The major objective of the PSYchiatric disorders and COmorbidities caused by pollution in the MEDiterranean area (PsyCoMed) project is to form an international and inter-sectoral consortium (i) to characterise the effect of pollutants on symptoms reflective of psychiatric disorders and comorbidity in validated animal models, in light of the clinical incidence of these pathologies in the Mediterranean area, (ii) to determine the role of the neuroinflammatory response in the development of these pathologies in the two sexes, and (iii) to propose innovative anti-inflammatory therapeutic treatments based on natural products.
To address the complex interactions between environmental pollutants, the immune system and the brain, various tasks are defined that operate at different levels of analysis and require complementary expertise. The PsyCoMed strategy relies on the key combination and exchange of knowledge and know-how toward complex problem solving, significant advances in understanding the role of the environment on health, and improving health care, especially for the most vulnerable groups.
All consortium members have the expertise and facilities needed to reach these different goals, which makes the scientific objectives both achievable and realistic.
Objective (O)1: Understand if and how various disease-predisposing aquatic and air pollutants are the origins of different neuropsychiatric phenotypes conditions across the Mediterranean area.
A list of pollutants, characteristic of the Mediterranean basin, will be tested based on their potential link with neuropsychiatric disorders. They will be correlated with clinical studies and epidemiological data from the Mediterranean areas to identify those pollutants with effects on psychiatric diseases and comorbidities.
Xenopus and Zebrafish will be used for high-throughput screening and mammal studies will confirm these pollutants’ roles in triggering anxiety disorders, depression and schizophrenia as well as hyperactivity, attentional deficit, compulsive and impulsive behaviour, alterations in reward sensitivity, and pain. The partners already have the necessary models established and all assays are routinely used in the different partner laboratories.
O2: Verify whether any pollutant-induced effects linked to psychiatric disorders and comorbidity occur in a sexually dimorphic and/or age-dependent manner.
Sex is a risk factor well known to modulate anxiety and depression, drug-induced psychosis, hyperactivity and attention deficit reward sensitivity, compulsive behaviours, impulsivity and pain. In light of the need for a gender-specific approach in psychiatric disease and pain treatment, this project will involve subjects of both sexes.
Since alterations in the HPA axis function in response to stress increase the vulnerability to develop neuropsychiatric disorders, the level of both sex and stress hormones will be measured to check for the effect of pollutants on the
hormonal milieu. Finally, as age (besides sex) is a factor that may influence effects of pollutants on mental health, adolescent and adult animals of both sexes will be used to assess sex and age-dependent effects of pollutants.
O3: Decipher the neuroinflammatory mechanisms triggered by pollutants in the central nervous system, and their consequences for the development and maintenance of neuropsychiatric disorders Previous studies revealed that pollutants can induce inflammatory processes which can be characterized by the expression of diverse components and modulators, e.g. pro-inflammatory cytokines and chemokines, oxidative stress, and apoptosis. Other conditions associated with inflammation are microglia activation, macrophage migration, disruption of the blood-brain barrier, and epigenetic modulations. PsyCoMed aims to quantify inflammatory identifiers in in vitro and in vivo models, as well as in human patients with psychiatric disorders.
O4: Decipher the nature of the neuronal plasticity and neural circuit activation occurring in the brain areas affected by pollutants and neuroinflammation.
Following validation of pollutants effects on psychiatric diseases and characterization of inflammatory messengers, the cross-talk between neuroinflammatory mechanisms and brain activity will be investigated using multi-scale approaches in pollutant-treated Zebrafish and rodents. We aim to determine the effects of immune peptides from the periphery and/or released within the brain on glial activation, neurotransmission, synaptic plasticity, and neural networks in brain regions implicated in neuropsychiatric disorders and pain sensitization (hippocampus, amygdala, frontal cortex, corticolimbic pathways, hypothalamus, nucleus accumbens, spinal cord and sensory ganglia).
