Solving the Metabolic Mystery of Human Neocortical Expansion in Health and Disease

The advantage of higher cognitive abilities that humans possess depends on the enlarged and highly interconnected human cerebral cortex. Its complexity, and prolonged timeline for maturation, predispose humans to developmental injuries.

During the period of cortical expansion, specialized progenitor cells multiply and, in a well-controlled fashion, differentiate to generate first neurons and later astrocytes.

Intracellular metabolism has been suggested to regulate the proliferation, differentiation and maturation of neural cells. However, our understanding of how metabolism regulates these processes remains extremely limited. This project bypasses the traditional limitations associated with the study of human cortical development.

It establishes novel multimodal analysis approaches by combining imaging mass spectrometry (IMS)-based chemical imaging of metabolites/lipids, single cell metabolic and cell-lineage profiling, and the use of extremely rare human fetal brain tissue and human brain organoids derived from induced pluripotent stem cells.

Further, it utilizes specifically developed tissue metabolic labeling in a dish to identify any changes in metabolite flows in conditions of nutrients deprivation (e.g. folate) and environmental insults (e.g. hypoxia).

These results will expand the fundamental knowledge of metabolic regulation of human cerebral cortex growth, and establish a platform for the investigation of many neurometabolic diseases that remain poorly understood.