily recurring changes in the environment (day/night) to find the best time for each molecular and cellular process.

Hierarchical Organization

It is organised hierarchically, with a master pacemaker in the hypothalamic suprachiasmatic nucleus (SCN), which is able to perceive environmental light and tell the body what time it is. Our modern 24/7 lifestyle favours a disruptive environment for the circadian system, which is especially negative during pregnancy.

Research Findings

We have found, in mice and pre-term infants, that when mothers are exposed to glucocorticoids (GCs) at the wrong time of day, the offspring show behaviour disorders later in life. Our mechanistic findings showed for the first time a role of the foetal clock before birth, challenging the view on the clock being immature and non-functional.

Project Overview

StarTicking proposes to answer a long-standing question in the field: When and how does the circadian clock start ticking? With a multidisciplinary and integrated approach, we will go beyond the state-of-the-art to understand mechanistically the development of the central circadian pacemaker in mice and humans.

Research Objectives

We will investigate:

1. How the SCN forms by a detailed assessment of the developmental trajectory of the mouse SCN with single cell resolution.
2. When the SCN becomes functional by testing a yet unexplored player: Astrocytes as drivers of the gain of functionality of the mouse SCN.
3. What the influence of the early environment on the human SCN maturation is. The generation of a human SCN organoid will allow us to test maternal signals in vitro with high-throughput.

Linking Findings

We will link mechanistic findings to the development of SCN-driven rhythms in a cohort of pre-term babies.

Conclusion

StarTicking will provide ground-breaking mechanistic evidence and valuable knowledge to alleviate the behavioural consequences of circadian disruption early in life.