# Human‐specific vulnerabilities and compensatory adaptations to age‐related stressors in selectively vulnerable midbrain dopaminergic neurons

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $866,764

## Abstract

PROJECT SUMMARY
The evolutionary expansion of the brain along the primate lineage involved unequal scaling of
brain regions, with telencephalon size increasing dramatically more than that of midbrain and
hindbrain. Coupled with increased human lifespan, this reconfiguration of brain structures may
put undue burden on neurons whose target regions have expanded disproportionately. These
vulnerable “joints” include the small populations of midbrain dopaminergic (DA) neurons that
project to vast target fields in the cortex and striatum and contribute to human-enriched disorders
such as Parkinson’s disease. In turn, human DA neurons may have evolved compensatory
neuroprotective mechanisms while adapting to supplying an enlarged telencephalon, but few
studies have examined the evolution of selective vulnerability or compensatory mechanisms in
the human lineage.
 We have designed an interdisciplinary approach to study human-specific properties of DA
neurons using interspecies stem cell-derived organoids, primary tissue from human, chimpanzee,
and rhesus macaque, machine learning approaches to genomics data, and functional analysis of
variants by CRISPR. Our approach will enable direct measurement of dynamic gene regulatory
responses and candidate protective pathways to age-related oxidative stress that cannot be
measured from post-mortem tissue alone. Convolutional neural nets will help decode a dynamic
regulatory grammar of oxidative stress responses, enabling predictions of the effects of all human-
specific variants. Interspecies tetraploid cell fusions further enable experimental analysis of the
effects of these variants in their native genomic context, with CRISPRi supporting further
validation. Finally, comparative loss of function screening in dopaminergic neurons exposed to
stress pathways will reveal conserved and human-specific genetic dependencies in these
vulnerable cell types.
 Through the successful completion of these studies, we will determine which genomic
elements and genetic changes underlie oxidative stress-dependent responses in dopaminergic
neurons laying the groundwork for further targeting these cellular protective mechanisms across
cell types and age-related stressors. Ultimately, this approach is generalizable to other age-
related stressors and vulnerable cell types.

## Key facts

- **NIH application ID:** 10936771
- **Project number:** 1R01AG087959-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** KATHERINE S. POLLARD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $866,764
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10936771

## Citation

> US National Institutes of Health, RePORTER application 10936771, Human‐specific vulnerabilities and compensatory adaptations to age‐related stressors in selectively vulnerable midbrain dopaminergic neurons (1R01AG087959-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10936771. Licensed CC0.

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