Affective disorders result from a gene-environment interaction with stress as a risk factor that may precipitate their emergence. Every individual experiences stressful life events. In some cases acute or repeated stress leads to affective disorders, but most people are resilient to such effects. The ability to adapt during stress has a significant impact on the functional outcome and long-term health of each individual. However, there are only a few studies in humans focusing on adaptive and maladaptive response to stress. A number of human and animal studies have reported the physiological and behavioral effects of stress. Recent studies combining behavioural, molecular and electrophysiological techniques and the use of animal models reveal that stress may induce memory impairment, neuroplastic changes in specific neural circuits and at the cellular level drastic effects, including cell death. The study of the temporal order of stress-induced events at individual level requires diachronic approaches; thus, the use of longitudinal in vivo magnetic resonance imaging (MRI) combined to ex vivo characterization (molecular and imaging) becomes critical for the analysis of the neurobiology of stress. In this project, we plan to investigate changes in the function and structure of the brain that are associated to the normal and pathological response to repeated stress in two rat strains using multimodal in vivo and ex vivo MRI methods. Concomitantly, we will explore the potential correlations between the quantitative MRI parameters and molecular markers of stress and their differences between high and low stress-sensitive rat strains. Brain imaging data will be acquired at NeuroSpin on a Bruker PharmaScan 7T. Using a defined stress paradigm (Task 1), we will quantify the stress-associated changes on different MRI parameters: cerebral structure (Task 2), function (Task 3), white matter microstructure and connectivity (Task 4), and on molecular correlates (markers of functional and structural brain activity, inflammatory signalling) of these stress-induced changes in the brain (Task 5). This longitudinal design will be used to assess significant brain changes at different times of exposure to stress and between high and low stress-sensitive rat strains: 1) Comparison between baselines will provide biomarkers of vulnerability to stress; 2) Comparison before and after exposure to acute stress will provide biomarkers of acute stress effects 3) Comparison before and after exposure to repeated stress will provide biomarkers of habituation. This project is a collaboration between internationally known groups, one of which specialized in stress mechanisms systems-level translational research (Partner 1), the pathogenesis of stress-related brain disorders (Partner 2) and translational brain imaging (Partner 3). Investigating the neural circuits and molecular pathways of resilience will not only provide a tool for mechanistic investigation of neural systems but also potentiate MRI to in vivo monitor the response to stress in preclinical and clinical research. Understanding the mechanisms of resilience to stress will offer a crucial new dimension for the development of fundamentally novel treatments to the protection of stress effects.

The brain is adept at recording memories of traumatic events, yet these fear memories can become pathological and contribute to incapacitating anxiety disorders often triggered by contextual cues associated with the initial event. While exposure-based therapies can be useful for treating these problems, fear relapse is common afterwards. Corticolimbic brain regions, including the hippocampus and medial prefrontal cortex (mPFC), are believed to be critically involved with the pathophysiology of these anxiety disorders, and these structures are connected via a direct projection, the ventral hippocampus-to-mPFC (vHipp-mPFC) pathway. It has been proposed that this pathway is crucial for contextual-mediated emotional regulation, which might make it a key mediator in fear relapse and anxiety. Despite its potentially important role the pathway’s function in emotional regulation is not well delineated. In recent years new optogenetics strategies have been developed which provide powerful and precise control of neuron activity within behaving animals. This project is a collaboration between internationally known groups, one of which specializes in systems-level translational research. This work will utilize optogenetic strategies to control the activity of the prelimbic and infralimbic branches of the vHipp-mPFC pathway during fear renewal and anxiety protocols. This will be correlated with associated changes in, vHipp-mPFC coherence, a potentially important marker of effective information transfer between the vHipp and mPFC. The resulting knowledge will be used to develop a novel optogenetic methodology that simulates the pathophysiology in this pathway implicated in emotional dysregulation. Thus, this project seeks to understand the vHipp-mPFC pathway’s contribution to contextually-mediated emotional behavior in order to provide an evidence-based model of anxiety disorders that can be used as a target for drug development and therapeutic strategies.

