Brain Resilience

The mammalian brain is formed through highly complex developmental processes that are controlled by thousands of genes and their interaction with the very specic environment of the embryo during pregnancy. Mutations in the underlying genes can predispose an individual to various neurodevelopmental disorders (NDDs), including autism spectrum disorders and intellectual disability. These disorders are hard to treat because of their developmental nature by the time the illness becomes manifest, it is usually too late to address the root causes. However, genetics research oers some hope: Surprisingly many individuals who carry a strong genetic predisposition to NDDs live a healthy life. The observation that disease-causing mutations can have incomplete penetrance is almost as old as genetics itself, but the underlying causes are not well understood. We propose that the environment in an uterus, intimately dependent on the state of the maternal system during pregnancy is a key factor in determining why some babies brains can develop physiologically, despite genetic vulnerabilities for NDDs. This project empowers the emerging eld of Brain Resilience, seeking to unravel the molecular processes by which a favorable prenatal environment overrides the genetic predisposition to NDD. Firmly rooted in molecular neuroscience, the project will: (1) investigate genetic mouse models of NDDs for the eects of alterations of the prenatal environmental; (2) identify molecular signals of the maternal organism that promote resilience on a biological level; (3) evaluate the identied biological processes in human brain organoids; and (4) explore the feasibility of developing molecular interventions that can therapeutically boost brain resilience. Using in vivo mouse models makes it possible to study brain resilience in a genetically dened setting, in which the conditions during pregnancy can be modulated in a highly controlled manner. Moreover, human brain organoids provide a system for the initial assessment of how well the observations translate to the human brain. The project will be conducted by an interdisciplinary scientic team that is uniquely suited for establishing and promoting the emerging eld of Brain Resilience, with strong expertise in cognitive neurobiology (Gaia Novarino), brain organoids and in vitro modeling of brain disorder (Juergen Knoblich), bioinformatics and genetics/epigenetics (Christoph Bock), developmental biology (Igor Adameyko), brain structure and function (Roman Romanov), and maternal-to-progeny communication (Daniela Pollak). This collective expertise guarantees scientic excellence i experimental design, implementation with state-of-the-art methodology, data analysis, n interpretation and communication. The transformative impact of this emerging eld extends even beyond the realm of brain disorders, as it may lay out a path toward learning from and enhancing the human bodys inherent resilience through targeted molecular interventions.