This project aims to determine how early life psychosocial exposures modify biological, in particular epigenetic processes leading to pathologies later in life. Such exposures, socially differentiated may explain some of the observed health inequalities. To achieve the project aim, six work-packages (WP) have been defined: The aim of WP1 will be to specify what is meant by “early life psychosocial environment” and which psychosocial exposures occurring in early life have a long term impact on health status. Understanding of the timing, periods during early development, especially brain development, will be a main point. This work will also serve to elucidate which factors are necessary for optimal development in childhood. WP1 will develop pre-existing standardised tools for identifying the important exposures or mechanisms to carrying out research on future or current epidemiological studies. WP2 aims to examine the biological processes involved in what ?. Animal models remain a vital tool for studying the influence of early events on adult health, by testing causality and having access to tissues that are inaccessible in humans. How the plasticity of the epigenome links early life psychosocial and nutritional exposures in early development and adult pathologies is a challenging issue. Allostatic load uses a number of so far traditional markers to measure the consequence of general adaption to the environment over time, on health status. This cannot be not limited to a few tissues and a few genes; however it necessarily results in a broad genome-wide and system-wide change in the epigenetic landscapes. Thus multiple functional gene networks remain to be elucidated at the genome-wide level, in a sex-specific manner. Most epigenetic marks supporting the memories of past environmental impacts are tissue-specific, generally not available in humans (prefrontal cortex, pancreas, liver). Recent data demonstrate that some changes may also affect WBC such as T-cells, tissue collected in human cohorts. WP2 will use three mouse models combined to next generation sequencing, MeDIP-seq and transcriptomic approaches. This genome-wide analysis of differential DNA methylation together with expression analysis will highlight specific causal mechanisms through the identification of genes, the methylation and the expression of which are altered. A short list of candidate sequences will be transfer to human cohorts in a sex-specific approach WP3 will focus on method and statistical issues raised by the analysis of early life exposures in relation to later health outcomes. These issues include how to select appropriate variables and statistical models that take into account the complexity of lifecourse trajectories and the direction of causal pathways over time (mediation). WP4 will focus on major ethical issues, on the way in which links between social and biological factors ought to be dealt as public health and gender issues. Also, how to disseminate these findings and bring about an appropriate public debate on results of the research are important issues to consider. WP5 will synthesise the results from the aforementioned WP to translate the findings into epidemiological research on human populations. This WP will aim to use data available from cohort studies to test hypotheses generated on the links between the early psychosocial environment and adult health. This innovative project explores the underlying mechanisms in the production of health inequalities using integrative approach (epidemiology, psychology, neuroscience, epigenetics, ethics, statistics) which produce knowledge useful for public health interventions to tackle social health inequalities.

Methylphenidate (MPH) is a common treatment for ADHD, but 20-30% of patients do not respond adequately. Animal studies have suggested that MPH may induce inflammation, potentially affecting its efficacy and tolerance, which could explain certain side effects and inadequate clinical responses in some individuals. However, the underlying mechanisms of ADHD-related brain inflammation and potential MPH-induced inflammation in humans have not been explored. Nutritional interventions, including the use of polyphenols, may potentially reduce inflammation associated with ADHD and MPH treatment. Further studies are needed to assess whether polyphenols can improve ADHD symptoms and the efficacy of MPH by reducing inflammation. The objectives of this project are as follows: i) Define nutritional and inflammatory profiles in children and adolescents with ADHD compared to age- and sex-matched typically developing peers; ii) Evaluate inflammatory profiles with and without MPH and their relationships with symptom severity, clinical tolerance, and treatment efficacy in children and adolescents with ADHD; iii) Analyze in detail associated pathophysiological mechanisms and potential therapeutic targets; iiii) Test the in vitro effects of anti-inflammatory and antioxidant agents such as polyphenols to identify candidates for future supplementary studies on MPH augmentation in humans. This project aims to discover anti-inflammatory pathways to alleviate ADHD symptoms and improve MPH tolerance, while providing insights into peripheral and cerebral immune profiles in ADHD patients.

