The hormone oxytocin has several adaptive functions at birth. The experiments proposed here stem from both exciting new research describing oxytocin's neuroprotective role for the fetal brain at birth and recent studies indicating that normal perineuronal net (PNN) architecture is essential for proper cognitive and emotional processing. PNNs are extracellular matrix complexes that enwrap fast-spiking, parvalbumin-positive interneurons (PVIs) and provide synaptic and network stability. While PNNs protect neurons against oxidative damage, PNNs themselves are sensitive to oxidative stress during development and their degradation is associated with altered interneuron circuitry, as well as enhanced microglial activation. Importantly, aberrant PNN structure and interneuron circuitry, as well as exaggerated microglial activation, are linked with neurodevelopmental disorders, psychiatric disorders and cognitive dysfunction. Interestingly, oxytocin signaling at birth buffers the fetal brain against oxidative stress, suggesting that this hormone may protect developing PNNs/PVIs. The regular use of synthetic oxytocin (sOT; Pitocin) to induce or augment labor, as well as the common occurrence of pre-labor cesarean sections, alter fetal exposure to oxytocin during delivery. However, how these OT-related birth manipulations affect the development of neural architecture of offspring remains largely unexplored in both animal models and humans. Because of OT's neuroprotective role, we hypothesize that OT-related manipulations at birth alter oxidative stress exposure and PNN formation.
In Aim 1, we will examine the dose-dependent effects of sOT administration at birth on oxidative stress and microglial activation, postnatal development of PVIs and PNNs, and social behavior within offspring.
In Aim 2, we will determine a) if a pre-labor cesarean delivery increases fetal oxidative stress exposure and microglial activation, disrupts postnatal development of PVIs and PNNs, and alters social behavior within offspring and b) if perinatal administration of OT shortly after a pre-labor C-section can rescue the predicted neural and social behavioral changes. The purpose of this proposal is to determine whether birth-related interventions that modulate oxytocin signaling during delivery alter a specific neural mechanism (PNN/PVI formation). Data from this study will inform our current understanding of the normal development of neural architecture and aid in the evaluation of treatments used to manipulate the birth process.
The hormone oxytocin is a potent anti-inflammatory molecule that provides neuroprotection to fetal brain tissue by minimizing oxidative stress exposure at birth. An increase in oxidative stress during early brain development can alter the formation of perineuronal nets (PNNs), which are brain extracellular matrixes that encase parvalbumin inhibitory neurons and are increasingly recognized for their importance in providing synaptic stability that is necessary for proper cognitive and emotional processing. The experiments proposed here use a rodent model to evaluate how birth interventions, which serve to alter the concentration of oxytocin at birth, affect oxidative stress exposure, microglia-mediated inflammation and the development of PNN architecture, so as to inform the development of methods to optimize the human delivery process and long-term neural outcomes for offspring.