Epigenetic regulation is crucial for neuronal functioning and synaptic plasticity and epigenetic mechanisms were consistently reported as highly involved in pathophysiology of psychiatric disorders. Epigenetic dysregulation could account for the high heterogeneity of these disorders, their phenotypic variability within the same subjects and are in line with the hypothesis of shared risk factors, genetic vulnerabilities and biological pathways between the addiction, mood, anxiety and psychotic disorders. In addition, serious psychiatric disorders preferentially affect young individuals, with the first symptoms (or prodromes) occurring between 15 and 25 years old, during the critical period of adolescence when the brain is undergoing major maturational processes and when the individuals are more likely to experience psychotropic substances. Substance use, especially cannabis is a recognized risk factor for schizophrenia raising the question of its role in the emergence of psychotic symptoms and in sustaining depressive and/or anxiety dimensions. The biological substratum of the interplay between substance use/abuse (mostly cannabis) and psychiatric risk lays in epigenetic regulation. This latter involves dynamic processes that have a role in controlling gene expression levels, among which methylation of genes on cytosine–phosphate–guanine (CpG) dinucleotides have been the main focus of research. Regulation by micro-ribonucleic nucleic acids (miRNAs) is another epigenetic process known to be more dynamic than DNA methylation changes. Little is known regarding the specific and dynamic epigenetic changes during conversion to psychosis. We hypothesize that the vulnerability to the emergence of psychosis is associated with changes in miRNAs and that cannabis exposure modifies that same critical pathways. EPI_young aims to go further in understanding the epigenetic changes that determine the emergence of a psychotic disorder and the precise influence of cannabis use/abuse in young people. We intend to use a systematic omics approach in a longitudinal cohort of UHR subjects exhaustively characterized at the phenotypic and molecular level. The specific objectives will be: 1. To determine the dynamic changes in the methylome and mirnome during the conversion to psychosis in young adults with longitudinal follow-up. 2. To determine the methylomic and miRNA signatures of cannabis use in young adults with longitudinal follow-up. 3. To identify the overlap between the previously identified epigenetic signatures of the psychotic transition and the cannabis use. EPI_young has many originality points and will contribute to said state of the art because it represents: a. a highly tailored approach to an evolutive and complex mental health condition : Dynamic processes need dynamic (clinical and molecular) evaluations, strongly supported by a network of clinical research and personalized care: The ICAAR cohort (Influence du Cannabis sur l'émergence de symptomes psychopathologiques des Adolescents et jeunes Adultes présentant un état mental à Risque) is the most clinically and biologically supplied longitudinal cohort of young UHR and non UHR individuals at the international level. b. an innovative approach to integrate longitudinal multi-omic levels: Multi-omic analysis of complex traits will be used to achieve a more through and informative interrogation of genotype-phenotype associations rather than an analysis that uses only a single data type. Combining multiple data types (with a translational approach) compensates for missing or unreliable information from a single level. Multiples sources of evidence pointing to the same pathway are less likely to lead to false positives. c. an unique opportunity to test predictive value of the epigenetic changes during conversion to psychosis and cannabis use/abuse in young adults opening roads for staging biomarkers and prospective research for therapeutic/preventive endpoints.

