Many physiological processes present near-24h oscillations, even in constant conditions (1). For example, the hormone cortisol is at high levels in the blood in the morning, and low levels in the evening; another well-defined rhythm is that of body temperature, which in human is high in the day and at its lowest point in the late night. These daily rhythms are called circadian rhythms, and they are generated by circadian clocks. The research in the Laboratory of Molecular Chronobiology aims at deciphering how these clocks work, and more specifically, to find an answer to three questions: What are the mechanisms or gears of these biological clocks? How can these clocks control physiology? How are these clocks controlled by the environment?

The master circadian clock in mammals such as mice or humans is located in the brain, more specifically in a region of the hypothalamus called the suprachiasmatic nucleus (figure). However, recent research has shown that clocks are also present in other brain regions and in most peripheral organs too. During evolution, circadian clocks have evolved by giving an advantage to living organisms, by adapting their physiology to the cyclically changing environment (e.g. light/dark, warm/cold daily cycles), and by organizing in time the processes occurring in various tissues and within cells. Thus, it is not a surprise that disturbances of circadian clocks have been associated with various diseases, including cancer, metabolic diseases and mood disorders.

1. The identification and study of clock components

Circadian clocks are made up of so-called "clock genes" (1), and animals or human subjects with mutated clock genes present rhythm disturbances, even arrhythmicity in some cases. Over the years, the work in the laboratory has led to the identification of new clock genes. One example of this is the finding that proteins of the REV-ERB and ROR families can act as clock components (2, 3). More recently, we have been interested in the circadian role of USP2, a protein known to remove ubiquitin tags from proteins. Indeed, tagging of clock proteins with ubiquitin, and the subsequent degradation of these tagged proteins, has been shown to be critical for circadian timing (4). We now found that the reverse reaction (removal of the ubiquitin tag) is important for the clock too: USP2 binds to and deubiquitinates the clock protein PER1, and mice devoid of USP2 present abnormal rhythms (figure) (5).

2. The circadian control of the immune response and infectious diseases

Circadian clocks are found everywhere in the body, including in cells of the immune system (6). Does it mean that immunity is more or less effective according to time of day? In collaboration with Dr. Nathalie Labrecque, of the Université de Montréal, we found that this was the case: the response to vaccination varies according to time of day. When mice receive this treatment in the middle of the day, their T cells respond more strongly to antigen presentation than at any other times of day or night (7, 8). Mice lacking a clock within their T cells do not exhibit this circadian rhythm. Our analysis of molecular rhythms in T cells has then allowed us to conclude that these cells are preset (by their own intrinsic clock) to be ready to be activated efficiently in the daytime, and to be more resistant to vaccination at night (8).

What is the impact of rhythms in the immune system for the fight against infectious diseases? In collaboration with Dr. Martin Olivier (McGill University), we aim to answer this question in the context of parasitic infections (9, 10). The parasite Leishmania causes a serious disease prevalent particularly in tropical regions, leishmaniasis. We discovered that the immune response varies according to the time of day at which the parasite is inoculated in mice (figure): infection in the evening leads to a stronger mobilization of immune cells, and since the parasite requires these cells for its development, an evening infections is beneficial for the parasite, which is replicating more efficiently (10).

3. Circadian disruption and schizophrenia

Up to 80% of patients with schizophrenia show disrupted sleep and circadian rhythms. In collaboration with Dr. Lalit Srivastava (Douglas Research Centre, McGill University), we are addressing two questions. First, what is the cause of this circadian rhythm disruption? Second, could these disrupted rhythms worsen schizophrenia symptoms, or act as a risk factor for the disease? To address these question, we use mouse models. For example, we showed that mice with a mutation in the Dysbindin-1 gene (which was associated with schizophrenia) present abnormal circadian rhythms (11). Moreover, lighting conditions that disrupt the mouse circadian rhythms exacerbate certain schizophrenia-related behaviours in the mutant mice (11). This work might allow developing novel strategies, taking circadian rhythms into consideration, for improving cognition in schizophrenia and other psychiatric conditions.

4. The regulation of human circadian clocks: implications for shift work

In order to study the regulation of human circadian clocks, we teamed up with Dr. Diane Boivin (Douglas Research Centre, McGill University). By simulating night shift work in the laboratory, and in field studies on actual shift workers, we showed that similarly to the central clock, human peripheral clocks do not adapt well to a night shift (12, 13). The consequence is a loss of synchronization of the molecular gene expression rhythms (14) and immune response rhythms (15) with the environment and the sleep-wake cycle. In contrast, most rhythms of blood metabolites adapt to the shifted sleep-wake cycle (16). Light treatment can adjust these peripheral rhythms, as it does for the central clock (12). Furthermore, we made the first demonstration of a pharmacological resetting of peripheral clocks in humans (17). Finally, we also looked at clock gene expression in post-mortem brain tissue, and found that rhythms of clock gene RNAs differed between the brains of Alzheimer’s disease patients compared to those of control subjects, which might underlie the sleep and circadian rhythms of these patients (18).