The identification of high-risk biomarkers associated with neurodevelopmental pathogenesis of major psychiatric disorders (such as schizophrenia, bipolar disorder and major depression disorder) is a foremost challenge to develop better treatments and primary prevention strategies. A promising path towards the identification of these biomarkers lies at the interface between non-invasive high-resolution multimodality optical microscopy and cellular reprogramming and differentiation technologies. These reprogramming and differentiation processes have started to exhibit the capacity to recapitulate in vitro some major steps of the neurodevelopment. In addition, the development of cutting-edge microscopy techniques enables cytomic approaches that have the capacity to simultaneously measure, at the nanometre scale, many molecular and cellular processes in a functional environment. We are then able to perform a cellular profiling to monitor in vitro the complex maturation process of neural progenitor cells to mature neuronal and glial cells. When these progenitor cells derive from patients or at-risk offspring, the identification of specific cellular phenotypes reflecting a state of vulnerability or pathological neurodevelopment processes leading to the onset of the psychiatric disorder is made possible. These phenotypes are therefore conducive to the identification of new high-risk biomarkers. In this context, our team focuses on the design and implementation of two non-invasive multimodality imaging platforms involving different modes of coherent detection. These coherent detection-based platforms allow to record the optical field either diffracted or emitted by the sample.
The first platform, based mainly upon the use of linear optics, is devoted to the exploration of cellular structure and dynamics at the nanometre scale. Revolving around transmission digital holographic microscopy technology, the platform also incorporates an electrophysiology rig for patch-clamp recording as well as an epifluorescence module. Several engineering strategies will be investigated in order to use optical diffraction tomography to measure the complete first order 3D dielectric tensor of living neurons in culture.
Based on the use of nonlinear optics, the second platform is dedicated to study the histoarchitecture of thick biological tissues such as living slices. Built around a multiphoton experimental microscope, this platform combines, in addition to two-photon fluorescence, different coherent nonlinear modalities including 2nd and 3rd harmonic generation and coherent Raman.< Back
Major technological advances made during the last decades in the field of neuroimaging enable a detailed understanding of the brain structure and its functional organisation. So far, these imaging techniques, including magnetic resonance imaging (MRI), have had only a marginal influence on psychiatrists’ clinical practice. However, they have the potential to provide a new understanding of the human mind by highlighting the biological underpinnings of psychiatric disorders. These outstanding tools allow to delineate neural correlates of our mental states. These techniques are also highly promising for the identification of neurodevelopmental biomarkers of major psychiatric disorders that might contribute to an accurate characterisation of childhood at-risk syndrome. Specifically, we will use structural and functional MRI techniques to identify these neurodevelopmental biomarkers.
Another part of our research aims at combining optical imaging techniques to functional MRI to gain a better understanding of the neurovascular coupling mechanisms underlying the Blood-Oxygen-Level-Dependent (BOLD) signals and the neural activity.< Back
The biological processes underlying major psychiatric disorders are operating way before the onset of clinical symptomatology. These clinical manifestations correspond to advanced stages of the disease, where currently only palliative treatments can be offered. The neurodevelopment biology axis of our research program includes a platform for both the cellular culture of primary murine neural cells and immortalised neural cell lines (Neuro-2a, N1E-115, etc.) and a platform for human neural cells cultures differentiated from induced pluripotent stem cells (iPSC), themselves derived from cells collected form patients as well as their high-risk children. With the help of neurophotonics tools, the study of the differentiation process of these iPSCS cells into neural cells allows, to some extent, the investigation of the main steps of neurodevelopment in vitro. It thus enables a better understanding of the biological mechanisms underpinning these neurodevelopmental processes. For iPSC-derived neurons collected from patients or their at-risk offspring, the cell maturation process is favourable to the development of specific phenotypes allowing the establishment of cellular models of major psychiatric disorders. Such models would be relevant for the study of the pathophysiology mechanisms involved in the genesis of these disorders, and therefore the identification of high-risk biomarkers.
We use different cellular lines, including immortalised cells and primary cells from transgenic mice, in order to set up experimental protocols aimed at the study of various aspects of the neurodevelopment.
Advances in reprogramming technology now allow us to induce the generation of pluripotent stem cells (iPSCs) from somatic cells by the overexpression of transcription factors, such as Oct4, Klf4, Sox2 and cMyc. Depending on the in vitro culture conditions, these iPSCs are capable of proliferating (divide into more iPSCs) and of differentiating into any cell type (cardiomyocytes, osteocytes, blood cells, epithelial cells, neural cells, etc.) while maintaining the same genetic material as the original somatic cells. We currently derive iPSC lines from large high-risk cohorts of both patients as well as their offspring at risk of developing major psychiatric disorders. These iPSC lines are then differentiated into neural cells to be used as in vitro models. Study of such human neural cells at different stages of differentiation using high-resolution multimodal microscopy represents a promising avenue to identify neurodevelopmental biomarkers and endophenotypes that could contribute to define childhood at-risk syndrome of major psychiatric disorders. This will pave the way for developing more efficient early treatments before the appearance of disabling symptoms in young adulthood.< Back
Neurodevelopmental psychiatry expands the study of psychiatric disorders with a developmental perspective. Its main focus is to study links between developmental processes taking place during the first two decades of life and the occurrence of the neurodevelopmental psychiatric disorder in young adulthood with its specific signs and symptoms. This framework integrates theoretical, biological, cognitive and behavioural scopes to a systemic dimension. Each of them contributes to a better systemic understanding of the development of the psychopathology and the pathophysiology. Including all those scopes, our aim is to characterize both infantile at-risk syndrome as well as their corresponding developmental trajectories for these major affective and non-affective psychoses. To this end, we endeavour to identify a set of various types of endophenotypes or biomarkers in at-risk offspring of patients. Endophenotypes are subclinical markers, such as cognitive, physiological, cellular, biochemical or neuroanatomic measurements, useful to underlie a genetic susceptibility to a disease.
In conjunction with the clinical symptomatology, we will focus on endophenotypes or biomarkers related to the development of self-experience and cognition, as well as to specific cellular phenotypes. Neurophotonics tools are used to reveal the existence of these cellular phenotypes which have been expressed in cultured neural cells obtained by reprogramming and differentiating somatic cells from at-risk children. Development over time of all these endophenotypes or biomarkers forms the developmental trajectory of risk. Identification of a childhood at-risk syndrome and its corresponding developmental trajectories will allow to better understand the infantile determinants and the pathogenesis of major psychiatric disorders. It is also an essential step toward the introduction of early interventions within a primary prevention strategy, taking place long before the clinical onset of disabling symptoms of the disease.< Back