Reduction of the Olfactory Bulb and Reuse of its Inhibitory Neurons in the Primate Cerebrum

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PROJECT SUMMARY/ABSTRACT Inhibitory neurons are critical to the balance of excitation and inhibition, rhythmic activity and logic-based computation that underlies healthy brain function. The lateral ganglionic eminence (LGE) of the developing brain is well known to give rise to inhibitory olfactory bulb neurons and projection neurons of the basal ganglia in the mouse. In the rhesus macaque brain, I have shown that the LGE also generates large numbers of white matter inhibitory neurons and tyrosine hydroxylase-expressing striatal interneurons. These poorly-understood cell types have not been studied in the human brain. However striatal dopamine system failure in Parkinson's disease and an abnormal density of neurons in the white matter in schizophrenia suggests possible intersection between this lineage of neurons and devastating neurological diseases. While the olfactory bulb is diminished relative to the cerebral cortex in rhesus macaques when compared to mice, it is even more so in humans. Understanding what has changed in primate brain evolution is key to translating findings in animal models to human medicine, and how neurological disease may arise due to novel features, which have not been "tuned" by extended evolution. I hypothesize that evolutionary forces increasing the size of the cortex and conjoined LGE domain, coupled with the simultaneous decrease in size of the olfactory bulb has caused a progressive redistribution of olfactory bulb inhibitory neurons to the cortex and striatum. In my first aim, I propose to use imaging to quantify these cell densities across species and to test the sufficiency of olfactory bulb reduction to cause redistribution. In my second aim I propose to study the transcriptomic divergence of newborn neurons from their common LGE origin to distinct cortical and olfactory bulb types using single nucleus RNA sequencing. Then, I will examine the signaling cues that may drive this divergence using an induced pluripotent stem cell differentiation system. My sponsor Alex Pollen has pioneered the use of pluripotent stem cell models of brain development to study the context of human brain evolution across species. My co-sponsor Arturo Alvarez-Buylla has performed much of the foundational work in mapping the birth of the inhibitory neurons of the mouse olfactory bulb, and has deep expertise in experimental developmental neuroscience. My co-sponsor, Dr. Chun (Jimmie) Ye, has an expertise in experimental and statistical single cell genomics and has developed cutting-edge methods that will facilitate the project. This work will investigate uncharacterized, novelly redistributed cells in the primate brain, and will inform future efforts toward understanding the role of these cells in health and disease. Fellowship support for this project will foster my developing expertise to achieve my ultimate goal of becoming an independent academic scientist leading a combined experimental and computational developmental neuroscience group.