O5: Explore the therapeutic potential of bioactive natural molecules from the Mediterranean area to modulate inflammatory processes and their effects on behavioural symptoms. We aim to provide proof-of-concept that bioactive molecules derived from natural compounds represent an innovative targeted therapeutic strategy to treat pathologies caused by pollutants. Natural compounds with antiinflammatory
properties can be identified and will be tested on pollutant-treated animals:
- Natural phytocompounds (purple corn extracts, beetroot root extracts, and C. sativa extracts, neuroTERPAIN01 and a microneedle patch against pain) as possible innovative therapeutic molecules to treat neuropsychiatric disorders. The phytocompounds, normally disposed, display antiinflammatory properties and their use would be an interesting way to recover waste.
- Food lipids with anti-inflammatory and neuro-protective actions in the brain represent interesting
complementary therapies for neuropsychiatric disorders. - Peptide analogues (e.g. insulin-like peptide mimics) with pleiotropic effects in preclinical models on mental health disorders (e.g. anxiety and depression, addiction), neuroendocrine control, as well as pain.
O6: Develop 3i (international, intersectoral, interdisciplinary) exchanges for young researchers’ training.
The training objective includes acquiring novel expertise through workshops and secondments in the partner institutions and implementing new technologies in partner laboratories by transferring know-how between institutions. The strategy to ensure efficient knowledge and know-how sharing between participants is centred on researcher secondments at the individual level, and workshops and meetings at the consortium level. The secondments serve to optimise the flow of expertise in support of PsyCoMed scientific objectives and to improve the individual skills of participants, and their access to the academic and private sectors. Workshops/meetings will serve to disseminate individual experiences to the entire consortium. Interactive tools will further contribute to this internal dissemination. Moreover, by proposing common protocols or experiment flow charts, they will foster standardization of experimental procedures and diffusion of good clinical and laboratory practise.
Scientific impacts
The PsyCoMed beneficiaries have a strong track record in publishing in leading general science and neuroscience journals. During the last 10 years, research articles and reviews have been published in, amongst others: Nature, Science, Nature Neuroscience, Neuron, Nature Communications, Cell Reports, eLife, PNAS, EMBO Journal. Members of the consortium also hold editorial board positions in their fields, as well as executive board membership of relevant learned societies, thus ensuring world class scientific networking. We fully expect that the output of
PsyCoMed research, which will benefit enormously from the added value of the network collaboration, will be at the same level. In addition to research articles in leading journals, further dissemination will be achieved through reviews and international conferences (e.g. Gordon Conferences, Society for Neuroscience Meetings, FENS Forum). Interdisciplinary dissemination will also be ensured through the participation to the eco-toxicology international conference, in relation to the PLASTICØPYR European project. This link will open future research avenues to determine the role of pollutant-induced intestinal dysbiosis on psychiatric disorders. The creation of new networks at both the senior and ESR level enhances cooperation between partners and boosts the R&I capacity among them. Indeed, secondments and participation in international conferences, and workshops – through 3i mobility – enhances talent and knowledge circulation across the research and innovation landscape. In addition, the dedicated and transversal skill training offered by PsyCoMed will strengthen Europe human capital base in R&I.
PsyCoMed will develop new processes to improve screening tools by combining the expertise of IN-CNR on Zebrafish and Watchfrog on Xenopus. In particular, the consortium will adapt Watchfrog Xenopus tests to characterize endocrine effects of Mediterranean pollutants.
