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- Creators: Barrett, The Honors College
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
Rasopathies are a family of developmental syndromes that exhibit craniofacial abnormalities, cognitive disabilities, developmental delay and increased risk of cancer. However, little is known about the pathogenesis of developmental defects in the nervous system. Frequently, gain-of-function mutations in the Ras/Raf/MEK/ERK cascade (aka ERK/MAPK) are associated with the observed pathogenesis. My research focuses on defining the relationship between increased ERK/MAPK signaling and its effects on the nervous system, specifically in the context of motor learning. Motor function depends on several neuroanatomically distinct regions, especially the spinal cord, cerebellum, striatum, and cerebral cortex. We tested whether hyperactivation of ERK/MAPK specifically in the cortex was sufficient to drive changes in motor function. We used a series of genetically modified mouse models and cre-lox technology to hyperactivate ERK/MAPK in the cerebral cortex. Nex:Cre/NeuroD6:Cre was employed to express a constitutively active MEK mutation throughout all layers of the cerebral cortex from an early stage of development. RBP4:Cre, caMEK only exhibited hyper activation in cortical glutamatergic neurons responsible for cortical output (neurons in layer V of the cerebral cortex). First, the two mouse strains were tested in an open field paradigm to assess global locomotor abilities and overall fitness for fine motor tasks. Next, a skilled motor reaching task was used to evaluate motor learning capabilities. The results show that Nex:Cre/NeuroD6:Cre, caMEK mutants do not learn the motor reaching task, although they performed normally on the open field task. Preliminary results suggest RBP4:Cre, caMEK mutants exhibit normal locomotor capabilities and a partial lack of learning. The difference in motor learning capabilities might be explained by the extent of altered connectivity in different regions of the corticospinal tract. Once we have identified the neuropathological effects of various layers in the cortex we will be able to determine whether therapeutic interventions are sufficient to reverse these learning defects.
ContributorsRoose, Cassandra Ann (Author) / Newbern, Jason M. (Thesis director) / Olive, Foster (Committee member) / Bjorklund, Reed (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
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
Description
Traumatic brain injury (TBI)—sudden impact or acceleration trauma to the head—is a major cause of death and disability worldwide and is particularly amplified in pediatric cases. TBI is the leading cause of mortality and morbidity in children and adolescents. Adolescence is a critical time where the brain undergoes cognitive development and brain injury-induced disruptions to these processes can lead to life-long debilitating morbidities. The aim of this study was to determine if exercising spatial and contextual memory circuits using a novel rehabilitation strategy called Peg Forest Rehabilitation (PFR) could mitigate the onset of injury-induced cognitive deficits in juvenile rats subjected to diffuse TBI. The PFR aims to synthesize neuroplasticity-based enrichment to improve cognitive outcomes after TBI. We hypothesized that PFR treatment would mitigate the onset of brain injury-induced cognitive deficits and reduce neuroinflammation. Juvenile male Sprague-Dawley rats (post-natal day 35) were subjected to diffuse traumatic brain injury via midline fluid percussion injury or a control surgery. One-week post-injury, rats were exposed to PFR or cage control exploration (15 min/day). PFR allowed free navigation through random configuration of the peg-filled arena for 10 days over 2 weeks. Control rats remained in home cages in the center of the arena with the peg-board removed for 15 min/day/10 days. One-week post-rehabilitation (one-month post-injury), cognitive performance was assessed for short-term (novel object recognition; NOR), long-term (novel location recognition; NLR), and working (temporal order recognition; TOR) memory performance, calculated as a discrimination index between novel and familiar objects. Tissue was collected for immunohistochemistry and stained for ionized calcium binding proteins (Iba-1) to visualize microglia morphology, and somatostatin. PFR attenuated TBI-induced deficits on the NOR task, where the TBI-PFR treatment group spent significantly more time with the novel object compared with the familiar (*p=0.0046). Regardless of rehabilitation, brain-injured rats had hyper-ramified microglia in the hypothalamus indicated by longer branch lengths and more endpoints per cell compared with uninjured shams. Analysis of somatostatin data is ongoing. In this study, passive, intermittent PFR that involved dynamic, novel spatial navigation, prevented TBI-induced cognitive impairment in adolescent rats. Spatial navigation training may have clinical efficacy and should be further investigated.
ContributorsAftab, Umar (Author) / Rowe, Rachel K. (Thesis director) / Newbern, Jason M. (Thesis director) / Ortiz, J. Bryce (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05