Neural stem cell/progenitors cells give rise to mature neurons, astrocytes and oligodendrocytes throughout life. However, neurogenesis rapidly declines during aging and the mechanism for age-dependent neural stem cell dysfunction is not clear. The ventricular-subventricular zone (V- SVZ), lining the lateral ventricle, is home to the largest pool of neural stem cells in the murine brain. We have found that microglia, the innate immune cells of the brain, are prominently positioned throughout the young and aged V-SVZ niche. During aging, microglia undergo a morphological and phenotypical shift from a resting state to a pro-inflammatory state. Preliminary data suggest that secreted molecules from young microglia support proliferation and neuronal differentiation in vitro. In contrast, microglia isolated from aged mice appear to lose this influence on proliferation in vitro. Together, these data suggest microglia play a critical age- dependent role in regulating neurogenesis. Although microglia are known to be important in phagocytosis of neuroblasts, their influence on type B neural stem cells, type C transit amplifying cells and niche cytoarchitecture is essentially unknown. Using 3-dimensional image analysis of niche cytoarchitecture and flow activated cell sorting (FACS), we will test the hypothesis that microglia have opposing roles in the young and aged neurogenic niche.
In aim 1, we will pharmacologically and genetically deplete microglia from the young neurogenic niche and interrogate the impact on neurogenesis, Type B, C and neuroblast cell survival as well as number, proliferation and position near the vascular compartment.
In aim 2, we will use heterochronic infusion of secreted molecules from young and aged microglia to directly test if these molecules have opposing roles in neurogenesis.
In aim 3, we will test if mitigating the inflammatory phenotype of aged microglia restores neural stem/progenitor cell function. We will also explore novel molecular candidates for microglia derived secreted molecules that support or hinder neurogenesis. Understanding how the microglia activation state regulates neurogenesis will have far-reaching consequences. It is widely accepted that V-SVZ neural stem cells and their progeny contribute to brain repair. Thus, understanding how microglia contribute to neurogenesis during tissue homeostasis and aging will not only further our basic understanding of neurogenesis but will help in the eventual goal of using neural stem/progenitor cells in brain therapeutics.

Public Health Relevance

Brain injury can cause permanent memory, learning and motor deficits. Adult neural stem cells divide and give rise to neurons and other support cells in the brain throughout life. These properties make neural stem cells an attractive source for brain repair. However, neural stem cell function declines during aging. This proposal aims to understand how the immune cells of the brain signal to neural stem cells during tissue homeostasis and aging. Understanding how neural stem cells are regulated will be important to identify ways we can use neural stem cells to enhance brain repair.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS102448-01A1
Application #
9594799
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Lavaute, Timothy M
Project Start
2018-08-01
Project End
2023-06-30
Budget Start
2018-08-01
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Health Science Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229