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Systemic lupus erytematosus (SLE) is an autoimmune disease where the immune system is reactive to self antigens resulting in manifestations like glomerulonephritis and arthritis. The immune system also affects the central nervous system (known as CNS-SLE) leading to neuropsychiatric manifestations such as depression, cognitive impairment, psychosis and seizures.

Systemic lupus erytematosus (SLE) is an autoimmune disease where the immune system is reactive to self antigens resulting in manifestations like glomerulonephritis and arthritis. The immune system also affects the central nervous system (known as CNS-SLE) leading to neuropsychiatric manifestations such as depression, cognitive impairment, psychosis and seizures. A subset of pathogenic brain-reactive autoantibodies (BRAA) is hypothesized to bind to integral membrane brain proteins, affecting their function, leading to CNS-SLE. I have tested this BRAA hypothesis, using our lupus-mouse model the MRL/lpr mice, and have found it to be a reasonable explanation for some of the manifestations of CNS-SLE. Even when the MRL/lpr had a reduced autoimmune phenotype, their low BRAA sera levels correlated with CNS involvement. The correlation existed between BRAA levels to integral membrane protein and depressive-like behavior. These results were the first to show a correlation between behavioral changes and BRAA levels from brain membrane antigen as oppose to cultured neuronal cells. More accurate means of predicting and diagnosing lupus and CNS-SLE is necessary. Using microarray technology I was able to determine peptide sets that could be predictive and diagnostic of lupus and each specific CNS manifestation. To knowledge no test currently exists that can effectively diagnose lupus and distinguish between each CNS manifestations. Using the peptide sets, I was able to determine possible natural protein biomarkers for each set as well as for five monoclonal BRAA from one MRL/lpr. These biomarkers can provide specific targets for therapy depending on the manifestation. It was necessary to investigate how these BRAA enter the brain. I hypothesized that substance P plays a role in altering the blood-brain barrier (BBB) allowing these BRAA to enter and affect brain function, when bound to its neurokinin-1 receptor (NK-1R). Western blotting results revealed an increase in the levels of NK-1R in the brain of the MRL/lpr compared to the MRL/mp. These MRL/lpr with increased levels of both NK-1R and BRAA displayed CNS dysfunction. Together, these results demonstrate that NK-1R may play a role in CNS manifestations. Overall, the research conducted here, add to the role that BRAA are playing in CNS-lupus.
ContributorsWilliams, Stephanie (Author) / Hoffman, Steven A (Thesis advisor) / Conrad, Cheryl (Committee member) / Chen, Julian (Committee member) / Orchinik, Miles (Committee member) / Arizona State University (Publisher)
Created2011
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Description
Food is an essential driver of animal behavior. For social organisms, the acquisition of food guides interactions with the environment and with group-mates. Studies have focused on how social individuals find and choose food sources, and share both food and information with group-mates. However, it is often not clear how

Food is an essential driver of animal behavior. For social organisms, the acquisition of food guides interactions with the environment and with group-mates. Studies have focused on how social individuals find and choose food sources, and share both food and information with group-mates. However, it is often not clear how experiences throughout an individual's life influence such interactions. The core question of this thesis is how individuals’ experience contributes to within-caste behavioral variation in a social group. I investigate the effects of individual history, including physical injury and food-related experience, on individuals' social food sharing behavior, responses to food-related stimuli, and the associated neural biogenic amine signaling pathways. I use the eusocial honey bee (Apis mellifera) system, one in which individuals exhibit a high degree of plasticity in responses to environmental stimuli and there is a richness of communicatory pathways for food-related information. Foraging exposes honey bees to aversive experiences such as predation, con-specific competition, and environmental toxins. I show that foraging experience changes individuals' response thresholds to sucrose, a main component of adults’ diets, depending on whether foraging conditions are benign or aversive. Bodily injury is demonstrated to reduce individuals' appetitive responses to new, potentially food-predictive odors. Aversive conditions also impact an individual's social food sharing behavior; mouth-to-mouse trophallaxis with particular groupmates is modulated by aversive foraging conditions both for foragers who directly experienced these conditions and non-foragers who were influenced via social contact with foragers. Although the mechanisms underlying these behavioral changes have yet to be resolved, my results implicate biogenic amine signaling pathways as a potential component. Serotonin and octopamine concentrations are shown to undergo long-term change due to distinct foraging experiences. My work serves to highlight the malleability of a social individual's food-related behavior, suggesting that environmental conditions shape how individuals respond to food and share information with group-mates. This thesis contributes to a deeper understanding of inter-individual variation in animal behavior.
ContributorsFinkelstein, Abigail (Author) / Amdam, Gro V (Thesis advisor) / Conrad, Cheryl (Committee member) / Smith, Brian (Committee member) / Neisewander, Janet (Committee member) / Bimonte-Nelson, Heather A. (Committee member) / Arizona State University (Publisher)
Created2017
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Description
Body size plays a pervasive role in determining physiological and behavioral performance across animals. It is generally thought that smaller animals are limited in performance measures compared to larger animals; yet, the vast majority of animals on earth are small and evolutionary trends like miniaturization occur in every animal clade.

