# Determinants of selective vulnerability and functional replacement of olfactory bulb dopaminergic neurons

> **NIH NIH F32** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $70,458

## Abstract

PROJECT SUMMARY
Loss of specific types of neurons is a hallmark of many neurodegenerative diseases. Replacing these lost or
damaged neurons to restore normal brain function through stem cell-based therapies has long been a major
goal in the fight against neurodegenerative diseases. However, we know little about either why certain
populations of neurons are selectively vulnerable to cell death, or how functional integration of stem cell-derived
neurons can be promoted. Few areas of the mammalian brain retain the capacity to generate new neurons in
adulthood. Understanding how endogenously generated stem cell-derived neurons can successfully integrate
without disrupting existing circuits may provide important mechanistic insights into the successful therapeutic
use of stem cell-derived neurons. Dopaminergic (DA) neurons in the mouse olfactory bulb (OB) are a highly
activity dependent population, with a subset undergoing cell death when sensory input is blocked. DA neurons
are also generated continuously throughout life from progenitor cells in the subventricular zone. These two
properties make OB DA neurons an ideal model system in which to investigate the determinants of both selective
vulnerability and newborn neuron integration. To do so, I will employ an experimental system that enables
sensory input to be eliminated and then gradually restored. I have two aims in this proposal. First, I will determine
the size of OB DA neurons that are vulnerable or resilient to cell death during loss of sensory input and the
location of newborn neurons that integrate once sensory input is restored. Second, I will determine the odor
response properties of vulnerable, resilient and newborn OB DA neurons when odor input is removed and then
restored. Based on previous studies, I predict that a subtype of small, postnatally-generated DA neurons will be
particularly susceptible to cell death but can be functionally replaced by ongoing neurogenesis when sensory
input is restored. I will use chronic in vivo 2-photon structural and functional imaging to track the survival and
integration of individual neurons over long periods of time (10 weeks). By tracking the size and odor response
properties of DA neurons, I will be able to assess whether these important properties differ between vulnerable
and resilient neurons, and also to determine whether newborn neurons can functionally replace lost neurons in
OB circuits. These data will advance our understanding of the mechanisms underlying selective neuronal
vulnerability and functional integration of newborn neurons.

## Key facts

- **NIH application ID:** 10231299
- **Project number:** 1F32DC018431-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Tenzin Kunkhyen
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $70,458
- **Award type:** 1
- **Project period:** 2021-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231299

## Citation

> US National Institutes of Health, RePORTER application 10231299, Determinants of selective vulnerability and functional replacement of olfactory bulb dopaminergic neurons (1F32DC018431-01A1). Retrieved via AI Analytics 2026-07-26 from https://api.ai-analytics.org/grant/nih/10231299. Licensed CC0.

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