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Each year, millions of aging women will experience menopause, a transition from reproductive capability to reproductive senescence. In women, this transition is characterized by depleted ovarian follicles, declines in levels of sex hormones, and a dysregulation of gonadotrophin feedback loops. Consequently, menopause is accompanied by hot flashes, urogenital atrophy, cognitive

Each year, millions of aging women will experience menopause, a transition from reproductive capability to reproductive senescence. In women, this transition is characterized by depleted ovarian follicles, declines in levels of sex hormones, and a dysregulation of gonadotrophin feedback loops. Consequently, menopause is accompanied by hot flashes, urogenital atrophy, cognitive decline, and other symptoms that reduce quality of life. To ameliorate these negative consequences, estrogen-containing hormone therapy is prescribed. Findings from clinical and pre-clinical research studies suggest that menopausal hormone therapies can benefit memory and associated neural substrates. However, findings are variable, with some studies reporting null or even detrimental cognitive and neurobiological effects of these therapies. Thus, at present, treatment options for optimal cognitive and brain health outcomes in menopausal women are limited. As such, elucidating factors that influence the cognitive and neurobiological effects of menopausal hormone therapy represents an important need relevant to every aging woman. To this end, work in this dissertation has supported the hypothesis that multiple factors, including post-treatment circulating estrogen levels, experimental handling, type of estrogen treatment, and estrogen receptor activity, can impact the realization of cognitive benefits with Premarin hormone therapy. We found that the dose-dependent working memory benefits of subcutaneous Premarin administration were potentially regulated by the ratios of circulating estrogens present following treatment (Chapter 2). When we administered Premarin orally, it impaired memory (Chapter 3). Follow-up studies revealed that this impairment was likely due to the handling associated with treatment administration and the task difficulty of the memory measurement used (Chapters 3 and 4). Further, we demonstrated that the unique cognitive impacts of estrogens that become increased in circulation following Premarin treatments, such as estrone (Chapter 5), and their interactions with the estrogen receptors (Chapter 6), may influence the realization of hormone therapy-induced cognitive benefits. Future directions include assessing the mnemonic effects of: 1) individual biologically relevant estrogens and 2) clinically-used bioidentical hormone therapy combinations of estrogens. Taken together, information gathered from these studies can inform the development of novel hormone therapies in which these parameters are optimized.
ContributorsEngler-Chiurazzi, Elizabeth (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Sanabria, Federico (Committee member) / Olive, Michael F (Committee member) / Hoffman, Steven (Committee member) / Arizona State University (Publisher)
Created2013
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Description
When a rolling ball exits a spiral tube, it typically maintains its final inertial state and travels along straight line in concordance with Newton's first law of motion. Yet, most people predict that the ball will curve, a "naive physics" misconception called the curvilinear impetus (CI) bias. In the current

When a rolling ball exits a spiral tube, it typically maintains its final inertial state and travels along straight line in concordance with Newton's first law of motion. Yet, most people predict that the ball will curve, a "naive physics" misconception called the curvilinear impetus (CI) bias. In the current paper, we explore the ecological hypothesis that the CI bias arises from overgeneralization of correct motion of biological agents. Previous research has established that humans curve when exiting a spiral maze, and college students believe this motion is the same for balls and humans. The current paper consists of two follow up experiments. The first experiment tested the exiting behavior of rodents from a spiral rat maze. Though there were weaknesses in design and procedures of the maze, the findings support that rats do not behave like humans who exhibit the CI bias when exiting a spiral maze. These results are consistent with the CI bias being an overgeneralization of human motion, rather than generic biological motion. The second experiment tested physics teachers on their conception of how a humans and balls behave when exiting a spiral tube. Teachers demonstrated correct knowledge of the straight trajectory of a ball, but generalized the ball's behavior to human motion. Thus physics teachers exhibit the opposite bias from college students and presume that all motion is like inanimate motion. This evidence supports that this type of naive physics inertial bias is at least partly due to participants overgeneralizing both inanimate and animate motion to be the same, perhaps in an effort to minimize cognitive reference memory load. In short, physics training appears not to eliminate the bias, but rather to simply shift it from the presumption of stereotypical animate to stereotypical inanimate behavior.
ContributorsDye, Rosaline (Author) / Mcbeath, Michael K (Thesis advisor) / Sanabria, Federico (Committee member) / Megowan, Colleen (Committee member) / Arizona State University (Publisher)
Created2013
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Description
The brain is a fundamental target of the stress response that promotes adaptation and survival but the repeated activation of the stress response has the potential alter cognition, emotion, and motivation, key functions of the limbic system. Three structures of the limbic system in particular, the hippocampus, medial prefrontal cortex