Body size plays a pervasive role in determining physiological and behavioral performance across animals. It is generally thought that smaller animals are limited in performance measures compared to larger animals; yet, the vast majority of animals on earth are small and evolutionary trends like miniaturization occur in every animal clade. Therefore, there must be some evolutionary advantages to being small and/or compensatory mechanisms that allow small animals to compete with larger species. In this dissertation I specifically explore the scaling of flight performance (flight metabolic rate, wing beat frequency, load-carrying capacity) and learning behaviors (visual differentiation visual Y-maze learning) across stingless bee species that vary by three orders of magnitude in body size. I also test whether eye morphology and calculated visual acuity match visual differentiation and learning abilities using honeybees and stingless bees. In order to determine what morphological and physiological factors contribute to scaling of these performance parameters I measure the scaling of head, thorax, and abdomen mass, wing size, brain size, and eye size. I find that small stingless bee species are not limited in visual learning compared to larger species, and even have some energetic advantages in flight. These insights are essential to understanding how small size evolved repeatedly in all animal clades and why it persists. Finally, I test flight performance across stingless bee species while varying temperature in accordance with thermal changes that are predicted with climate change. I find that thermal performance curves varied greatly among species, that smaller species conform closely to air temperature, and that larger bees may be better equipped to cope with rising temperatures due to more frequent exposure to high temperatures. This information may help us predict whether small or large species might fare better in future thermal climate conditions, and which body-size related traits might be expected to evolve.
ContributorsDuell, Meghan (Author) / Harrison, Jon F. (Thesis advisor) / Smith, Brian H. (Thesis advisor) / Rutowski, Ronald (Committee member) / Wcislo, William (Committee member) / Conrad, Cheryl (Committee member) / Arizona State University (Publisher)
Created2018
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Description
Estrogen-containing hormone therapy (HT) is approved for treatment of symptoms associated with menopause by the Food and Drug Administration. A common estrogen used in HT is 17β-estradiol (E2). Rodent models of menopause, and some clinical work as well, suggest a cognitively-beneficial role of E2. However, as of the 2017 statement

Estrogen-containing hormone therapy (HT) is approved for treatment of symptoms associated with menopause by the Food and Drug Administration. A common estrogen used in HT is 17β-estradiol (E2). Rodent models of menopause, and some clinical work as well, suggest a cognitively-beneficial role of E2. However, as of the 2017 statement released by the North American Menopause Society, HT is not currently advised for use as cognitive therapy in healthy, menopausal women, given that the data so far from existing clinical studies are not yet definitive. Indeed, the delivery of E2 treatment can be optimized to yield more consistent results on cognitive function, particularly considering that exogenously administered E2 gets rapidly metabolized and cleared from the body. Further, E2-containing HT must include a progestogen if prescribed to women with a uterus to oppose its undesired uterine stimulating effects, such as increased endometrial hyperplasia and cancer risks. Studies have shown that the addition of a progestogen to E2 treatment can attenuate the effects of E2 on cognition and brain variables associated with cognitive function. Thus, a brain-specific delivery platform of E2 treatment that would minimize the hormone’s effects in the periphery while maintaining the beneficial cognitive effects is desirable. To achieve this goal, my dissertation work bridged two distinct scientific fields – behavioral neuroendocrinology and polymeric drug delivery – with the overarching aim of targeting the delivery of E2 to the brain to achieve maximal cognitively-beneficial effects with minimal undesired uterine stimulation. This aim was addressed via three distinct delivery strategies: 1) combining E2 with a cognitively-beneficial progestogen, 2) encapsulating E2 in polymeric nanoparticles, and 3) solubilizing E2 using cyclodextrins for intranasal administration. Findings revealed that although all E2-containing treatments increased uterine horn weights, a marker of uterine stimulation, in middle-aged ovariectomized rats, some E2 treatment formulations yielded memory improvements, others were neutral in their effects on memory, and some impaired memory. Together, data from this dissertation set the stage for targeted E2 delivery research to optimize the cognitive therapeutic effects of E2 in the context of menopause while minimizing peripheral burden, leading to translationally relevant clinical implications for women’s health.
ContributorsPrakapenka, Alesia (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Conrad, Cheryl (Committee member) / Stabenfeldt, Sarah (Committee member) / Sirianni, Rachael (Committee member) / Arizona State University (Publisher)
Created2018
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Description
The current study investigated whether intermittent restraint stress (IRS) would impair fear extinction learning and lead to increased anxiety and depressive- like behaviors and then be attenuated when IRS ends and a post- stress rest period ensues for 6 weeks. Young adult, male Sprague Dawley rats underwent restraint stress using

