Martynyuk Laboratory: Neurosciences in Anesthesiology

Our Current & Long-Term Goals

• Our studies, funded by the NIH, are focused on testing the following hypotheses:
  • The GABAergic general anesthetics (GAs), by acting via the GABA type A receptor mechanism, induce stress- and endocrine disruptor-like effects in neonatal and young adults rats.
  • They induce two distinct types of long-term adverse effects: neuroendocrine effects (the somatic effects) and epigenetic reprogramming of germ cells (the germ cell effects). The latter may pass neurobehavioral abnormalities to male offspring.
  • Compared to the somatic cells, the germ cells may be more sensitive to the deleterious effects of GAs, raising the possibility that the offspring may be affected even when levels of anesthesia are not harmful to the exposed parents.
• Our long-term goal is to develop translational strategies to study and mitigate long-term adverse effects of general anesthesia in humans.

Our Strategy

We test the roles of changes in GABA_AR signaling, neuroendocrine functioning, and epigenetic regulations at the time of anesthesia in intergenerational effects of GABAergic anesthetics administered to neonatal and young adult rats.

Our Techniques

We employ a wide spectrum of techniques from molecular biology and patch-clamp electrophysiology to different behavioral paradigms in rodents.

Our Findings

Our most recent findings provide the first experimental evidence that male and female Sprague-Dawley rats exposed to sevoflurane on postnatal days 56, 58, and 60 had an epigenetically altered (hypermethylated) germ cell gene for the neuron-specific K⁺-2Cl^– (KCC2) Cl^– exporter, measured 3 months later (Ju et al., 2019; see also example 6).

Notably, the Kcc2 gene was hypermethylated and exhibited reduced expression in the brains of the male but not female offspring of the exposed parents. These changes in the Kcc2 gene were accompanied by behavioral deficiencies. Contrary to the generally accepted view that adults are largely resilient to such adverse effects of GAs, exposed young adult males, but not females, also developed long-term neuroendocrine and behavioral deficiencies, including reduced expression of the hypothalamic and hippocampal Kcc2 gene.

These results, along with our recently published similar, but not identical, findings in rats that were neonatally exposed to sevoflurane (Ju et al., 2018; see also example 5) point to epigenetic reprogramming of parental germ cells in transmitting adverse effects of sevoflurane exposure to the next generation.

List of our publications in PubMed

Examples of our findings can be seen by clicking on the following hyperlinks:

• Examples Part 1
• Examples Part 2
• Examples Part 3
• Examples Part 4
• Examples Part 5
• Example Part 6

Our Current Team

• Ling-sha Ju, MD
• Alexander J. Gomez
• Jordan D. Hacker
• Adithi Jeevan
• Emily McFarlane
• Kasey M. Permenter
• Regina Pina Martin
• Treasure A. Ray
• Alec Szatkowski

Faculty Involved in Our Research

• Nikolaus Gravenstein, MD……………..Professor, Anesthesiology
• Tim Morey, MD……………………………..Professor, Anesthesiology
• Christoph Seubert, MD, PhD………….Professor, Anesthesiology

Our Collaborators

• Jim Resnick, PhD, Department of Molecular Genetics and Microbiology, University of Florida
• Barry Setlow, PhD, Department of Psychiatry, University of Florida
• Paul Cooke, PhD, Department of Physiological Sciences, University of Florida
• Jia-Qiang Zhang, MD, Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China
• Jian-Jun Yang, MD, PhD, Department of Anesthesiology, First affiliated hospital of Zhengzhou University, Zhengzhou, Henan, China
• Mu-Huo Ji, MD, Department of Anesthesiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China

Join the Team!

*We currently have an open Lab tech or Postdoc position to work on an NIH funded project investigating heritable effects of general anesthetics in rodent models.

We welcome undergraduates, residents, and faculty who would like to contribute to our research.