Infants born premature are at risk for brain injury and long-term neurological and cognitive deficits. Currently, there is no treatment for preventing or treating premature brain injury and the neural mechanisms underlying the array of long-term neurological sequelae are poorly understood. Hypoxia is a risk factor for diffuse white matter injury (DWMI) and neuronal/axonal abnormalities. Previous work has shown that DWMI and decreased myelin caused by chronic sublethal hypoxia (CSH) in neonatal mice are prevented by deletion of A1 adenosine receptors (A1ARs), which are ubiquitously expressed in the brain. Thus, the adenosinergic system is an attractive target for therapies aimed at preventing and/or ameliorating the long-term effects of perinatal brain injury. However, the role of adenosine signaling in mediating the effects of hypoxia on long-term neural circuit function is unknown. We recently obtained preliminary data showing that CSH in neonatal mice causes lasting perturbations in axonal connectivity patterns and synaptic plasticity in the primary visual cortex (V1). Together, these phenotypes provide a unique opportunity to determine the window of vulnerability of the development and plasticity of specific cortical circuits to perinatal insults,and to establish whether A1ARs mediate the effects of neonatal hypoxia on long-term synaptic connectivity and plasticity. We hypothesize that cortical circuit connectivity and function in V1 are sensitive to the timing of hypoxic exposure and that A1ARs mediate the effects of neonatal hypoxia on synaptic connectivity, plasticity, and visual learning in V1. We will test our hypothesi through experiments in the following Specific Aims: (1) Determine how the timing and duration of neonatal hypoxia affect synaptic connectivity and plasticity in V1; and (2) Determine the extent to which A1ARs mediate the effects of hypoxia on axon connectivity and synaptic plasticity in V1. We anticipate that our findings will fill a critical knowledge gap regarding how the timing of perinatal insults affects the formation and long-term plasticity of cortical circuitr. Furthermore, they will provide new insights into the role of the adenosinergic system in premature brain injury and reveal potential therapeutic targets for the prevention and/or treatment of this injury and its long-term consequences.

Public Health Relevance

Infants born premature are at risk for brain injuries that cause a range of neurodevelopmental problems and long-term cognitive deficits. This project will fill a critical knowledge gap regarding how the formation and plasticity of cortical circuitry are affecte by perinatal insults and determine the extent to which adenosinergic signaling mediates these effects. Together, these studies will provide important new information on therapeutic strategies and targets for preventing or treating premature brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS091866-02
Application #
9035447
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Koenig, James I
Project Start
2015-04-01
Project End
2017-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Florida
Department
Pediatrics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611