An evolutionary model for human-specific vulnerabilities in dopaminergic neurons

The human brain has evolved remarkable cognitive and social abilities over the last 6 million years, but these adaptations involved trade-offs that may leave us more vulnerable to uniquely human disorders such as Parkinson’s disease and schizophrenia.

Dopaminergic neurons in particular may be under increased stress in the human brain because their target regions in the striatum and cortex have 1) disproportionately increased in size and 2) require increased functional innervation compared to other primates.

I propose a novel model in which these twin selection pressures have driven cell-intrinsic adaptations in dopaminergic neurons that control increased axonal arborization and metabolism, and may partially compensate for the increased stress these neurons experience.

To test this hypothesis, my aim is to use novel approaches, involving human and non-human primate stem cells and brain organoids, to disentangle the cell-intrinsic and -extrinsic species differences that have evolved at functional, morphological, and molecular levels.

Since my arrival at the University of California San Francisco (UCSF), I have established the requisite cell models and approaches, and I intend to spend the three-year grant period at UCSF in pursuit of these aims.

The results of my work will illuminate the mechanisms underlying the selective vulnerability of dopaminergic neurons in multiple human disorders, and will increase our understanding of how to treat or even prevent these diseases.