Depression affects approximately 7% of adults in the US annually and is one of the most common mental disorders. One striking
aspect of this disorder, is that it affects women at about twice the rate as compared to men. Furthermore, women with cardiovascular
diseases are more likely to experience depression as compared to male counterparts. Thus, women with cardiovascular complications
represent an extremely vulnerable population for mood disorder. Given the disparity in depression prevalence, it is not surprising that
women are also more likely to take antidepressant treatments as compared to men. While the dose of the antidepressant prescribed is
similar across the board, there is mounting evidence that the efficacy of and sensitivity to these treatments differ between the sexes.
However, the majority of preclinical investigations into the effectiveness and biochemical mechanisms of antidepressants have been
conducted in male subjects. This is a serious gap in our knowledge, and investigations into the mechanisms underlying differences in
depression prevalence and antidepressant response is imperative. As such, this dissertation aimed to identify potential peripheral and
neural changes associated with onset of depression in females with cardiovascular disease, and to examine the neural mechanisms underlying
the sex differences in sensitivity to antidepressants. There is substantial evidence that depression is experienced at a much higher rate
in individuals with chronic conditions, such as cardiovascular disease. Within this population, women with cardiovascular diseases
represent an extremely vulnerable population for mood disorder, comorbid for these conditions at about twice the rate as compared to men.
Despite the well-established comorbidity, the mechanisms linking these disorders remain elusive. The first chapter of this dissertation
aimed to identify the expression of core behavioral features of mood disorder in female mice bearing a knock-in sarcomeric mutation, which
is exhibited in human hypertrophic cardiomyopathy (HCM). We then investigated peripheral physiological indicators of stress in these mice,
and discovered significant adrenal gland hypertrophy and a dominant sympathetic nervous system tone. Through the use of magnetic resonance
imaging, we found reduced volume in mood-related brain regions in females with HCM. We also observed significant reductions in hippocampal
neurotrophic signaling markers in females with HCM as compared to controls. These results suggest that prolonged systemic HCM stress is
central to mood disorder expression; possibly through induction of structural and functional brain changes. In direct contrast to the
negative impact of stress/depression on the structure and function of the brain, many antidepressants reverse these changes and promote
neurogenesis. In recent years, ketamine has shown great promise as an antidepressant. A single infusion can exert effects within hours of
treatment, and this rapid action is a unique feature of ketamine. Most antidepressants need to be taken for weeks to months to exert
therapeutic effects, and often the first medication prescribed is not effective. Ketamine represents a great advancement in the field,
especially for individuals suffering from depression and cardiovascular dysfunction. In this population, the use of ketamine could
circumvent the potential for negative interactions between cardiac medications and chronic antidepressants. Since females are more likely
to take antidepressants as compared to males, we wanted to examine how the males and females differed in behavioral and neurochemical
responses to ketamine. Our group and others have previously reported that female rodents are more sensitive to the antidepressant-like
effect of ketamine. There is some evidence that ovarian hormones may promote sensitivity to antidepressants, yet the precise molecular
mechanism of females’ heightened sensitivity to ketamine remains unclear. In order to fill these critical gaps in our knowledge, the
second chapter of this dissertation aimed to determine the role of endogenous ovarian hormones and their respective receptor subtypes to
promote ketamine sensitivity. Behavioral responses to ketamine were examined in males, females in diestrus 1 (D1, low hormone), and
females in proestrus (Pro, high hormone) using the forced swim test. Males and D1 females exhibited similar sensitivity, while Pro females
responded to doses of ketamine that were subthreshold for effects in male and D1 counterparts. Through the use of selective estrogen
receptor modulators (SERMS), we examined the role of estrogen receptor subtypes (ERα and ERβ) and progesterone receptors (PR) to promote
ketamine sensitivity. We found that D1 females treated with ERα and ERβ SERMS responded to ketamine treatment, which suggests that
estrogen action at these receptors may enhance ketamine sensitivity. Another aim of chapter two was to determine if the molecular
mechanisms previously shown to mediate ketamine’s antidepressant effects in male rodents also apply to females. Since many of the rapid
intracellular signaling cascades initiated by ketamine are also influenced by ovarian hormones (e.g., brain-derived neurotrophic factor),
we used Western blot to investigate the expression and activation of their shared targets. We confirmed previous reports in males that
ketamine activated a variety of neurotrophic signaling cascades in the prefrontal cortex and hippocampus, and extended them to include D1
and Pro females. As a first step towards identifying the neural mechanism of Pro females’ sensitivity, we found that these females
exhibited activation of Akt and CaMKIIα in response to a dose of ketamine that only they were sensitive to. While these results need to be
confirmed in vivo, together they suggest that ovarian hormones increase behavioral sensitivity to ketamine by enhancing ketamine’s effects
on PI3K and CaMKIIα signaling within mood-related brain regions. These studies examined the expression and molecular mechanisms of mood
disorder-like behaviors in a mouse model of cardiovascular dysfunction. We focused on females with HCM, since they represent an especially
vulnerable population for mood disorder. We also investigated the hormonal and biochemical contributors to sex differences in sensitivity
to ketamine. This work lays a foundation for future investigation of the effectiveness of ketamine to reverse depression-associated
features in females with HCM. By targeting the natural flux in ovarian hormones, it may be possible to safely and effectively treat these
females with a low dose of ketamine. / A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the
Doctor of Philosophy. / Fall Semester 2016. / November 21, 2016. / Depression, Diastolic Dysfunction, Estrogen, Hypertrophy Cardiomyopathy, Ketamine, Sex
differences / Includes bibliographical references. / Mohamed Kabbaj, Professor Directing Dissertation; Thomas C. S. Keller, University Representative;
Elaine M. Hull, Committee Member; Jose R. Pinto, Committee Member; Zuoxin X. Wang, Committee Member.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_405652 |
| Contributors | Dossat, Amanda Marie (authoraut), Kabbaj, Mohamed (professor directing dissertation), Keller, Thomas C. S. (university representative), Hull, Elaine M. (committee member), Pinto, Jose R. (Jose Renato) (committee member), Wang, Zuoxin (committee member), Florida State University (degree granting institution), College of Medicine (degree granting college), Department of Biomedical Sciences (degree granting departmentdgg) |
| Publisher | Florida State University, Florida State University |
| Source Sets | Florida State University |
| Language | English, English |
| Detected Language | English |
| Type | Text, text |
| Format | 1 online resource (143 pages), computer, application/pdf |
| Rights | This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). The copyright in theses and dissertations completed at Florida State University is held by the students who author them. |
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