SublimAE (“Sublime and Aesthetic Experiences”) is an interdisciplinary research project, involving philosophers, psychologists, social scientists and artists, and aiming at the development of a new cognitive account of experiences of the sublime and its close emotional relative, namely awe. The project should throw light on the relationship between the category of the sublime, aesthetic experiences, and self-awareness, by tightly integrating philosophical analysis and empirical hypothesizing and testing. The notion of the sublime has roots in ancient rhetoric, but it emerges in the 18th century as a central category of aesthetic experience, typically contrasted with the aesthetic experience of the beautiful. While the latter experience is mainly positive and pleasurable, the former experience is characterised by ambivalent feelings. On the one hand, the sublime involves an overwhelming vastness, or power, which disturbs and unsettles. On the other hand, the sublime poses a challenge, which is enlightening and elating. The overall experience of the sublime is also frequently associated with the feeling of the insignificance of human life, of our smallness compared to the grandeur we are confronted with. Our main philosophical hypothesis, which we construe as testable, is that the sublime gives rise to an aesthetic experience that, contrary to the experience of the beautiful, involves a diminished sense of the self. We intend to clarify this hypothesis by putting forward a notion of experiential immersion that we think is specific to sublimity experiences. The sublime overwhelms us in a way which blurs the boundary between oneself and the world. Sublimity experiences are immersive in the sense that the self tends to disappear from the subject’s experiential field while her attention is fully captured by the sublime entities or scenes. Since self-awareness is known to involve several levels of representation, the minimal self and the narrative self being two prominent examples, a crucial part of our enquiry will be to determine which levels are involved and in what ways. This will allow us to differentiate sublimity experiences from other experiences involving immersion or “ego-dissolution”, such as the oceanic feeling. SublimAE pursues three main lines of investigations, which all have both theoretical and empirical dimensions. First, we will create new experimental materials, starting from what has been defined as a core elicitor of sublimity experiences, namely vastness. The main challenge here is to go beyond classical experimental approaches to the sublime, which have often relied on impoverished visual materials, and introduce VR and music as two sources of more realistic sublime stimuli. Second, we will use the created (visual and/or auditory) stimuli to capture relevant differences between sublimity experiences and other, opposed or similar aesthetic experiences, such as prettiness or terrible beauty. Finally, we will test the impact of the experience of the sublime on self-awareness, and assess the hypothesis that this experience involves a diminished sense of the self, using embodiment, agentivity and episodicity tasks.

Schizophrenia is a multifactorial disease with a strong genetic component that is characterized by positive symptoms, negative symptoms and cognitive impairment. It is currently hypothesized that schizophrenia is a neurodevelopmental disorder that affects neuronal dendritogenesis and synaptogenesis. The Brain Angiogenesis Inhibitor family of receptors is a new family of seven-transmembrane receptors whose role in the brain is still poorly described. Several studies have shown the association of polymorphisms or copy number variations in the gene coding for BAI3 with schizophrenia. The characteristics of these receptors and data obtained by the coordinator’s team suggest an important role for BAI receptors in the formation of neuronal networks. In particular, they might coordinate the development of neuronal architecture with synatogenesis during brain development. The proposed project presents a multidisciplinary approach that will bridge basic research with translational research by providing a better understanding of the role of the BAI3 signaling pathway during brain development and of its direct involvement in the symptoms of schizophrenia. The BAI3 receptor is expressed in diverse brain regions including in cerebellar Purkinje cells. Because increasing evidence implicate cerebellar deficits in schizophrenia, especially in patients with high scores of neurological soft signs and stronger cognitive dysfunction, and because of the well-described cellular, physiological and behavioral characteristics of the olivo-cerebellar network, we will focus on the role of BAI3 in Purkinje cell development for our studies of BAI3 signaling and function. First, we will generate genetically modified mouse models with deficits of BAI3 signaling specifically in Purkinje cells and characterize the induced deficits in neuronal network organization at the morphological level, at the physiological level in vitro and in vivo, and at the level of behavior using a neurophenotyping strategy. This study will thus provide a description of the morphological and physiological correlates of behaviors relevant to schizophrenia and identify the symptoms that are due to cerebellar deficits. Second, we will combine genetic tagging in mice, biochemistry and mass spectrometry to identify the synaptic partners of the BAI3 receptor in neurons in vivo, and use a knockdown approach in vivo to validate the role of these candidates in the formation and function of neuronal networks. Finally, we will combine genetic association studies in patients with schizophrenia and functional studies of identified polymorphisms in cultured neurons to provide direct evidence of the role of the BAI3 signaling pathway in schizophrenia. This study will help us identify patients with relevant polymorphisms. We will then be able to transdifferentiate cells from these selected patients into “neurons” so as to confirm the effects of deficits in the BAI3 pathway on neuronal development and more importantly to test whether these deficits can be rescued by genetic modifications. Overall, this project takes advantage of the complementarities of the three partners not only to provide a comprehensive study of the role of a new signaling pathway in schizophrenia, but also new animal models for this disease and functional confirmation of genetic association studies using cellular models established directly from patients. Thus, our study will provide a better understanding of the etiology of schizophrenia, open new avenues of research and provide new potential therapeutic targets for this disease.