Joint Fellows seminar - The role of the circadian clock

Image - Gerd Altmann - Pixabay

By Atish Mukherji and Tsvetan Serchov

Both these 2020 Fellows work on different aspects of the circadian clock. They will present their respective research during a joint seminar, with two separate talks.

Atish Mukherji - The hepatic circadian clock and its connection to chronic liver disease

To anticipate and respond to the daily geophysical variabilities, e.g. the light-dark cycle, species of many phyla - including metazoans - have evolved an endogenous “timing” device known as the circadian clock. The mammalian “clock” system is a hierarchical network of biological oscillators that ensures temporal control of physiology and behaviour, according to the time of the day. The discovery of the mechanisms, which drive the molecular ‘clock’ system, was the driving force for the Nobel Prize in Physiology and Medicine 2017.

Recent investigations have started revealing the mechanistic links that could connect the clock-system with different pathologies. However, our understanding of the clock-controlled, tissue-specific temporal gene expression, and how it contributes to homeostasis at both cellular and organismal levels, is rudimentary and evolves continuously. These investigations are essential, not only in order to reveal the molecular mechanisms through which an “altered/broken” clock could possibly lead to the development of chronic disease, but also for their therapeutic targeting.

Tsvetan Serchov - The role of the molecular circadian clock in the neurobiology and treatment of depression

Depression is one of the most-diagnosed disabling mental diseases. It is characterized by a disrupted sleep regulation and biological rhythm. However, whether these dysregulations of the circadian clock and sleep homeostasis are caused by, or are consequences of, depression is not clear.

In order to find out, we have investigated the effects of chronic stress and rapid antidepressants (acute sleep deprivation (SD) and low-dose ketamine application (KET)) on the circadian clock gene’s oscillation in the brain. The mice subjected to chronic stress have an increased amplitude of expression of several clock genes, while rapid antidepressant treatments normalize their expression.

Then, we tested the effects of pharmacological modulators of the circadian clockwork on the mood. We found that acute treatment with RevERBa activator SR10067 enhances depression-like behaviour and inhibits the antidepressant effects of SD and KET, while treatment with RORa/g agonist SR1078 elicits antidepressant effects in several behavioural paradigms. In addition, the deletion of RevERB leads to increased stress resilience and decreased depression-like behaviour. Moreover, virally-induced impairment of the circadian clock selectively in the PFC – the prefrontal cortex - (CaMK2a-BMAL1KO) inhibits the antidepressant effects of KET.

We have previously demonstrated that the rapid antidepressant effects of KET and SD are mediated by enhanced glutamatergic signaling. Similarly, we now show that the modulation of the circadian clock affects homeostatic plasticity and AMPAR trafficking.

Taken together, our data indicate that the circadian clock plays an important role in stress response and rapid antidepressant treatment, and allows us to propose that pharmacological modulation of the circadian clockwork might be a novel approach for the effective treatment of depression.