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A Tale of Two Cell Populations: Anesthetic Effects on Immature Dentate Granule Cells and Cortical Interneurons

Hofacer, Rylon D
http://orcid.org/0000-0003-2393-8774
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1491561814934545

Abstract Details

2017, PhD, University of Cincinnati, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary.
Anesthetic drugs significantly increase neuronal cell death in subcortical and cortical regions of the early postnatal rodent brain. Additionally, rodent pups treated with anesthesia during this sensitive age period develop cognitive deficits that persist into adulthood. The pathology underlying the cognitive impairment observed in rodent models is believed to be increased cell death caused by anesthesia, but additional studies are needed to determine differences in the viability of specific neuron subtypes, neural circuit formation, and neural circuit function in order to fully understand the impact of anesthesia on the developing mammalian brain. Advancing our knowledge of these side effects is important to public health, as recent epidemiological clinical studies have discovered a similar relationship between pediatric patient age at the time of anesthesia treatment and an increased risk for developing cognitive deficits. The studies contained in this dissertation address these challenges by using cell labeling strategies that mark specific neuron subpopulations in the brain. In the first study, the thymidine analog bromodeoxyuridine (BrdU) is used to label newly generated dentate granule cells in the adolescent and young adult mouse brain in order to determine the relationship between neuron age and vulnerability to anesthetic drugs. In addition to that approach, traditional immunohistochemistry was applied to examine anesthesia-induced cell death in populations of phenotypically immature and mature dentate granule cells. The second study used a transgenic labeling strategy with the Dlx5/6EGFPcre transgenic mouse to examine the vulnerability of cortical interneuron precursors in the highly sensitive developing murine neocortex. Cortical interneuron development was analyzed and described in adult study animals by immunostaining with antibodies for parvalbumin- (PV) and somatostatin- (SST) expressing cortical interneurons. Additionally, mature cortical interneuron function was challenged by using the excitatory chemoconvulsant pentylenetetrazole (PTZ) and an electroencephalogram (EEG) recording approach. The results of these studies demonstrate that anesthesia preferentially targets immature neuron populations in the neonatal, adolescent, and young adult brain. Specifically, we report that anesthesia significantly increases cell death in a population immature, post-mitotic dentate granule cells less than 15 days of age in the adolescent and young adult dentate gyrus. In the neonatal murine neocortex, we found a significant increase in cell death detected in Dlx5/6-derived cortical interneuron precursors in the ten day old (P10) superficial layer II/III of the motor cortex. This loss of cortical interneurons resulted in a decreased density of PV+ interneurons in superficial layer II/III of the mature motor cortex, as well as increased spindle wave bursts following a PTZ challenge. Considered together, these studies provide evidence that neuronal vulnerability to anesthetic toxicity is independent of subject age and are instead dependent upon the maturational stage of the neuron. Furthermore, anesthesia-induced loss of cortical interneuron precursors is permanent, and this loss is detectable in mature PV+ density and cortical inhibitory function.
Kim Seroogy, Ph.D. (Committee Chair)
Robert C. Coghill, Ph.D. (Committee Member)
Steve Danzer, Ph.D. (Committee Member)
Christina Gross, Ph.D. (Committee Member)
Andreas Loepke, M.D.Ph.D. (Committee Member)
131 p.
Neurology
Neuroscience; Anesthesia; Development; Interneurons; Cortex

Recommended Citations

Citations

  • Hofacer, R. D. (2017). A Tale of Two Cell Populations: Anesthetic Effects on Immature Dentate Granule Cells and Cortical Interneurons [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1491561814934545

    APA Style (7th edition)

  • Hofacer, Rylon. A Tale of Two Cell Populations: Anesthetic Effects on Immature Dentate Granule Cells and Cortical Interneurons. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1491561814934545.

    MLA Style (8th edition)

  • Hofacer, Rylon. "A Tale of Two Cell Populations: Anesthetic Effects on Immature Dentate Granule Cells and Cortical Interneurons." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1491561814934545

    Chicago Manual of Style (17th edition)

ucin1491561814934545
157
© 2017, some rights reserved.Creative Commons License A Tale of Two Cell Populations: Anesthetic Effects on Immature Dentate Granule Cells and Cortical Interneurons by Rylon D Hofacer is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.