UC San Diego

The brain is a complex organ that contains hundreds of diverse cellular subtypes which organize into unique regions and build intricate neural circuits. Neurons all transition through developmental stages where they must specify into cellular subtypes, migrate to appropriate brain regions, and extend axons to innervate postsynaptic targets as well as elaborate dendritic trees to receive incoming information. These stages are shaped by a balance of intracellular transcriptional programs and extracellular signals such as guidance molecules, adhesion proteins, and neuronal activity. While an extensive list of factors contributing to these processes has been catalogued, the details remain unclear on how they converge within a cell to direct its development. Therefore, we developed novel genetic systems to decipher the rules that shape neuronal development and circuit formation. In one set of studies, we selectively blocked synaptic activity from a subset of neurons within the rodent olfactory bulb to investigate their role in shaping olfactory circuit development. We observed a dramatic impact on the maturation of newborn inhibitory neurons which could not be completely rescued by inhibiting cell death. By assessing the transcriptome of these developmentally-stalled neurons, we identified gene networks that regulate the maturation and integration of neurons into established circuits. For the second set of experiments, we injected rat stem cells into mouse blastocysts to generate rat-mouse brain chimeras and determine whether rat neurons are flexible to develop into, and contribute to foreign neural circuits. In brain-complemented chimeras, we observed diverse rat neuronal subtypes that adopt their host’s developmental timeline and functionally integrate into the mouse brain. Furthermore, we identified species-specific barriers to rat complementation when these neurons are challenged to reconstitute degenerated mouse circuits. Together, these studies provide insights into the mechanisms governing neuronal integration into foreign and compromised neural circuits, which will inform efforts in regenerative medicine.