Research

Sleep

While we all experience sleep, and so believe we know what it is, sleep remains a scientific enigma. We still don’t know why we sleep. Sleep is present throughout the animal kingdom. As of today, sleep has been documented and studied in a wide range of vertebrates and invertebrates, and there is currently no clear evidence of an animal species that does not sleep. Such conservation suggests a critical function yet to be uncovered.

Our laboratory hypothesize that sleep is a recurring neurodevelopmental state critical for synaptic remodeling to stabilize memories but most importantly to prepare the brain for the day to come, to achieve optimal learning and cognitive performances. Combining animal models such as zebrafish and mice, we investigate how neuronal connections vary during wake and sleep stages. Importantly, as most if not all psychiatric and neurological disorders have sleep abnormalities, they are likely an aggravating factor in the etiology of those diseases preventing correct synaptic remodeling and worsening memory and cognitive capabilities.

Synaptopathies (Fragile X syndrome, ASD, Alzheimer’s …)

A critical gap in our understanding of the cognitive Psychiatric & Neurological disorders in humans is the lack of characterization of synaptic defects induced across the brain. High Fidelity Proteomic Imaging (HFPI) is a new high-throughput imaging method offering unprecedented capabilities for high-resolution imaging of tissue molecular architectures. Using HFPI on large populations of normal and Fragile X syndrome synapses (>1 million) in the mouse neocortex we discovered specific synaptic defects that revealed region and circuit specific heterogeneity in disease etiology, and represent diagnostic markers of FXS. The precise identification of synaptic phenotypes facilitates (1) the characterization of positive drug impacts on synaptic normalization, (2) the exclusion of drugs with detrimental effects at the synapse, (3) the choice of drug combination for broader normalization of synapse populations and dramatic behavioral improvement. Overall this approach is now mature to be extended to most synaptopathies and brain disorders such as autism spectrum disorders, Alzheimer’s, Parkinson’s and many others. This approach yields enhanced methods and metrics for better characterization of research and therapeutic strategies across all aspects of cognitive diseases.

Regeneration

In humans, brain and eye injuries and associated neurodegenerative diseases are often followed by permanent incapacity. Consequently, an important challenge is to develop safe and effective methods to replace neurons and thereby restore neuronal functions. Identifying cellular and molecular mechanisms allowing to replace damaged neurons is a major goal for basic and translational research in regenerative medicine. Contrary to mammals, the zebrafish has the capacity to fully regenerate entire parts of the nervous system, including retina. This regenerative process depends on endogenous neural stem cells. Following injury, zebrafish stem cells go back into cell cycle to proliferate and generate new neurons, while mammalian cells undergo reactive gliosis. Recently, transcription factors and microRNAs have been identified to control the formation of new neurons derived from zebrafish and mammalian neural stem cells, indicating that cellular reprogramming can be an efficient strategy to regenerate human neurons in the brain and retina. Our laboratory investigates the use of endogenous neural stem cell reprogramming for neuronal regeneration, and the differences between zebrafish and mammalian stem cells epi/genetic programs. We pursue the identification and characterization of new molecular factors with an instructive and potent function in order to develop therapeutic strategies for brain and eye diseases.

Gene regulation

Thousands of human disease-associated single nucleotide polymorphisms (SNPs) lie in the non- coding genome, but only a handful have been demonstrated to affect gene expression and human biology. Deciphering how SNPs located in intronic or intergenic regions alter human disease susceptibility remains a significant challenge, due to our incomplete understanding of regulatory codes. Moreover, the genes they regulate, which could give us clues to their function, can be located tens or hundreds of kilobase-pairs away and mingled among other genes, making the discovery of the actual cis-regulated gene a tremendous challenge. To date, very few intronic or intergenic GWAS-SNPs have been functionally validated in vivo as likely causal mutations in human phenotypes. In collaboration with the Bejerano lab at Stanford, we have developed and validated developed an extremely sensitive method for detecting GWAS-SNPs that fall in evolutionarily conserved genomic regions which are likely functional cis- regulatory elements (conserved non-exonic DNA elements, CNEs) by focusing on the identification of non-coding SNPs deeply conserved across vertebrate genomes that also preserve gene synteny. The intersection of conserved GWAS-SNPs with deep non-coding sequence conservation likely selects elements of functional relevance, and has the added benefit of providing an immediate path for in vivo testing in a vertebrate animal model: the zebrafish.

Behavior modelling

Most behaviors and their neuronal regulations are conserved across vertebrates from fishes to mammals including humans. The zebrafish represents an extremely attractive system to understand the molecular and neuronal substrates of behaviors. Zebrafish behavior assessment methods are relevant in an increasing number of experimental contexts as a result of the growing usability of video processing. Not only does video processing allow for measure automation and increased accuracy, leading to higher research throughput, it also allows the definition of entirely new measures based on features that would not be detectable or countable by manual methods. We develop novel key processing components relevant to the video-based macroscopic observation of free-swimming zebrafish during wake and sleep.