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Sex differences in stress responsivity, glucocorticoid signaling, and disease

Nguyen, Elizabeth T
http://rave.ohiolink.edu/etdc/view?acc_num=ucin156327275069323

Abstract Details

2019, PhD, University of Cincinnati, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary.
Excessive glucocorticoid (cortisol, corticosterone) secretion is associated with depression and Alzheimer’s disease (AD). Glucocorticoids act on low-affinity mineralocorticoid (MR) and high-affinity glucocorticoid (GR) receptors to regulate endocrine, mood, and cognitive processes. Previous findings from our laboratory indicate sex differences in central glucocorticoid signaling in rats and mice in response to stress, which may in part explain the female-biased prevalence in depression and AD. Given the deleterious consequences of hypercortisolemia, GR modulators are being advanced as therapeutics for depression and AD. While preclinical work with GR targeting compounds seems promising, the majority of studies investigating their efficacy have relied on male rodents. Therefore, the goal of this dissertation was to investigate whether GR targeting compounds modulate endocrine, behavioral (i.e., depression-like, cognitive), and brain plasticity in a sex-dependent manner. We hypothesized that sex differences in the inherent organization of stress-related neurocircuitry underlie sex differences in the development of stress-related disorders (i.e., depression, AD) and associated treatment. First, we evaluated the impact of a newly developed compound, CORT118335 (GR/MR modulator), or the tricyclic antidepressant imipramine, on endocrine, behavioral, and central stress responsivity in adult male and female rats. While CORT118335 decreased endocrine stress responses to two stressors (restraint, forced swim) in both sexes, it had no effect on depression-like behavior. CORT118335 attenuated stress-induced neural activation (c-Fos) in the hippocampus in males, but not females, and increased hypothalamic c-Fos in females only. In contrast, imipramine reduced depression-like behavior in both sexes but had no effect on corticosterone levels. Unlike CORT118335, imipramine reduced stress-induced hippocampal and basolateral amygdala c-Fos in both sexes, but increased central amygdala c-Fos only in females. These findings demonstrate sex differences in the corticolimbic stress circuitry even in the face of similar endocrine and behavioral phenotypes. AD is associated with hypercortisolemia and there is a female bias for earlier disease onset and increased severity in AD. Thus, our intended goal for the final study was to determine if CORT118335 (administered during the prodromal state) prevents or attenuates AD-related pathology in young 3xTg-AD mice in a sex-dependent manner. However, the AD phenotype was not robust in male 3xTg mice at the targeted age, precluding completion of this goal. We assessed corticosterone stress responses in male and female 3xTg mice relative to their genetic background controls. In the first cohort, only 3xTg females exhibited a heightened corticosterone stress response and social memory impairment. However, 3xTg mice of both sexes showed depression-associated behavior. In the second cohort, the heightened corticosterone stress response in 3xTg females was not accompanied by social memory deficits nor a depression-associated phenotype. These findings suggest that enhanced corticosterone responsivity in female 3xTg mice is insufficient to induce these behavioral phenotypes. Finally, our findings suggest that alterations in GR expression across corticolimbic brain regions may be associated with AD pathology in a sex-dependent manner. Overall, we demonstrate sex differences in the corticolimbic stress circuitry with pharmacological and genetic manipulations, which may have important implications for sex differences in the treatment of stress-related diseases.
Christina Gross, Ph.D. (Committee Chair)
Teresa Reyes, Ph.D. (Committee Member)
Kim Seroogy, Ph.D. (Committee Member)
Matia Solomon, Ph.D. (Committee Member)
Stephen Woods, Ph.D. (Committee Member)
216 p.
Neurology
corticosterone; hypothalamic-pituitary-adrenal axis; Alzheimer disease; depression; CORT118335; 3xTg

Recommended Citations

Citations

  • Nguyen, E. T. (2019). Sex differences in stress responsivity, glucocorticoid signaling, and disease [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin156327275069323

    APA Style (7th edition)

  • Nguyen, Elizabeth. Sex differences in stress responsivity, glucocorticoid signaling, and disease. 2019. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin156327275069323.

    MLA Style (8th edition)

  • Nguyen, Elizabeth. "Sex differences in stress responsivity, glucocorticoid signaling, and disease." Doctoral dissertation, University of Cincinnati, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin156327275069323

    Chicago Manual of Style (17th edition)

ucin156327275069323
285
© 2019, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.