Identification of metabolic states that stimulate the diversification of interneurons and the assembly of cortical circuits.

Brains are composed of a multitude of neuronal cell types that
assemble together into specific functional circuits. Elucidating how a
small number of neural progenitors generates the vast diversity of
neuronal cell types in the brain remains a major goal in
neuroscience, since the different types of neuron — and their specific
connectivity — are the basis for information processing. This problem
is very challenging in the cerebral cortex, where dozens of different
types of neuron come together, during development, to form
microcircuits. Importantly, miswiring of microcircuits is often the
hallmark of major neurodevelopmental diseases. Recent studies,
including my own, have used novel sequencing approaches to
classify neocortical neurons and their progenitors based on their
gene expression. We found that metabolic genes, which are
traditionally associated with housekeeping functions, are among the
most differentially expressed in distinct classes of neuronal
progenitors. This finding, together with other works describing
instructive changes in metabolic states during cell differentiation,
points to a probable role for the metabolome in interneuron
diversification. Based on these published data, the central goal of this
proposal is to identify metabolic states in neuronal progenitors that
specify cell fate and lineage diversification, with a long-term goal to
design new cell reprogramming and replacement strategies to treat
brain disorders.