The brain is a fundamental target of the stress response that promotes adaptation and survival but the repeated activation of the stress response has the potential alter cognition, emotion, and motivation, key functions of the limbic system. Three structures of the limbic system in particular, the hippocampus, medial prefrontal cortex (mPFC), and amygdala, are of special interest due to documented structural changes and their implication in post-traumatic stress disorder (PTSD). One of many notable chronic stress-induced changes include dendritic arbor restructuring, which reflect plasticity patterns in parallel with the direction of alterations observed in functional imaging studies in PTSD patients. For instance, chronic stress produces dendritic retraction in the hippocampus and mPFC, but dendritic hypertrophy in the amygdala, consistent with functional imaging in patients with PTSD. Some have hypothesized that these limbic region's modifications contribute to one's susceptibility to develop PTSD following a traumatic event. Consequently, we used a familiar chronic stress procedure in a rat model to create a vulnerable brain that might develop traits consistent with PTSD when presented with a challenge. In adult male rats, chronic stress by wire mesh restraint (6h/d/21d) was followed by a variety of behavioral tasks including radial arm water maze (RAWM), fear conditioning and extinction, and fear memory reconsolidation to determine chronic stress effects on behaviors mediated by these limbic structures. In chapter 2, we corroborated past findings that chronic stress caused hippocampal CA3 dendritic retraction. Importantly, we present new findings that CA3 dendritic retraction corresponded with poor spatial memory in the RAWM and that these outcomes reversed after a recovery period. In chapter 3, we also showed that chronic stress impaired mPFC-mediated extinction memory, findings that others have reported. Using carefully assessed behavior, we present new findings that chronic stress impacted nonassociative fear by enhancing contextual fear during extinction that generalized to a new context. Moreover, the generalization behavior corresponded with enhanced functional activation in the hippocampus and amygdala during fear extinction memory retrieval. In chapter 5, we showed for the first time that chronic stress enhanced amygdala functional activation during fear memory retrieval, i.e., reactivation. Moreover, these enhanced fear memories were resistant to protein synthesis interference to disrupt a previously formed memory, called reconsolidation in a novel attempt to weaken chronic stress enhanced traumatic memory. Collectively, these studies demonstrated the plastic and dynamic effects of chronic stress on limbic neurocircuitry implicated in PTSD. We showed that chronic stress created a structural and functional imbalance across the hippocampus, mPFC, and amygdala, which lead to a PTSD-like phenotype with persistent and exaggerated fear following fear conditioning. These behavioral disruptions in conjunction with morphological and functional imaging data reflect a chronic stress-induced imbalance between hippocampal and mPFC regulation in favor of amygdala function overdrive, and supports a novel approach for traumatic memory processing in PTSD.
ContributorsHoffman, Ann (Author) / Conrad, Cheryl D. (Thesis advisor) / Olive, M. Foster (Committee member) / Hammer, Jr., Ronald P. (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2013
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Description
Patients with schizophrenia have impaired cognitive flexibility, as evidenced by behaviors of perseveration. Cognitive impairments may be due to dysregulation of glutamate and/or loss of neuronal plasticity in the medial prefrontal cortex (mPFC). The purpose of these studies was to examine the effects of mGluR5 positive allosteric modulators (PAMs) alone

Patients with schizophrenia have impaired cognitive flexibility, as evidenced by behaviors of perseveration. Cognitive impairments may be due to dysregulation of glutamate and/or loss of neuronal plasticity in the medial prefrontal cortex (mPFC). The purpose of these studies was to examine the effects of mGluR5 positive allosteric modulators (PAMs) alone and in combination with the NMDAR antagonist MK-801, a pharmacological model of schizophrenia. An operant-based cognitive set-shifting task was utilized to assess cognitive flexibility, in vivo microdialysis procedures to measure extracellular glutamate levels in the mPFC, and diolistic labeling to assess the effects on dendritic spine density and morphology in the mPFC. Results revealed that chronic administration of the mGluR5 PAM CDPPB was able to significantly reduce the effects of chronically administered MK-801 on both behavioral perseveration and glutamate neurotransmission. Results also showed that CDPPB had no evidence of an effect on dendritic spine density or morphology, but the mGluR5 negative allosteric modulator fenobam caused significant increases in spine density and the frequency of occurrence of spines with smaller head diameters. Conclusions include that CDPPB is able to reverse MK-801 induced cognitive deficits as well as alterations in mPFC glutamate neurochemistry. The culmination of these studies add further support for targeting mGluR5 with PAMs as a novel mechanism to alleviate cognitive impairments in patients with schizophrenia.
ContributorsLaCrosse, Amber (Author) / Olive, Michael (Committee member) / Gallitano-Mendel, Amelia (Committee member) / Sanabria, Federico (Committee member) / Hammer, Ronald (Committee member) / Arizona State University (Publisher)
Created2014
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Description
The unpleasant bitter taste found in many nutritious vegetables may deter their consumption. While bitterness suppression by prototypical tastants is well-studied in the chemical and pharmacological fields, mechanisms to reduce the bitterness of foods such as vegetables remain to be elucidated. Here tastants representing the taste primaries of

