How do neurons stay healthy despite extreme spatial separation of their parts? We will understand how core signaling pathways are remodeled within the exquisite cellular architecture of neurons. As a starting point, we will study pathways which have fundamental spatial constraints and whose inputs and outputs remain poorly defined in the brain, including nutrient detection and nuclear to mitochondrial signaling. We will define their dynamics across time, space, and neuronal classes to reveal fundamental insights into neuronal biology.

Why do some neurons die in disease while others live? We will study how metabolic dependencies vary across the brain. As a starting point, we will understand how neurotransmitter production impacts these dependencies. Many neurotransmitters are derived from amino acids, a central building block for multiple metabolic pathways. Moreover, neurotransmitters are chemically diverse and impart unique liabilities to neurons, from the highly oxidizing nature of dopamine metabolites to the integration of glutamate into ATP production. We will establish how neurons adapt their cell biology to accommodate different neurotransmitters, and how this may vary in disease.

Organelles are essential for every cell in our bodies to survive, from the mitochondria that generate energy to the lysosomes that recycle waste. Neurons have specialized organelles to support their functions, including synaptic vesicles for neurotransmitter release and dense core vesicles for neuropeptide and neurotrophin release. Despite their importance, many of these organelles remain poorly characterized. We have developed powerful tools that couple biochemistry, metabolomics, and proteomics to study these organelles at scale and reveal their contents, dynamics, and regulation within the cell. This work will unlock the study of major understudied areas of neuroscience.