Understanding brain asymmetry: from genes and developmental mechanisms to circuits and behaviour (360G-Wellcome-225445_Z_22_Z)

Despite left-right asymmetry being a universal feature of animal nervous systems, we understand little about how such asymmetries arise, how they are encoded in circuits and what roles they play in nervous system function. Our programme of research will elucidate all these aspects of brain asymmetry through the implementation of a comprehensive genetic, developmental, physiological and behavioural platform to study habenular lateralisation in zebrafish. Our first aim is to resolve the developmental processes that establish habenular asymmetry. One focus will be on Cachd1, a transmembrane Wnt-receptor binding protein that modulates asymmetric neurogenesis; additionally, we will perform a large-scale Crispr/Cas9-based screen to identify novel genes that influence habenular asymmetry. Next, we aim to understand how lateralised neurons diversify and will combine functional calcium imaging with spatial transcriptomics to explore the emergence of neuronal diversity in terms of transcriptional and physiological profiles of left- and right-sided habenular neurons. To understand the functional consequences of normal and disrupted brain asymmetry, we will characterise a range of innate behaviours, including context-dependent exploration, in wild- type and mutant animals. Finally, by subjecting our multimodal datasets to methods including canonical correlation analysis and directly manipulating circuit activity, we will determine how neural asymmetry impacts behavioural outcomes.