The unpleasant bitter taste found in many nutritious vegetables may deter their consumption. While bitterness suppression by prototypical tastants is well-studied in the chemical and pharmacological fields, mechanisms to reduce the bitterness of foods such as vegetables remain to be elucidated. Here tastants representing the taste primaries of salty and sweet were investigated as potential bitterness suppressors of three types of Brassicaceae vegetables. The secondary aim of these studies was to determine whether the bitter masking agents were differentially effective for bitter-sensitive and bitter-insensitive individuals. In all experiments, participants rated vegetables plain and with the addition of tastants. In Experiments 1-3, sucrose and NNS suppressed the bitterness of broccoli, Brussels sprouts, and cauliflower, whereas NaCl did not. Varying concentrations of NaCl and sucrose were introduced in Experiment 4 to assess the dose-dependency of the effects. While sucrose was a robust bitterness suppressor, NaCl suppressed bitterness only for participants who perceived the plain Brussels sprouts as highly bitter. Experiment 5, through the implementation of a rigorous control condition, determined that some but not all of this effect can be accounted for by regression to the mean. Individual variability in taste perception as determined by sampling of aqueous bitter, salty, and sweet solutions did not influence the degree of suppression by NaCl or sucrose. Consumption of vegetables is deterred by their bitter taste. Utilizing tastants to mask bitterness, a technique that preserves endogenous nutrients, can circumvent this issue. Sucrose is a robust bitter suppressor whereas the efficacy of NaCl is dependent upon bitterness perception of the plain vegetables.
ContributorsWilkie, Lynn Melissa (Author) / Capaldi Phillips, Elizabeth D (Thesis advisor) / Cohen, Adam (Committee member) / Johnston, Carol (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2014
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Description
Globally, addiction to stimulants such as methamphetamine (METH) remains a significant public health problem. Despite decades of research, no approved anti-relapse medications for METH or any illicit stimulant exist, and current treatment approaches suffer from high relapse rates. Recently, synthetic cathinones have also emerged as popular abused stimulants, leading to

Globally, addiction to stimulants such as methamphetamine (METH) remains a significant public health problem. Despite decades of research, no approved anti-relapse medications for METH or any illicit stimulant exist, and current treatment approaches suffer from high relapse rates. Recently, synthetic cathinones have also emerged as popular abused stimulants, leading to numerous incidences of toxicity and death. However, contrary to traditional illicit stimulants, very little is known about their addiction potential. Given the high relapse rates and lack of approved medications for METH addiction, chapters 2 and 3 of this dissertation assessed three different glutamate receptor ligands as potential anti-relapse medications following METH intravenous self-administration (IVSA) in rats. In chapters 4 through 7, using both IVSA and intracranial self-stimulation (ICSS) procedures, experiments assessed abuse liability of the popular synthetic cathinones 3,4-Methylenedioxypyrovalerone (MDPV) , methylone, α-pyrrolidinovalerophenone (α-PVP) and 4-methylethylcathinone (4-MEC). Results from these seminal studies suggest that these drugs possess similar abuse potential to traditional illicit stimulants such as METH, cocaine, and 3,4-methylenedioxymethamphetamine (MDMA). Finally, studies outlined in chapter 8 assessed the potential neurotoxic or adverse cognitive effects of METH and MDPV following IVSA procedures for the purpose of identifying potential novel pharmacotherapeutic targets. However, results of these final studies did not reveal neurotoxic or adverse cognitive effects when using similar IVSA procedural parameters that were sufficient for establishing addiction potential, suggesting that these parameters do not allow for sufficient drug intake to produce similar neurotoxicity or cognitive deficits reported in humans. Thus, these models may be inadequate for fully modeling the adverse neural and psychological consequences of stimulant addiction. Together, these studies support the notion for continued research into the abuse liability and toxicity of METH and synthetic cathinones and suggest that refinements to traditional IVSA models are needed for both more effective assessment of potential cognitive and neural deficits induced by these drugs and screening of potentially clinically efficacious pharmacotherapeutics.
ContributorsWatterson, Lucas (Author) / Olive, Michael F (Thesis advisor) / Czyzyk, Traci (Committee member) / Neisewander, Janet (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2014
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Description
Smoking remains the leading cause of preventable death in the United States, and early initiation is associated with greater difficulty quitting. Among adolescent smokers, those with attention-deficit hyperactivity disorder (ADHD), characterized by difficulties associated with impulsivity, hyperactivity, and inattention, smoke at nearly twice the rate of their peers.

