Title: The role of the cerebellum in thalamic development
Funder: The Academy of Medical Sciences

Abstract: Brain development is susceptible to genetic or environmental perturbations that can disrupt normal maturation and produce life-long deficits. This has primarily been studied in sensory systems, where manipulations of the external environment (for example sensory deprivation) profoundly impact the maturation of the thalamo-cortical system. However, we lack understanding of the development of higher-order regions, such as the prefrontal cortex (PFC), whose function is linked to cognition rather than sensory perception. This knowledge is important given many neurodevelopmental disorders display cognitive symptoms associated with PFC dysfunction. To date, it has been unclear what would be analogous to sensory deprivation for cognitive brain regions. The cerebellum plays a role in cognition and provides excitatory drive to thalamo-cortical circuits targeting the PFC and other frontal cortices, in many ways mirroring ascending sensory innervation. Based on this evidence, my hypothesis is that the cerebellum fulfils a similar role to the external environment in sensory cortices, relaying a cognitive and motor map to frontal cortices via parallel outputs to thalamus. This proposal will use powerful genetic tools in mice to determine the topography of cerebellar outputs and test the cerebellum’s role in the maturation of thalamic regions that project to the PFC. This question is important to our understanding of cognitive development and relevant to neurodevelopmental disorders, including schizophrenia and autism, whose pathophysiology includes dysfunction within these brain networks. These findings will therefore provide key insight into the potential for miswiring in neurodevelopmental disorders and help guide therapeutic interventions to improve the lives of patients.

Lay abstract: Communication within the brain occurs along signalling highways, which work much like roads to link regions involved in particular brain functions, such as speech, vision, movement, or processing the contents of our internal thoughts. These neural pathways are constructed during brain development and there is significant evidence that disorders such as schizophrenia and autism are associated with failure of this process, yielding pathways ill-equipped to support the required volume of traffic, or that end up at the wrong destination. This proposal will focus on key pathways implicated in neurodevelopmental disorders such as autism and schizophrenia, determining when and how they form. Consequently, these findings will highlight periods of development best suited for therapeutic intervention aimed at combating these disorders. These studies will use mice, as they allow me to apply a range of powerful genetic techniques to control specific pathways in the brain. First, I will measure the precise organisation of circuits linking the cerebellum and cortex, pathways thought to be dysfunctional in both schizophrenia and autism. Second, I will record how the properties of these pathways change during development, highlighting key periods of maturation. I will track changes in these circuits from birth to adulthood, a transition that only takes a few months in mice. Finally, I will silence these pathways during development and determine how it influences their strength and connectivity. In the future I hope to take these findings and apply them to help design new targeted therapies for people with neurodevelopmental disorders.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: NEUROLOGICAL;MENTAL HEALTH