Economic and technological impacts
PsyCoMed is dedicated to increase high impact research & innovation (R&I) output and to have a greater contribution to the knowledge-based economy and society and thus Europe’s sustainable competitiveness. Secondments to non-academic partners and workshop with industrial involvement encourage the creation of startups and an engagement with the non-academic eco-system leading to sustainable collaborations between the academic and non-academic sector and thus potential commercialization activities. In particular, contacts with biotech companies will be fostered to develop new screening processes (Watchfrog), and innovative therapies based on natural products (FlaNat and BenePhyt). As such, peptide analogues with pleiotropic effects in preclinical models of mental health disorders are currently being developed at Florey-FINMH and expected to play a
role in the mitigation of pollutant effects. In addition, food lipids with anti-inflammatory and neuro-protective actions in the brain represent interesting complementary therapies for neuropsychiatric disorders. FlaNat and BenePhyt
have identified and characterized different classes of complementary phytocompounds (flavonoids and terpenes, respectively) as possible innovative therapeutic molecules to treat neuropsychiatric disorders and pain. Purple corn
extracts (rich in anthocyanins) display potent anti-inflammatory actions in vivo, while Beetroot root extracts (rich in betaine) have been recently shown to reverse cortical inflammation, oxidative stress, hormonal alterations and apoptosis induced by organophosphorus pesticide and Camelia sativa extracts (rich in sulforaphane) prevent the depression-like phenotype observed after inflammation or chronic social defeat stress. Notably, this compound also displays promising effects in schizophrenia. BenePhyt recently submitted a patent about a mix of monoterpenes
with anti-inflammatory properties and will be able to commercialize anti-inflammatory pain drugs. BenePhyt is also developing a microneedle patch filled with phytocompounds to alleviate pain related to rheumatic conditions.
Societal impacts
PsyCoMed will follow the FAIR data principles through its Open Science approach. In addition, the collaborations within and outside the consortium lead to 3i interactions, thereby fostering a culture of Open Science, innovation and entrepreneurship. Indeed, PsyCoMed partners are spread across Europe, showing the interest in international cooperation within the neuroscience community. The increased internationalisation of the participating organisations, the inclusion of private partners, and the strengthening of existing collaborations will lead to an improvement in the quality of supervision and exchange programmes. Good practices of the different local research actions and lessons learnt through PsyCoMed management will have a great impact on the quality of exchange programmes.
Together with challenging research projects, the use of breakthrough technologies and internationalisation offices increases Europe’s attractiveness as a leading research destination. In addition, PsyCoMed will support the European Green Deal through its actions towards the improvement of the health and well-being of citizens (natural therapeutic approaches against pollutants effects, awareness of pollutants effects on psychiatric health, strengthening pollutant monitoring and potentially banning the use of controversial chemicals) and pays attention to organizing its activities along-side existing conferences and meetings in order to decrease CO2 emission.
At a societal level outside the scientific community, PsyCoMed will act in three directions to (1) decrease avoidable mortality, (2) raise consumer awareness and (3) improve policies and decision-making.
Understanding how environmental pollutants impact the brain and the mechanisms underlying their central actions will ultimately lead to novel biologically-driven approaches for treatment and prevention of mental disorders.
PsyCoMed will develop an inventory of substances which can contribute to mental illness and determine the gravity of their impact on mental health. Since prevention has a strong societal impact to mitigate the often-inadequate mental health budget in North African Mediterranean low-income countries, PsyCoMed will also promote preventing and managing mental ill-health to policy-makers. It will thereby support the United Nations Sustainable Development Goals (SDG), Goal 3 ‘Good Health and well-being’ in particular. Indeed, a report by the United Nations highlighted rampant drug abuse and trafficking in Africa, pointing to the role of North Africa in all
pharmaceutical opiates seized globally. This situation led AU, our Egyptian partner, to launch the “Alexandria Free of Addiction” campaign in May 2019. As such, it will be a major player in converting the therapeutic and prevention strategies of PsyCoMed into direct applications for the benefit of patient management, and in limiting the spread of substance abuse. By preventing mental illness and fostering the development of appropriate treatments, PsyCoMed will significantly promote sustainable development in Mediterranean countries. Finally, our project will raise
awareness about mental health disorders through education and advocacy for less stigma and more respect for human rights. PsyCoMed will thus help civil society, public authorities, citizens, social partners and the private sector identify climate and environmental risks and take action to prevent, mitigate and adapt to them, and foster their engagement in closing knowledge gaps. In additions, it aims to develop social and environmental cross-border activities through joint strategies fostering sustainable territorial development.