Neonatal anesthesia-induced delay of axon pruning in hippocampus

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Project Summary Millions of human fetuses and infants are exposed every year to anesthetic drugs in doses that trigger widespread neuroapoptosis in the developing brains of rodents and non-human primates. Alarmingly, several clinical studies now link human infant anesthesia to cognitive deficits in later life. However, the adult mammalian brain has orders of magnitude more neurons that survive the insult than those that are deleted and why a young and pliable brain cannot recover from a brief anesthetic insult is not understood. A plausible hypothesis is that the surviving neurons form dysfunctional neural circuits. Indeed, neonatal exposure to anesthetic drugs deranges nearly every microscopic component of neural circuits, which, we hypothesize, compromises neural circuit function, synaptic morphology, and ultimately, cognition. For Specific Aim 1, we test the hypothesis that anesthetic drug interference with normal developmental axon pruning leads to neural circuit excitability in animals treated with ketamine as neonates. For Specific Aim 2, we test the hypothesis that ketamine-induced deficits in hippocampus-dependent memory and axonal pruning can be prevented through pharmacological enhancement of BDNF signaling pathways. During the tenure of the award, the applicant will benefit from a highly-tailored professional development curriculum that leverages the strengths of the University of Colorado, generally, and its Department of Anesthesiology, specifically. At the conclusion of the award, the applicant will have mastery of patch clamp electrophysiology, neurobehavioral, molecular, and morphological techniques that will help launch his career investigating the anesthesia effects on neural circuits. The applicant’s long-term goal is to identify safe and effective strategies that prevent anesthetic drugs from exerting deleterious effects, which will be a valuable contribution to the health and well-being of millions of infants and children worldwide.