Adult neurogenesis persists in the dentate gyrus of mammals. Neural production is perturbed by a large number of pathological conditions, and there is a growing realization that disrupted neurogenesis in disease models can contribute to cognitive and emotive dysfunction. Despite the highly documented impairments of adult neurogenesis in rodent disease models, less is known about how adult-born neurons contribute to normal and abnormal hippocampal function at the cellular and circuit level. It is unclear how such a small number of neurons, estimated to be 1-3% of the total population of granule cells in young adults, could have sizable and varied consequences for behavior. Most theories implement the idea that neurogenesis produces a continually renewing population of immature granule cells that have distinct functions from pre-existing cells, with considerable attention focused on their intrinsic hyperexcitability. Surprisingly, the potential role of distinct synaptic connectivity of adult-born granule cells has not been fully explored. Our long-term goal is to understand how the physiological characteristics of immature granule cells contribute to their function. The goal of this project is to determine how differences in synaptic connectivity across maturation affect granule cell recruitment, potentially allowing immature and mature cells to process distinct components of network activity. Based on our preliminary data, we hypothesize that distinct innervation from cortical and hippocampal sources results in greater recruitment of immature granule cells by intra-hippocampal network activity compared to mature granule cells. We will use in vitro slice physiology and a variety of transgenic mouse models and optogenetics to address this hypothesis. First, we will compare innervation of granule cells across their development to test the idea that immature granule cells have high cortical input specificity, corresponding to low levels of cortical innervation, that limits their responsiveness to cortical activity. Second, we will determine how mossy cell activity contributes to granule cell spiking across maturation. Mossy cells are glutamatergic neurons within the hilus that provide feedback excitation to the granule cell layer via predominately long-range projections. Whereas mossy cell activation typically generates inhibition of mature granule cells via di-synaptic inhibition, he synaptic connectivity of immature granule cells suggests that excitation predominates. Little is known about mossy cell control of granule cell synaptic integration, thus the results of these experiments will provide novel information about this important but often neglected hippocampal circuit. Finally, we will examine how hilar mossy cell activity contributes to granule cell population activity using imaging and in vivo approaches. Together the results of these studies will provide fundamental insight into how distinct synaptic connectivity contributes to the activation of immature GCs and thus controls their participation in DG network activity. These results will provide novel insight into the function of adult neurogenesis, a dramatic form of brai plasticity that has become a therapeutic target for numerous pathological conditions.

Public Health Relevance

Neurogenesis persists in the adult hippocampus but it is not known how newly generated neurons contribute to hippocampal functions. The goal of this project is to determine how distinct synaptic connectivity endows newly generated neurons with capabilities that are different from the much larger population of mature neurons. The results of these studies will help determine how adult neurogenesis contributes to normal and pathological brain function.

Agency
National Institute of Health (NIH)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56NS064025-06
Application #
8809033
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lavaute, Timothy M
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Birmingham
State
AL
Country
United States
Zip Code
35294