The project “teenage obesity” (OBETEEN) aims at providing France and Mexico with high profile research concerning the neurocognitive impact of juvenile obesity. Current surveys attest that the obesity epidemic is reaching an alarming level since about 45% of French adults and over 71% of Mexican adults are considered overweight or obese. The prevalence and severity of overweight are also increasing dramatically in children and adolescents. Mexico is now the country with more childhood/juvenile obesity in the world. This is of crucial importance considering that obesity during infancy and adolescence predicts obesity at adulthood. Obesity is a major health issue because it clearly reduces life expectancy due to an increased prevalence of resulting diseases (hypertension, cancers, diabetes …). In addition, obesity is associated with neurocognitive features, affecting in particular learning and memory function, which could consequently impair the quality of life and require a more extended disease management. This can be particularly problematic as childhood and adolescence are crucial periods for the maturation of some brain structures, like the hippocampus and the amygdala, necessary for shaping cognitive function for the whole life duration. Given its socioeconomical importance, the OBETEEN project aims at providing a multilevel, multicenter analysis of the neurocognitive impact of juvenile obesity focusing on hippocampal and amygdala-dependent memory function. This project relies heavily upon complementary approaches that are provided by the unique arrangement of expertise of the French and Mexican partners. In this project we have the ambition to provide the scientific community a comprehensive model that includes behavioural, systemic and neuronal levels. Using a correlative approach, the first aim of this project is to perform a bicenter human study on the impact of obesity in adolescents on memory performance in France and Mexico. This will be achieved by performing standardized and sophisticated tests of amygdala and hippocampal-dependent memory functions in obese adolescent subjects (French Partners 1 and 3 and Mexican Partner 4) and by evaluating brain functioning and connectivity between these 2 brain areas by functional magnetic resonance imagery (French Partners 1, 2 and 3 and Mexican Partner 4). Using animal models, the second aim of the OBETEEN project is to provide mechanisms concerning the impact of diet-induced obesity during adolescence on memory and to investigate the beneficial effects of voluntary exercise. In particular we will establish whether memory alterations (in tasks addressing amygdala and hippocampal functions) induced by obesogenic diet consumption during adolescence involved changes in coordinated amygdalo-hippocampal functioning as assessed with state of the art electrophysiological and microdialysis approaches (Mexican Partners 6 and 7). Then the causal link between amygdalo-hippocampal interactions and memory alterations will be determined using pharmacogenetic tools allowing to specifically manipulating amygdalo-hippocampal pathways (French Partner 2). Finally, the beneficial effect of running activity will be evaluated at both cellular and behavioural levels on juvenile obesity-induced alterations of amygdalo-hippocampal functions (French Partner 1). This consortium is therefore very well armed to conduct a comprehensive analysis of the crucial question of how and where in the brain of developing subjects obesogenic diet influences memory abilities. All the partners are convinced that the research undertaken in the OBETEEN project is of great scientific and socio-economical importance.

Animals, including humans, primates as well as rodents, often exhibit hesitancy towards consuming new foods due to a lack of information about their safety or toxicity. The initial reluctance is termed taste neophobia, typically a temporary effect that diminishes with repeated exposure as the individual learns the food is harmless. Habituation of neophobia, termed familiarization, continues until the food is accepted as safe and familiar. The highly integrative processes of taste neophobia and familiarization occur within a dedicated cortical area called the gustatory cortex (GC). In rodents, the GC occupies the central portion of the insular cortex and is located on the ventral lateral brain surface, divided by the middle cerebral artery. The GC not only encodes the chemical identity of food but also integrates additional information, such as its hedonic value (e.g., palatability) and novelty, to promptly regulate feeding behaviors. The GC receives chemosensory information from the gustatory thalamus (VPMpc) and palatability input from the amygdala (BLA), with cholinergic projections from the nucleus basalis magnocellularis (NBM) conveying tastant novelty. While the importance of GC and these projecting areas in identifying novel or familiar taste has been previously established, the cellular and circuit mechanisms by which GC neurons dynamically integrate thalamic, amygdalar, and cholinergic inputs remain unknown. The goal of the NeoTaste project is to investigate how GC integrates gustatory inputs to form neuronal representations of novel and familiar taste. We hypothesize that the unique anatomical and functional properties of dendrites of GC layer 5 pyramidal neurons play a pivotal role in integrating gustatory inputs during neophobia and familiarization. To test our hypothesis, we have created a consortium that enables multi-level analysis leveraging the diverse expertise of the partners. This includes functional synaptic mapping ex vivo, cellular and dendritic physiology, in vivo two-photon imaging in head-fixed behaving mice, fiber-photometry in freely moving mice, and circuit-specific manipulation combined with mouse behaviour. This project represents the first attempt to comprehensively investigate the impact of dendritic active properties in GC processing. With the NeoTaste project, led by M. Carta (IINS, Bordeaux), N. Takahashi (IINS, Bordeaux), and G. Ferreira (NutriNeuro, Bordeaux), we aim to elucidate the mechanisms by which the GC circuit integrates gustatory information to guide behavior. We anticipate that the results of the Neotaste project will yield novel insights into the mechanisms by which taste chemical identity, hedonic value (e.g. palatability), and novelty are integrated within the GC at both the single-neuron and network levels, ultimately guiding behaviour.

The aim of the project is to implement a new technology for the controlled delivery of molecules in the brain. Several brain disorders are not efficiently treated, due to the very low accessibility of the drugs to the diseased brain area. To encounter these limitations, intracranial pharmacotherapy is increasingly used, however, this approach does not control over time the release of drugs. In parallel, the field of neuroprosthetics (brain stimulation, optogenetics, brain-machine interface) is under intense development, in order to target precise pathological brain areas. However, neuroprosthetics are not designed for the time-controlled delivery of molecules in the brain. Here, I conceived a neurotechnology that combines efficiency of drugs and precision of neurostimulation technologies with the use of controllable encapsulation and release. It consists in employing photoactivable microparticles that enable the local delivery of encapsulated molecules into the brain through light activation, precisely controlled in time, space and concentration. Particularly encouraging results have been obtained for the photorelease of bioactive molecules at a given wavelength. The objective of the present ANR JCJC proposal is to optimise this neurotechnology in vivo and to implement it in a model of glioblastoma. This project is highly innovative and multidisciplinary, bringing together two sophisticated technologies, microparticles for encapsulation and light-based control of brain circuits. This neurotechnology ambitions to be a breakthrough in the therapeutic options for localised brain diseases, such as brain tumour, epilepsy, stroke or Parkinson’s disease. Since conceiving this project, I have been coordinating a multidisciplinary consortium composed of internationally renowned chemists and biologists who will participate in the ANR project. This project will in turn be a cornerstone for the development of my carrier. My ambition in research for the next years is to accomplish this project and deploy it in clinic, in order to propose a new therapeutic option for brain disorders.