The Effects of Anesthetic and Sedative Exposure on Brain Development

PROJECT SUMMARY/ABSTRACT A large body of animal model evidence supports the conclusion that lengthy early life exposure to anesthetic and sedative drugs (ASDs) can impair the development of brain circuitry such that the organism exhibits lasting impairments in a range of neurologic functions. If ASD exposure has similar consequences for the developing human brain this poses a major challenge for public health, as tens of thousands of children receive medical care each year in the U.S. that is dependent on these medications. The clinical literature on this topic is comprised of a few clinical trials focused on determining whether short exposures in healthy children are safe and many diverse epidemiological investigations, and it does not allow for any clear conclusions about the concerns raised by animal studies, particularly given the confounds of surgery and co- morbid disease. There are important knowledge gaps in our understanding of the putative neurotoxicity of ASDs, which the research program described in this proposal is designed to address. First, given the substantial differences between animal and human neurobiology, it is unknown whether ASDs act on human brain development to impair processes that are critical for the formation of neural circuitry and ongoing during the window of vulnerability in humans. Second, the extensive investigations in animal models have not yet generated a coherent understanding of a fundamental underlying molecular mechanism by which a limited exposure to ASDs could have lasting, harmful effects on brain development that are translatable between animal models and humans. The broad, long-term objective of this R35 MIRA proposal is to use cutting-edge translational laboratory approaches in neuroscience to address the fundamental knowledge gap surrounding whether ASD developmental neurotoxicity that is observed in animals poses a risk to human brain health. To accomplish this goal we will conduct studies of the effects of ASDs on the formation of synapses and myelin, both of which are putatively vulnerable processes that are critical for the development of neural circuitry, in a three-dimensional model of developing human brain tissue. We will also conduct studies in both rodent and human brain development model systems to determine whether the lasting effects of ASDs on the mechanistic/mammalian target of rapamycin signaling system represent an overarching mechanism to explain ASD neurotoxicity. The work described in this proposal is designed to have an immediate and lasting effect on our understanding of the impact of ASD exposure on brain health, to provide needed insights to move this field forward, and additionally to contribute broadly to the field of neurotoxicity during development.