# Neuronal Integration of Newborn Granule Cells in Aged Brains

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $308,616

## Abstract

The birth of new neurons (called neurogenesis) in the adult hippocampus is critical for learning and memory,
and disruption of this process during aging is associated with neuropsychiatric illnesses that undermine
cognition in the aged brain. Most of our knowledge about adult neurogenesis relates to the survival and
differentiation of newborn neurons in the young adult brain. Much less is known about how these neurons
integrate into existing neural circuits in the aged hippocampus. Neuronal progenitors in the hippocampus give
rise to granule cells that, when fully differentiated, send axons along the mossy fiber pathway, where they form
synaptic connections (called boutons) to CA3 pyramidal neurons. Previously we developed a serial immuno-
electron microscopic approach to study the development of these newborn mossy fiber boutons in the adult
brain. Here, using a reporter mouse that we can induce to label the new neurons that are born in a particular
time period, we investigate the development and integration of newborn granule cells in the aged hippocampus.
This mouse line allows us to birth-date and characterize neurogenesis at any age, including in aged mice 18
months or older. Our preliminary studies show that the progenitor pool changes in the aged hippocampus;
more quiescent (inactive) progenitors are present compared to young-adult brain. We have also found the
potential for newborn granule cells to form de novo synapses in aged brain is significantly reduced; instead
existing boutons have to be replaced when these newborn neurons form synapses. These results reveal
previously unknown changes in newborn neurons and their progenitors in the aged brain. In this proposal, we
focus on three questions. (1) What are the molecular phenotype and developmental origin of the neuronal
progenitors in aged hippocampus? These experiments will reveal how progenitors in the aged brain are
different from those in young adults. (2) What is the age and developmental origin of the existing boutons that
are replaced by the newborn mossy-fiber boutons in aged brain? Why do the newborn granular cells in the
aged brain lose their ability to form de novo synapses? Is this loss due to changes in the neuronal progenitors
or to changes to the environment in the aged hippocampus? The answers to these questions will help us
understand the specific functional role of adult neurogenesis in the aged brain. (3) How do changes in neuronal
activity affect neurogenesis in the aged brain? We have found that the aged hippocampus loses a voltage-
gated potassium channel that regulates neuronal intrinsic excitability, and that this channel has a significant
effect on adult neurogenesis. We will ask how the changes in neuronal activity resulting from the loss of this
channel affect the development and integration of newborn granule cells in the aged hippocampus. These
experiments will fill an important gap in our knowledge about neurogenesis in the aged brain, which we expect
will...

## Key facts

- **NIH application ID:** 10137166
- **Project number:** 5R01AG054649-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** KARL Daniel MURRAY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $308,616
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137166

## Citation

> US National Institutes of Health, RePORTER application 10137166, Neuronal Integration of Newborn Granule Cells in Aged Brains (5R01AG054649-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10137166. Licensed CC0.

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