Towards a molecular and neurobiological understanding of mental health and mental illness for the benefit of citizens and patients Mental illnesses represent a huge and growing burden for Europe, both at individual and societal level. There is an enormous stigma and they often remain undetected as diagnoses largely depend on symptom-based criteria without any biological markers linked to causative mechanisms. Currently available medications are primarily used by trial and error (rather than in a targeted and personalised manner) and they are all very similar in their mechanisms of action with rather little breakthrough innovation in the last few decades. There is further a lack of evidence base on the optimal use of different pharmacological and non-pharmacological prevention strategies. A deeper molecular and neurobiological understanding of the interplay between genetic, epigenetic and environmental risk and resilience factors, including neural circuit alterations, is critical for the development of objective biomarkers and evidence-based interventions that will significantly improve mental health outcomes.Accordingly, the proposed research is expected to deliver on several of the following:Significantly advance the molecular and neurobiological understanding of how genetic, epigenetic and environmental risk and resilience factors (such as psychosocial experiences, diet, sleep, natural and artificial light, use or abuse of drugs, infections and other exposures) interact to drive or prevent the transition from mental health to mental illness[[This may include any mental and behavioural disorder(s) according to ICD-10 Chapter V (https://icd.who.int/browse10/2019/en#/V) except dementia. Neurological disorders are outside the scope of this topic. Psychiatric disorders to be studied may be acute, chronic or relapsing-remitting in nature and applicants are encouraged to also study the molecular/neurobiological changes brought about by interventions and associated with remission.]] throughout the life course as well as how such molecular and neurobiological changes could be reversed. The use of computational modelling and/or artificial intelligence tools is encouraged for the analysis of big, complex and heterogeneous data[[Data needs to meet the FAIR principles: findable, accessible, interoperable and reusable.]].Develop relevant predictive models through federated analysis of large European cohorts of psychiatric disorders and investigate the biological and neural basis of pathogenetic mechanisms and symptoms shared by different disorders. If relevant to the disorders studied, develop neurobiologically-grounded models of cognition and social behaviour and apply these models and their simulation potential to the understanding and improved management of mental health conditions associated with behavioural or emotional dysfunction.Identify, validate and document different types or combinations of biomarkers for all of the following purposes: development of robust quantitative, clinical measures of mental health;identification of signatures, for example genetic and epigenetic blueprints, conferring susceptibility to and protection against mental illnesses;establishment of more objective diagnostic and monitoring criteria (complementing current symptom-based criteria) to improve patient outcomes and reduce the stigma associated with mental illness; prediction of treatment response and risk of relapse for better, more scientifically-guided and targeted use of currently available preventive and therapeutic interventions for different population groups. For biomarker discovery, applicants are encouraged to take stock of advances in disciplines such as for instance neuropsychology, neurophysiology, neuroendocrinology, neuroimaging, electrophysiological monitoring, e-health/m-health, -omics (genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, exposomics, microbiomics including the role of the microbiota-gut-brain axis), optogenetics, nanomedicine, stem cell biology, neuroimmunology and immunopsychiatry.Discover new disease pathways and drug targets (including pathways involved in maintaining mental health) to boost the development of new (or repurposed) classes of safer and more effective medications[[Going beyond monoaminergic neurotransmitter systems by targeting novel pathways and addressing also the challenge of getting drugs pass through the blood-brain barrier.]] for the prevention and treatment of mental illnesses (including relapse prevention).Establish the molecular and neurobiological effects as well as cognitive and psychological consequences of both pharmacological and non-pharmacological prevention strategies (for example: neurostimulation, neurofeedback, psychotherapy and other psychological/behavioural interventions, light therapy, diet, exercise, lifestyle, mindfulness or a combination of them) and assess their efficacy and side effects as part of clinical trials (also determining windows of opportunity when preventive actions are most effective throughout the life course). Proposals may cover different stages in the continuum of the innovation cycle (from basic and translational research to the validation of findings in real-world settings) and should ensure strong involvement of end-users, including citizens and patients. Sex and gender differences and the effects of age should be duly taken into account. International cooperation is encouraged and the proposed research is expected to be multidisciplinary, including through the involvement of medical sciences, psychological sciences, social sciences and the humanities.All projects funded under this topic are strongly encouraged to participate in networking and joint activities, as appropriate. These networking and joint activities could, for example, involve the participation in joint workshops, the exchange of knowledge, the development and adoption of best practices, or joint communication activities. This could also involve networking and joint activities with projects funded under other clusters and pillars of Horizon Europe, or other EU programmes, as appropriate. Therefore, proposals are expected to include a budget for the attendance to regular joint meetings and may consider to cover the costs of any other potential joint activities without the prerequisite to detail concrete joint activities at this stage. The details of these joint activities will be defined during the grant agreement preparation phase. In this regard, the Commission may take on the role of facilitator for networking and exchanges, including with relevant stakeholders, if appropriate.