An important part of neural development involves setting up and refining the architecture and function of dendrites, the “receiving ends†of nerve cells that communicate with their partners in circuits. The biological processes involved in building and maintaining dendrites require high levels of metabolic activity that needs to be turned on and off repeatedly in a spatially and temporally restricted way. The metabolic processes that synthesize (anabolism) and break down (catabolism) complex molecules involved in dendrite building and remodeling are not completely understood. This project examines the interplay between anabolic and catabolic pathways during the formation of Purkinje cell dendrites (which have some of the largest dendritic trees in the brain) within the mouse cerebellum. Experiments will determine the differential impact that anabolic and catabolic pathways have on dendritic growth, patterning and synaptic connectivity of Purkinje cells, including how these changes affect mouse behavior. This research project will lead to a deeper understanding of how metabolic processes affect dendritic development and how functional disruption of these processes lead to behavioral deficits observed in neurodevelopmental disorders. This research project will involve the direct participation of undergraduate and graduate students; two project-based laboratory neuroscience courses for undergraduate and graduate students will expand the impact of this project to a larger number of students. In order to increase the training and participation of students from underrepresented and disadvantaged backgrounds in neuroscience research, this project includes a summer internship program involving undergraduate students from Puerto Rico who will participate in the research project in the PI’s laboratory.
Nutrient-rich conditions (which promote anabolism) and starvation (which induces catabolism) have significant and opposing effects on dendritic arbor size and patterning of Drosophila sensory neurons during development, suggesting that nutrient and energy availability importantly regulate dendritic differentiation. In the mouse cerebellum, the postnatal growth of Purkinje cell dendrites is increased by genetic overactivation of nutrient-sensing anabolic pathways. However, it is not currently known how the metabolic balance between anabolism and catabolism regulates the differentiation, patterning and synaptic activity of dendrites during postnatal brain development. This project uses conditional knockout mice, drug interventions, histological and molecular approaches, and sophisticated tissue imaging and analysis to more precisely define the contribution of anabolic and catabolic pathways to Purkinje cell dendritic differentiation, cerebellar synaptogenesis and mouse behavior during postnatal development. This research project will significantly expand our scientific understanding about the role that metabolic balance plays in the development and plasticity of synaptic connections in the brain.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
