Unraveling the neural circuits controlling the circadian modulation of locomotion in a diurnal vertebrate – CIRCOLOCO

Most biological activities follow a nearly-24 hours rhythm entrained to the daily environmental Light/Dark cycle referred to as circadian rhythm. Circadian rhythms are driven by an internal clock. This clock regulates locomotor activity quantitatively, as an ON/OFF switch of movements. Our consortium of two experts, a specialist of circadian activity (E.Cau) and an expert of locomotor circuits (C.Wyart) will analyze whether the circadian system also regulates qualitative aspects of locomotor activity (type of movements, chain of movements), using a diurnal vertebrate: the zebrafish larva. Especially, we have recently described two different locomotor styles, referred to as ‘cruising’ (involving forward locomotion) and ‘wandering’ (where the larvae turn a lot more) that we postulate could prevail during day and night respectively.
Ablation of the pineal gland impairs circadian rhythms in a number of species. We have obtained strong indications that the pineal gland control quantitative rhythms of locomotion. Based on these, we will study the roles of the pineal gland during the establishment of circadian rhythms of locomotor activity as well as their regulation by light, together with a possible role in controlling qualitative aspects of locomotor activity (aim1).
How can the pineal gland control locomotion? One of the main functions of the pineal gland is the nocturnal secretion of the neurohormone melatonin. However, in lower vertebrates and fetal mammals, the pineal gland also sends axonal projections whose functions have never been addressed. Our unpublished data shows the existence of a neuronal projection from the pineal gland to a high motor center: the posterior tuberculum. The posterior tuberculum corresponds to the mammalian substantia nigra, a dopaminergic center involved in the etiology of Parkinson Disease. The posterior tuberculum is directly implicated in locomotion. It projects onto the MLR (Mesencephalic Locomotor Region), an area which we recently showed controls movements. We will perform a complete characterization of the sites of projection of the larval pineal gland with specific focus on other locomotor centers onto which the pineal gland is known to project at adult stages.
We will address the respective roles of melatonin (aim2) and of projection to synaptic targets (aim3) in mediating the effects of the pineal gland on quantitative and qualitative (type of movements, chain of movements) control of locomotor rhythms.
At the root circadian organization, the molecular clock, a transcriptional regulatory loop, regulates circadian rhythms in every cell of the body. We will use an innovative live-imaging strategy to report for this molecular clock. This tool will help us assess if melatonin controls the phase of the clock in melatonin responding cells located in the locomotor circuit (aim2) as well as whether neural activity in the pineal gland modifies the phase of the molecular clock through synaptic contact within its neuronal target cells (aim3).
Our research program will contribute to understanding how the pineal gland controls the activity of a dopaminergic locomotor center involved in the etiology of Parkinson disease and restless leg syndrome, two diseases that associate motor and circadian disturbances. Our study performed in a diurnal vertebrate will inspire future mammalian studies. More generally, highlighting a qualitative effect of the circadian system on locomotion represents a major conceptual advance in the circadian field, opening the possibility that different locomotor sub-circuits are activated depending on the time in the day/night cycle. Finally, our program will provide a conceptual framework to understand how circadian rhythms control a “simple” behavior.