Matching Items (31)
Description
Chronic restraint stress impairs hippocampal-mediated spatial learning and memory, which improves following a post-stress recovery period. Here, we investigated whether brain derived neurotrophic factor (BDNF), a protein important for hippocampal function, would alter the recovery from chronic stress-induced spatial memory deficits. Adult male Sprague-Dawley rats were infused into the hippocampus with adeno- associated viral vectors containing the coding sequence for short interfering (si)RNA directed against BDNF or a scrambled sequence (Scr), with both containing the coding information for green fluorescent protein to aid in anatomical localization. Rats were then chronically restrained (wire mesh, 6h/d/21d) and assessed for spatial learning and memory using a radial arm water maze (RAWM) either immediately after stressor cessation (Str-Imm) or following a 21-day post-stress recovery period (Str-Rec). All groups learned the RAWM task similarly, but differed on the memory retention trial. Rats in the Str-Imm group, regardless of viral vector contents, committed more errors in the spatial reference memory domain than did non-stressed controls. Importantly, the typical improvement in spatial memory following recovery from chronic stress was blocked with the siRNA against BDNF, as Str-Rec-siRNA performed worse on the RAWM compared to the non-stressed controls or Str-Rec-Scr. These effects were specific for the reference memory domain as repeated entry errors that reflect spatial working memory were unaffected by stress condition or viral vector contents. These results demonstrate that hippocampal BDNF is necessary for the recovery from stress-induced hippocampal dependent spatial memory deficits in the reference memory domain.
ContributorsOrtiz, J. Bryce (Author) / Conrad, Cheryl D. (Thesis advisor) / Olive, M. Foster (Committee member) / Taylor, Sara (Committee member) / Bimonte-Nelson, Heather A. (Committee member) / Arizona State University (Publisher)
Created2013
Description
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
Description
Chronic stress results in functional and structural changes to the hippocampus. Decades of research has led to insights into the mechanisms underlying the chronic stress-induced deficits in hippocampal-mediated cognition and reduction of dendritic complexity of hippocampal neurons. Recently, a considerable focus of chronic stress research has investigated the mechanisms behind the improvements in hippocampal mediated cognition when chronic stress ends and a post-stress rest period is given. Consequently, the goal of this dissertation is to uncover the mechanisms that allow for spatial ability to improve in the aftermath of chronic stress. In chapter 2, the protein brain derived neurotrophic factor (BDNF) was investigated as a mechanism that allows for spatial ability to show improvements following the end of chronic stress. It was found that decreasing the expression of BDNF in the hippocampus prevented spatial memory improvements following a post-stress rest period. Chapter 3 was performed to determine whether hippocampal CA3 apical dendritic complexity requires BDNF to show improvements following a post-stress rest period, and whether a receptor for BDNF, TrkB, mediates the improvements of spatial ability and dendritic complexity in a temporal manner, i.e. during the rest period only. These experiments showed that decreased hippocampal BDNF expression prevented improvements in dendritic complexity, and administration of a TrkB antagonist during the rest period also prevented the improvements in spatial ability and dendritic complexity. In chapter 4, the role of the GABAergic system on spatial ability following chronic stress and a post-stress rest period was investigated. Following chronic stress, it was found that male rats showed impairments on the acquisition phase of the RAWM and this correlated with limbic glutamic acid decarboxylase, a marker for GABA. In chapter 5, a transgenic mouse that expresses a permanent marker on all GABAergic interneurons was used to assess the effects of chronic stress and a post-stress rest period on hippocampal GABAergic neurons. While no changes were found on the total number of GABAergic interneurons, specific subtypes of GABAergic interneurons were affected by stressor manipulations. Collectively, these studies reveal some mechanisms behind the plasticity seen in the hippocampus in response to a post-stress rest period.
ContributorsOrtiz, J. Bryce (Author) / Conrad, Cheryl D. (Thesis advisor) / Newbern, Jason M. (Committee member) / Orchinik, Miles (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2018
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 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
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. 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
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 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
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 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
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 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
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 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
Neuroinflammation Following Experimental Diffuse Brain Injury in Pre-pubertal and Peri-pubertal Rats
Description
Traumatic brain injury is the leading cause of mortality and morbidity in children and adolescents. Adolescence is a critical time in development where the body and brain undergoes puberty, which not only includes reproductive maturation, but also adult social and cognitive development. Brain-injury-induced disruptions can cause secondary inflammation processes and as a result, pediatric TBI can lead to significant life-long and debilitating morbidities that continue long after initial injury. In this study, neuroinflammation following diffuse brain injury was explored in prepubertal and peripubertal rats using an adapted method of midline fluid percussion injury (mFPI) for juvenile rats to further understand the relationship between pediatric TBI and puberty disruption due to endocrine dysfunction. We expect the adapted mFPI model to be effective in producing diffuse, moderate brain injury in juvenile rats and hypothesize that pre-pubertal rats (PND35) will have increased neuroinflammation compared to peri-pubertal rats (PND17) and shams because of the potential neuroprotective nature of sex steroids. Male Sprague-Dawley rats (n=90) were subjected to either a diffuse midline fluid percussion injury (mFPI) or sham injury at post-natal day (PND) 17 (pre-puberty) or PND35 (peri-puberty). Animals were sacrificed at different time points defined as days post injury (DPI) including 1DPI, 7DPI and 25DPI to represent both acute and chronic time points, allowing for comparisons within groups (injury vs. sham) and across groups (PND17 vs PND35). Body weight of the rats was measured postoperatively at various time points throughout the study to follow recovery. Tissue was collected and subjected to Heamatoxylin and Eosin (H&E) stain to visualize histology and evaluate the application of diffuse mFPI to juvenile rats. In addition, tissue underwent immunohistochemical analysis using 3,3'-diaminobenzidine (DAB) to stain for ionized calcium binding proteins (Iba1) in order to assess injury-related neuroinflammation in the form of microglia activation. Diffuse brain injury using the mFPI model did not affect rat body weight or cause overt cell death, suggesting adaption of the adult mFPI model for juvenile rats is representative of moderate diffuse brain injury. In addition, diffuse TBI lead to morphological changes in microglia suggesting there is an increased inflammatory response following initial insult, which may directly contribute to improper activation of pubertal timing and progression in adolescent children affected. Since there is little literature on the full effects of puberty dysfunction following TBI in the pediatric population, there is a significant need to further assess this area in order to develop improved interventions and potential therapies for this affected population.
ContributorsNewbold, Kelsey Bevier (Author) / Newbern, Jason (Thesis director) / Rowe, Rachel (Committee member) / Ortiz, J. Bryce (Committee member) / School of Mathematical and Natural Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05