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- All Subjects: Behavioral Neuroscience
- Creators: Bimonte-Nelson, Heather
Description
Women are now living longer than ever before, yet the age of spontaneous menopause has remained stable. This results in an increasing realization of the need for an effective treatment of cognitive and physiological menopausal and post-menopausal symptoms. The most common estrogen component of hormone therapy, conjugated equine estrogens (CEE; Premarin) contains many estrogens that are not endogenous to the human body, and that may or may not be detrimental to cognition (Campbell and Whitehead, 1977; Engler-Chiurazzi et al., 2011; Acosta et al., 2010). We propose the use of a novel treatment option in the form of a naturally-circulating (bioidentical) estrogen called estriol. Due to estriol’s observed positive effects on synaptic functioning and neuroprotective effects in the hippocampus (Ziehn et al., 2012; Goodman et al., 1996), a brain structure important for spatial learning and memory, estriol is promising as a hormone therapy option that may attenuate menopausal- and age- related memory decline. In the current study, we administered one of the three bioidentical estrogens (17β-Estradiol, 4.0 µg/day; Estrone, 8.0 µg/day; Estriol, 8.0 µg/day) or the vehicle polyethylene glycol by subcutaneous osmotic pump to ovariectomized Fisher-344 rats. We compared these groups to each other using a battery of spatial learning tasks, including the water radial-arm maze (WRAM), Morris water maze (MM), and delayed-match-to-sample maze (DMS). We found that all estrogens impaired performance on the WRAM compared to vehicle, while 17β-estradiol administration improved overnight forgetting performance for the MM. The estriol group showed no cognitive enhancements relative to vehicle; however, there were several factors indicating that both our estriol and estradiol doses were too high, so future studies should investigate whether lower doses of estriol may be beneficial to cognition.
ContributorsStonebarger, Gail Ashley (Author) / Bimonte-Nelson, Heather (Thesis director) / Knight, George (Committee member) / Engler-Chiurrazzi, Elizabeth (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor)
Created2015-05
Description
Hormone therapy (HT) containing 17beta-estradiol (E2) can greatly reduce physiological symptoms associated with declines in ovarian hormones that are seen with menopause. HT containing E2 has also been shown to play a beneficial role in cognitive function. There is discrepancy, however, surrounding which dose of E2 is the most optimal for cognition. A previous rodent behavioral study in our laboratory evaluated the effects of different doses of E2 on spatial memory performance, and results indicated that rats treated with a low E2 dose (0.3 g E2) made fewer working memory incorrect (WMI) errors, indicating enhanced spatial memory performance, compared to vehicle (0.1ml sesame oil)- and high E2 (3.0 g E2)- treated groups. This finding warranted the present investigation with the overarching aim to evaluate underlying neuromolecular mechanisms that may be modulating these cognitive effects. Both the insulin-like growth factor-1 receptor (IGF1-R) and extracellular regulated kinase (Erk) 2 have been observed to mediate E2-induced memory enhancements. We used the Western Blot to measure IGF1-R and activated Erk1/2 expression in brain regions involved in learning and memory, including the dorsal hippocampus, ventral CA1/CA2 hippocampus, entorhinal cortex, and perirhinal cortex. Results demonstrated a linear relationship between IGF1-R expression and administered E2 dose in the perirhinal cortex, whereby IGF1-R expression increased as the dose of E2 increased. Additionally, in the perirhinal cortex, IGF1-R expression tended to increase as activated Erk1 increased for all treatment groups. Further, number of WMI errors tended to decrease as IGF1-R expression and activated Erk1 expression in the perirhinal cortex tended to increase in the low E2 treatment group. Collectively, these findings suggest a downstream-dependent relationship between IGF1-R and activated Erk1 in the perirhinal cortex that may be contributing to the enhancements in spatial memory performance observed in animals in the low E2 treatment group. These findings are a crucial piece in the greater understanding of what underlying molecular mechanisms may be modulating a cognitively beneficial dose of E2, and further contribute to the search for a HT that would be beneficial for cognition in menopausal women.
ContributorsNeeley, Rachel Elizabeth (Author) / Bimonte-Nelson, Heather (Thesis director) / George, Andrew (Committee member) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Menopause is associated with a wide array of negative symptoms. As average lifespan increases due to advances in healthcare and technology, more women are spending a larger portion of their lives in a menopausal state low in estrogen and progesterone. Hormone therapies such as Conjugated Equine Estrogens (CEE) and the bioidentical estrogen, 17-estradiol (E2), are commonly prescribed to treat the negative symptoms of menopause. Our laboratory has previously shown that CEE has differential effects on cognitive ability depending on whether menopause is transitional (VCD) or surgical (ovariectomy, OVX). Further, the negative impact of CEE on cognitive function in a transitional ovary-intact model of menopause was associated with high levels of serum androstenedione; the primary hormone circulating in a follicle-deplete menopausal state. Here, we investigate the cognitive effects of these two common hormone therapies separately, and in conjunction with the hormone androstenedione, in a "blank-slate" OVX mouse model. We assessed cognitive ability using two behavioral tasks such at the Water Radial Arm Maze (WRAM, measuring spatial working and reference memory) and the Morris water maze (MM, measuring spatial reference memory). In the WRAM, every treatment group saw impaired performance compared to Vehicle but the combination group of E2 plus Androstenedione. In the MM, the combination group of E2 plus Androstenedione actually enhanced performance in the maze compared to every other comparable group. Translationally, these results suggest that CEE given in the presence of an androstenedione-dominant hormone milieu is impairing to cognition, E2 in this same manner is not. These results yield valuable insight into optimal hormone therapies for menopausal women.
