SAMENTA - Santé Mentale - Addictions

THE IMPACT OF FETAL STRESS ON MENTAL HEALTH : Heat Shock Factors (HSF) as mediators of epigenetic events. – HSFEPISAME

Submission summary

Recently, two concepts have revolutionized our way of understanding neuropsychiatric disorders.
1) The notion of a continuum between the developing and the adult brain has emerged, based on the discovery that the same molecular components are involved in normal neuronal development and in neuronal dysfunction of the diseased brain. According to this "neuro-archeology" theory, the aetiology of many neurological and psychiatric illnesses has to be found in alteration of developmental process.
2) Fetal environmental stress increases the risk of developing psychiatric disorders and reduces the ability of the adult brain to perform normally, even in the absence of overt developmental defects.
Fetal stress leaves long lasting marks that are conserved via unknown mechanisms in the adult brain. The interplay between neurodevelopmental programmes and stress-responsive factors, and the unravelling of the epigenetic events that could underlie such ‘stress scars’, is central to the pathogenesis of brain disabilities. Strikingly, Heat Shock Factors (HSFs) are at the center of these processes, as regulators of stress responses and brain development, and mediators of epigenetic events.
HSFs may be pivotal to the disruption of neurodevelopmental programmes under fetal stress. HSFs are stress-responsive transcription factors, defined by their activation by heat shock (HS) and their binding to Heat Shock Elements (HSE) in the genome: HSFs trigger the expression of genes encoding Heat Shock Proteins (Hsp), which, as molecular chaperones, establish a cytoprotective state to various stress and pathological conditions (fever, aging, neuronal injuries …). HSF are also involved in broad epigenetic process in the targeting of histone modifications and chromatin condensation. In addition, HSFs act genome-widely and perform important physiological roles in normal brain development and integrity. HSF1, the major HS-responsive factor, has a protective role in diverse models of anxiety and affective disorders, and HSFs were found in genome-wide and meta-analyses of psychiatric disorder pathways.
HSFs therefore represent a unique entry point into a crosstalk between stress, epigenetics, and brain development and integrity. In this project, we aim to unravel the epigenetic mechanisms by which HSFs, upon fetal or perinatal stress mediate the deposition of epigenetic signatures/scars in a long-term manner that would compromise adult brain integrity. We eventually aim at establishing a parallel between this epigenetic trajectory and a behavioral trajectory from the prodromic to the syndromic traits in the adult.
To tackle these questions, we have created a Consortium:
V. Mezger (Partner 1) has played a major role in this field by demonstrating that HSF2, an enigmatic HSF inactivated by HS, is involved in normal brain cortical development. Furthermore, she identified HSF2 partners and target genes involved in epigenetics histone-acetylation and DNA methylation pathways, in a stress-dependent manner – pathways that are crucial for brain abilities.
Partner 1 and Partner 2 (P.Gressens) demonstrated that several prenatal stressors with known impact on brain development/integrity strongly modify HSF1 and 2 activities. Using a fetal alcohol exposure (FAE) as a paradigm, they unravelled a novel role for HSF2 upon FAE: HSF2 is a mediator of neural proliferation and migration defects characteristics for Fetal Alcohol syndrome (FAS), by mediating disturbances in the expression of genes involved in microtubule dynamics (MAPs). MAPs are important for cortical and hippocampal lamination, neurite growth, synaptogenesis, and neuronal plasticity. MAP mutations have been associated with brain disabilities and MAPs were identified as susceptibility genes for psychiatric disorders.
This combination should lead to major breakthroughs in shedding light in the molecular mechanisms that underlies the trajectory from the fetal brain exposed to stress to the onset of brain disabilities.

Project coordination

MEZGER Valérie (Organisme de recherche)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Inserm U676 U676 Physiopathologie et neuroprotection des atteintes du cerveau en développement Hôpital Robert Debré

Help of the ANR 420,417 euros
Beginning and duration of the scientific project: February 2014 - 42 Months

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