Date of Award

January 2013

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Flora M. Vaccarino

Subject Area(s)

Neurosciences, Medicine, Genetics

Abstract

Chronic perinatal hypoxia causes a significant loss of total brain volume, brain weight and cortical neuron number. These measures are completely reversed following recovery in normoxic conditions. Yet, the cellular and molecular mechanisms underlying this plasticity are not well understood. Here, we show that hypoxia from postnatal days 3 (P3) to 10-11 causes a 30% decrease in cortical neurons and a 24% decrease in cortical volume. Excitatory neuron numbers were completely recovered one month after the insult, but the mice showed a residual deficit in GABAergic interneurons. In contrast, hypoxic mice carrying a disrupted fibroblast growth factor receptor-1 (Fgfr1) gene in GFAP+ cells [Fgfr1 conditional knock-out (cKO)], showed a persistent loss of excitatory cortical neurons and an increased interneuron defect. Labeling proliferating progenitors at P17-18 revealed increased generation of cortical NeuN+ and Tbr1+ neurons in wild-type mice subjected to hypoxic insult, whereas Fgfr1 cKO failed to mount a cortical neurogenetic response. Hypoxic wild-type mice also demonstrated a twofold increase in cell proliferation in the subventricular zone (SVZ) at P17-18 and a threefold increase in neurogenesis in the olfactory bulb (OB) at P48-49, compared with normoxic mice. In contrast, Fgfr1 cKO mice had decreased SVZ cell proliferation and curtailed reactive neurogenesis in the OB. Thus, the activation of Fgfr1 in GFAP+ cells is required for neuronal recovery after perinatal hypoxic injury. In contrast, there is incomplete recovery of inhibitory neurons following injury, which may account for persistent behavioral deficits in adult mice following early perinatal injury.

Comments

This is an Open Access Thesis.

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