The current study investigated whether intermittent restraint stress (IRS) would impair fear extinction learning and lead to increased anxiety and depressive- like behaviors and then be attenuated when IRS ends and a post- stress rest period ensues for 6 weeks. Young adult, male Sprague Dawley rats underwent restraint stress using wire mesh (6hr/daily) for five days with two days off before restraint resumed for three weeks for a total of 23 restraint days. The groups consisted of control (CON) with no restraint other than food and water restriction yoked to the restrained groups, stress immediate (STR-IMM), which were restrained then fear conditioned soon after the end of the IRS paradigm, and stress given a rest for 6 weeks before fear conditioning commenced (STR-R6). Rats were fear conditioned by pairing a 20 second tone with a footshock, then given extinction training for two days (15 tone only on each day). On the first day of extinction, all groups discriminated well on the first trial, but then as trials progressed, STR-R6 discriminated between tone and context less than did CON. On the second day of extinction, STR- IMM froze more to context in the earlier trials than compared to STR-R6 and CON. As trials progressed STR-IMM and STR-R6 froze more to context than compared to CON. Together, CON discriminated between tone and context better than did STR-IMM and STR-R6. Sucrose preference, novelty suppressed feeding, and elevated plus maze was performed after fear extinction was completed. No statistical differences were observed among groups for sucrose preference or novelty suppressed feeding. For the elevated plus maze, STR-IMM entered the open arms and the sum of both open and closed arms fewer than did STR- R6 and CON. We interpret the findings to suggest that the stress groups displayed increased hypervigilance and anxiety with STR-R6 exhibiting a unique phenotype than that of STR-IMM and CON.
ContributorsShah, Vrishti Bimal (Author) / Conrad, Cheryl (Thesis director) / Newbern, Jason (Committee member) / Judd, Jessica (Committee member) / School of Life Sciences (Contributor) / Sanford School of Social and Family Dynamics (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
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Description
Monoamine neurotransmitters (e.g., serotonin, norepinephrine, and dopamine) are powerful modulators of mood and cognitive function in health and disease. We have been investigating the modulation of monoamine clearance in select brain regions via organic cation transporters (OCTs), a family of nonselective monoamine transporters. OCTs are thought to complement the actions

Monoamine neurotransmitters (e.g., serotonin, norepinephrine, and dopamine) are powerful modulators of mood and cognitive function in health and disease. We have been investigating the modulation of monoamine clearance in select brain regions via organic cation transporters (OCTs), a family of nonselective monoamine transporters. OCTs are thought to complement the actions of selective monoamine transporters in the brain by helping to clear monoamines from the extracellular space; thus, assisting to terminate the monoamine signal. Of particular interest, stress hormones (corticosterone; CORT) inhibit OCT3-mediated transport of monoamine, to putatively lead to prolonged monoamine signaling. It has been demonstrated that stress levels of CORT block OCT3 transport in the rat hypothalamus, an effect that likely underlies the rapid, stress-induced increase in local monoamines. We examined the effect of chronic variable stress (CVS) on the development of mood disorders and OCT3 expression in limbic and hypothalamic regions of the rat brain. Animals subjected to CVS (14-days with random stressor exposure two times/day) showed reduced body weight gain, indicating that CVS was perceived as stressful. However, behavioral tests of anxiety and depressive-like behaviors in rats showed no group differences. Although there were no behavioral effects of stress, molecular analysis revealed that there were stress-related changes in OCT3 protein expression. In situ hybridization data confirmed that OCT3 mRNA is expressed in the hippocampus, amygdala, and hypothalamus. Analysis of Western blot data by two-way ANOVA revealed a significant treatment effect on OCT3 protein levels, with a significant decrease in OCT3 protein in the amygdala and hippocampus in CVS rats, compared to controls. These data suggest an important role for CORT sensitive OCT3 in the reduction of monoamine clearance during stress.
ContributorsBoyll, Piper Savannah (Author) / Orchinik, Miles (Thesis director) / Conrad, Cheryl (Committee member) / Talboom, Joshua (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
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Description
The stress response facilitates our ability to deal effectively with threatening situations, but exposure to severe or chronic stressors can lead to undesirable neural, physiological, and behavioral outcomes. Chronic stress is associated with structural changes in the rat hippocampus, with corresponding deficits in learning and memory. Recent studies have uncovered

