The overall goal of this project is to understand the impact of early brain injury on subsequent brain plasticity. A common perception is that recovery from neonatal brain injury is augmented by plasticity of the immature brain. Yet often injury results in permanent neurologic deficits, highlighting the need for more detailed understanding of plasticity following injury. This proposal focuses on the most well studied model of cortical plasticity -- ocular dominance in the visual system of binocular mammals. Ocular dominance plasticity (ODP) refers to the change in strength of eye-specific inputs following monocular deprivation. A closely related condition in humans is known as amblyopia. An advantage of the model is recent progress identifying the factors controlling critical period timing, including maturation of cortical inhibitory circuits and myelination. The project uses a translational small animal (rat and mouse) model of very early hypoxic-ischemic brain injury. Using this model, we find that ODP is impaired. Visual cortical development is grossly normal in all but the most severely injured animals. Yet, impaired ODP is not an isolated finding, as plasticity in somatosensory cortex is also diminished. In this model, we have reported the selective vulnerability of subplate neurons, a transient population of neocortical neurons important for visual thalamocortical development. It is unclear why early subplate neuron death would restrict subsequent plasticity. However, early activity is transmitted into neocortex through transient circuits involving subplate neurons. Our hypothesis is that diminished cortical excitation, resulting from loss of subplate neurons, disrupts activity-dependent maturation and refinement of cortical circuits. Consistent with this idea, we find diminished and altered expression of cortical inhibitory neuronal markers following injury. With the development of this model, we are now positioned to investigate the role of specific plasticity mechanisms in recovery from neonatal brain injury. To accomplish this, our specific aims are: (1) determine the mechanism of altered inhibition following early HI and its relationship to impaired ODP and (2) measure the effect of disrupted myelination on ODP following early HI. ODP is quantified with intrinsic signal optical imaging. Inhibitory circuits and myelination are studied with histology, immunofluorescence and protein biochemistry. We will attempt to restore plasticity by specifically overcoming identified defects in cortical inhibition and myelination by pharmacologic or growth factor treatment, grafting of precursor cells, function blocking antibodies or the use of existing genetically modified mouse models. These experiments will offer fundamental insight into the normal role of subplate neurons in the maturation of cortical circuits and ODP. Understanding impaired plasticity will provide both a novel functional outcome measure and a model to guide strategies for regenerating functional cortical connections following brain injury.

Public Health Relevance

Brain injury in the newborn is a common problem following difficult or premature birth and in babies with congenital heart disease. The overall goal of this project is to understand the impact of newborn brain injury on subsequent brain plasticity, the ability of the brain to change by forming and modifying connections between neurons. Understanding plasticity following injury will provide both a new outcome measure and a model to guide therapy for recovering brain function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060896-03
Application #
7795704
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Hicks, Ramona R
Project Start
2008-07-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$301,130
Indirect Cost
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Mikhailova, Alexandra; Sunkara, Naveena; McQuillen, Patrick S (2017) Unbiased Quantification of Subplate Neuron Loss following Neonatal Hypoxia-Ischemia in a Rat Model. Dev Neurosci 39:171-181
Paredes, Mercedes F; James, David; Gil-Perotin, Sara et al. (2016) Extensive migration of young neurons into the infant human frontal lobe. Science 354:
Ranasinghe, Sumudu; Or, Grace; Wang, Eric Y et al. (2015) Reduced Cortical Activity Impairs Development and Plasticity after Neonatal Hypoxia Ischemia. J Neurosci 35:11946-59
Failor, Samuel; Nguyen, Vien; Darcy, Daniel P et al. (2010) Neonatal cerebral hypoxia-ischemia impairs plasticity in rat visual cortex. J Neurosci 30:81-92
Arnold, Thomas D; McQuillen, Patrick S (2010) From death to recovery following hypoxia ischemia: if TGFbeta is a central regulator, is integrin beta8 the switch? Neurotox Res 17:418-20
Spadafora, Ruggero; Gonzalez, Fernando F; Derugin, Nikita et al. (2010) Altered fate of subventricular zone progenitor cells and reduced neurogenesis following neonatal stroke. Dev Neurosci 32:101-13