ContributorsGranger, Steven Jay (Author) / Bimonte-Nelson, Heather (Thesis director) / Presson, Clark (Committee member) / Hiroi, Sheri (Committee member) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
Sports related concussions, or mild traumatic brain injuries (mTBI), have recently increased in prevalence, and thus gained a great deal of recognition from the public and the media. While the acute symptoms associated with concussions are well known, which include headaches, dizziness, vomiting, and fatigue, recent research has indicated that there can be severe chronic consequences of multiple conditions. Most notably, a disease called Chronic Traumatic Encephalopathy (CTE) has been linked to multiple mTBIs, which produces symptoms similar to Alzheimer's disease and dementia, in addition to personality changes, increased suicidality, and in some cases death. This knowledge has led the NFL to take steps to protect their players, and increase both the understanding and awareness of the problems associated with multiple concussions. This comes with many problems, however, as players and fans alike are quick to resist any type of change to the rules or policies present in football, in fear that it may damage the integrity of the game. The NFL is thus forced into a difficult position, and must balance public opinion and player safety. There are things that can be done, however, that do not threaten the game itself, such as investing in concussion research and safety equipment design that will more effectively protect the brain from concussions.
ContributorsAiello, Mimi Elizabeth (Author) / Olive, M. Foster (Thesis director) / Bimonte-Nelson, Heather (Committee member) / Camp, Bryan (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor)
Created2013-05
Description
Alzheimer’s disease (AD) is an irreversible brain disorder that plagues millions of people with no current cure. Current clinical research is slowly advancing to more definitive treatments in hopes of reducing the effects of progressive cognitive and behavioral decline, but none so far can slow AD’s onset. A brain area known as the nucleus incertus (NI) was recently discovered to potentially impact AD because of its connections to brain targets that degenerate; however, the NI’s role is unknown. This goal of this experiment was to use a transgenic mouse model (APP/PS1) that expresses AD pathology slowly as found in humans, and to test the mice in a variety of cognitive and anxiety assessments. Mice of both sexes and two different ages were used, with the first being young adult before AD pathology manifests (around 3-4 months old), and the second being around the cusp of when AD pathology manifests (late adult, 8-10 months old). The mice were tested in a variety of cognitive tasks that included the novel object recognition (NOR), Morris water maze (MWM), and the object placement (OP), with the latter being the focus of my thesis. Anxiety measures were taken from the open field (OF) and elevated plus maze (EPM) with the visible platform (VP) used to ensure mice could perform on the rigorous MWM task. In the OP, we found an age effect, where the older mice were less likely to explore the moved object during the OP compared to the younger mice; motor ability was unlikely to explain this effect. We did not find any significant age by genotype effects. These findings indicate that cognitive impairment only just started to affect the older cohort, since OP impairment was found on one measure and not another. Other measures currently being quantified will be helpful in understanding this data, and to see whether learning, memory, and anxiety are affected.
ContributorsDapon, Bianca (Author) / Conrad, Cheryl (Thesis director) / Bimonte-Nelson, Heather (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor)
Created2023-05
Description
The cerebellum is recognized for its role in motor movement, balance, and more recently, social behavior. Cerebellar injury at birth and during critical periods reduces social preference in animal models and increases the risk of autism in humans. Social behavior is commonly assessed with the three-chamber test, where a mouse travels between chambers that contain a conspecific and an object confined under a wire cup. However, this test is unable to quantify interactive behaviors between pairs of mice, which could not be tracked until the recent development of machine learning programs that track animal behavior. In this study, both the three-chamber test and a novel freely-moving social interaction test assessed social behavior in untreated male and female mice, as well as in male mice injected with hM3Dq (excitatory) DREADDs. In the three-chamber test, significant differences were found in the time spent (female: p < 0.05, male: p < 0.001) and distance traveled (female: p < 0.05, male: p < 0.001) in the chamber with the familiar conspecific, compared to the chamber with the object, for untreated male, untreated female, and mice with activated hM3Dq DREADDs. A social memory test was added, where the object was replaced with a novel mouse. Untreated male mice spent significantly more time (p < 0.05) and traveled a greater distance (p < 0.05) in the chamber with the novel mouse, while male mice with activated hM3Dq DREADDs spent more time (p<0.05) in the chamber with the familiar conspecific. Data from the freely-moving social interaction test was used to calculate freely-moving interactive behaviors between pairs of mice and interactions with an object. No sex differences were found, but mice with excited hM3Dq DREADDs engaged in significantly more anogenital sniffing (p < 0.05) and side-side contact (p < 0.05) behaviors. All these results indicate how machine learning allows for nuanced insights into how both sex and chemogenetic excitation impact social behavior in freely-moving mice.
ContributorsNelson, Megan (Author) / Verpeut, Jessica (Thesis director) / Bimonte-Nelson, Heather (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / School of Mathematical and Statistical Sciences (Contributor)
Created2024-05