The stress response facilitates our ability to deal effectively with threatening situations, but exposure to severe or chronic stressors can lead to undesirable neural, physiological, and behavioral outcomes. Chronic stress is associated with structural changes in the rat hippocampus, with corresponding deficits in learning and memory. Recent studies have uncovered an inherent neuroplasticity that allows the hippocampus to recover from these stress-induced neural changes. Underlying mechanisms likely involve several different cellular and molecular pathways. In order to gain a more comprehensive understanding of these pathways, we investigated differences in protein expression throughout the timeline of chronic stress and recovery. Male Sprague-Dawley rats were randomly assigned to chronic restraint stress for 6hr/d/10d or 6hr/d/21d, stress for 6hr/d/21d followed by a recovery period of no stress for 10 or 21 days, or a control group. The proteome from the hippocampus of these rats was sequenced using liquid chromatography tandem mass spectrometry (LC-MS/MS) and analyzed. We hypothesized that chronic stress alters interneuronal signaling in the hippocampus by enhancing or attenuating the expression of proteins responsible for synaptic plasticity (functional) and neuronal structure (morphology). So far we have found that structural proteins, such as alpha-internexin, homer protein homolog 3, neurofilament light, and vimentin were significantly altered by chronic stress and recovery. In contrast, proteins necessary for or associated with myelination such as 2',3'-cyclic-nucleotide 3'-phosphodiesterase, myelin-associated glycoprotein, myelin basic protein S, and myelin proteolipid protein were significantly downregulated by chronic stress. Collectively, these results will provide a resource for further investigations into the mechanisms of the brain's recovery from chronic stress.
ContributorsKachemov, Marketta Marilyn (Author) / Orchinik, Miles (Thesis director) / Pirrotte, Patrick (Committee member) / Conrad, Cheryl (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
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Description
Chronic stress often leads to cognitive deficits, especially within the spatial memory domain mediated by the hippocampus. When chronic stress ends and a no-stress period ensues (i.e., washout, WO), spatial ability improves, which can be better than non-stressed controls (CON). The WO period is often the same duration as the

Chronic stress often leads to cognitive deficits, especially within the spatial memory domain mediated by the hippocampus. When chronic stress ends and a no-stress period ensues (i.e., washout, WO), spatial ability improves, which can be better than non-stressed controls (CON). The WO period is often the same duration as the chronic stress paradigm. Given the potential benefit of a post-stress WO period on cognition, it is important to investigate whether this potential benefit of a post-stress WO period has long-lasting effects. In this project, chronic restraint (6hr/d/21d) in Sprague-Dawley rats was used, as it is the minimum duration necessary to observe spatial memory deficits. Two durations of post-stress WO were used following the end of chronic restraint, 3 weeks (STR-WO3) and 6 weeks (STR-WO6). Immediately after chronic stress (STR-IMM) or the WO periods, rats were tested on various cognitive tests. We corroborated past studies that chronic stress impaired spatial memory (STR-IMM vs CON). Interestingly, STR-WO3 and STR-WO6 failed to demonstrate improved spatial memory on a radial arm water maze task, performing similarly as STR-IMM. Performance outcomes were unlikely from differences in anxiety or motivation because rats from all conditions performed similarly on an open field task and on a simple object recognition paradigm, respectively. However, performance on object placement was unusual in that very few rats explored, suggesting some degree of anxiety or fear in all groups. One possible interpretation of the unusual results of the 3 week washout group may be attributed to the different spatial memory tasks used across studies or external factors from the study. Further exploration of these other factors led to the conclusion that they did not play a role and the STR-WO3 RAWM data were anomalous to other studies. This suggests that a washout period following chronic stress may not be fully understood.
ContributorsFlegenheimer, Aaron Embden (Author) / Conrad, Cheryl (Thesis director) / Bimonte-Nelson, Heather (Committee member) / Ortiz, J. Bryce (Committee member) / School of Life Sciences (Contributor) / School of Human Evolution and Social Change (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
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Description
The aim of this study was to determine whether IUD administration, with and without the presence of Levo, and with and without the presence of the ovaries, impacts cognition in a rat model. Rats received either Sham or Ovariectomy (Ovx) surgery (removal of the ovaries), plus either no IUD, a

The aim of this study was to determine whether IUD administration, with and without the presence of Levo, and with and without the presence of the ovaries, impacts cognition in a rat model. Rats received either Sham or Ovariectomy (Ovx) surgery (removal of the ovaries), plus either no IUD, a Blank IUD (without Levo), or a Levo-releasing IUD (Levo IUD), enabling us to evaluate the effects of Ovx and the effects of IUD administration on cognition. Two weeks after surgery, all treatment groups were tested on the water radial arm maze, Morris water maze, and visible platform task to evaluate cognition. At sacrifice, upon investigation of the uteri, it was determined that some of the IUDs were no longer present in animals from these groups: Sham\u2014Blank IUD, Ovx\u2014Blank IUD, and Sham\u2014Levo IUD. Results from the remaining three groups showed that compared to Sham animals with no IUDs, Ovx animals with no IUDs had marginally impaired working memory performance, and that Ovx animals with Levo IUDs as compared to Ovx animals with no IUDs had marginally enhanced memory performance, not specific to a particular memory type. Results also showed that Ovx animals with Levo IUDs had qualitatively more cells in their vaginal smears and increased uterine horn weight compared to Ovx animals with no IUDs, suggesting local stimulation of the Levo IUDs to the uterine horns. Overall, these results provide alternative evidence to the hypothesis that the Levo IUD administers Levo in solely a localized manner, and suggests that the possibility for the Levo IUD to affect reproductive cyclicity in ovary-intact animals is not rejected. The potential for the Levo IUD to exert effects on cognition suggests that either the hormone does in fact systemically circulate, or that the Levo IUD administration affects cognition by altering an as yet undetermined hormonal or other feedback between the uterus and the brain.
ContributorsStrouse, Isabel Martha (Author) / Bimonte-Nelson, Heather (Thesis director) / Glenberg, Arthur (Committee member) / Sirianni, Rachael (Committee member) / Conrad, Cheryl (Committee member) / School of Life Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2018-12
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Description
Chronic stress impairs spatial working memory, attention set-shifting, and response inhibition. The relationship between these functions and the potential underlying neurocircuitry, such as the medial prefrontal cortex (mPFC), needs further research to understand how chronic stress impacts these functions. This study focused on the infralimbic (IL) and prelimbic (PRL) regions

Chronic stress impairs spatial working memory, attention set-shifting, and response inhibition. The relationship between these functions and the potential underlying neurocircuitry, such as the medial prefrontal cortex (mPFC), needs further research to understand how chronic stress impacts these functions. This study focused on the infralimbic (IL) and prelimbic (PRL) regions of the mPFC, to examine its involvement in two behavioral tasks, fixed minimum interval (FMI) and radial arm water maze (RAWM), following chronic stress, and the relationship between the two paradigms. A previous study failed to find a significant correlation between spatial working memory and response, both functions mediated by the PFC, even though chronic stress disrupted both outcomes. Thus, the purpose of this study was to investigate the functional activation of the mPFC, following chronic stress in these two paradigms, in order to gain an understanding of the neurocircuitry involved within this region. The behavioral outcomes were performed prior to my involvement in the project, and the results corroborate previous findings that chronic stress impairs response inhibition on FMI and spatial working memory on RAWM. My honors thesis involved quantifying the immunohistochemistry-stained tissue to assess the functional activation of the mPFC. Over the course of six months, my work involved identifying the border between IL and PRL regions by overlaying captured images of tissues, starting at a lower magnification of 40x. Afterwards, images were recaptured at higher magnifications (100x) to quantify Fos-like counts of functional activation. No overt changes were found following chronic stress in Fos-like counts after performance on FMI or RAWM. However, response inhibition on the FMI task showed a relationship with the IL function; non-stressed rats displayed a positive correlation between response inhibition and Fos-like profiles. In contrast, chronically stressed rats revealed a negative correlation between response inhibition and Fos-like profiles. The IL cortex is revealed to facilitate extinction of a learned behavior. Thus, these results present a possible interpretation that there is an association, non-stressed rats suppressing a previously learned response, being formed.
ContributorsLe, Brittany Quynh (Author) / Conrad, Cheryl (Thesis director) / Sanabria, Federico (Committee member) / Judd, Jessica (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05