Smoking remains the leading cause of preventable death in the United States, and early initiation is associated with greater difficulty quitting. Among adolescent smokers, those with attention-deficit hyperactivity disorder (ADHD), characterized by difficulties associated with impulsivity, hyperactivity, and inattention, smoke at nearly twice the rate of their peers. Although cigarette smoking is highly addictive, nicotine is a relatively weak primary reinforcer, spurring research on other potential targets that may maintain smoking, including the potential benefits of nicotine on attention, inhibition, and reinforcer efficacy. The present study employs the most prevalent rodent model of ADHD, the spontaneously hypertensive rat (SHR) and its control comparison Wistar Kyoto (WKY) to examine the effects of acute and chronic subcutaneous nicotine injections on performance in three operant response inhibition paradigms. Functional activation in select regions of the prefrontal cortex and striatum was also explored. Acute (0.1, 0.3, 0.6 mg/kg) and chronic (0.3 mg/kg) nicotine increased impulsive responding regardless of strain, dose, or operant schedule. Dose-dependent decreases in latency to initiate the task were also observed. SHR receiving daily nicotine injections showed less activation in the nucleus accumbens shell compared to saline controls. Despite close similarities, one of the three operant tasks did not detect response inhibition deficits in SHR relative to WKY. A closer examination of these tasks may highlight critical components involved in the amelioration of response inhibition deficits.
ContributorsMazur, Gabriel Joseph (Author) / Sanabria, Federico (Thesis advisor) / Killeen, Peter R (Committee member) / Neisewander, Janet L (Committee member) / Wynne, Clive DL (Committee member) / Arizona State University (Publisher)
Created2014
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Description
Nicotine is thought to underlie the reinforcing and dependence-producing effects of tobacco-containing products. Nicotine supports self-administration in rodents, although measures of its reinforcing effects are often confounded by procedures that are used to facilitate acquisition, such as food restriction, prior reinforcement training, or response-contingent co-delivery of a naturally reinforcing light.

Nicotine is thought to underlie the reinforcing and dependence-producing effects of tobacco-containing products. Nicotine supports self-administration in rodents, although measures of its reinforcing effects are often confounded by procedures that are used to facilitate acquisition, such as food restriction, prior reinforcement training, or response-contingent co-delivery of a naturally reinforcing light. This study examined whether rats acquire nicotine self-administration in the absence of these facilitators. A new mathematical modeling procedure was used to define the criterion for acquisition and to determine dose-dependent differences in rate and asymptote levels of intake. Rats were trained across 20 daily 2-h sessions occurring 6 days/week in chambers equipped with active and inactive levers. Each active lever press resulted in nicotine reinforcement (0, 0.015, 0.03, 0.06 mg/kg, IV) and retraction of both levers for a 20-s time out, whereas inactive lever presses had no consequences. Acquisition was defined by the best fit of a logistic function (i.e., S-shaped) versus a constant function (i.e., flat line) for reinforcers obtained across sessions using a corrected Akaike information criterion (AICc) as a model selection tool. The results showed an inverted-U shaped function for dose in relation to the percentage of animals that acquired nicotine self-administration, with 46% acquiring at 0.015 mg/kg, 73% at 0.03 mg/kg, and 58% at 0.06 mg/kg. All saline rats failed to acquire as expected. For rats that acquired nicotine self-administration, multiple model comparisons demonstrated that the asymptote (highest number of reinforcers/session) and half learning point (h; session during which half the assymptote had been achieved) were justified as free parameters of the reinforcers/session function, indicating that these parameters vary with nicotine dose. Asymptote exhibited an inverted U-shaped function across doses and half learning point exhibited a negative relationship to dose (i.e., the higher the dose the fewer sessions to reach h). These findings suggest that some rats acquire nicotine self-administration without using procedures that confound measures of acquisition rate. Furthermore, the modeling approach provides a new way of defining acquisition of drug self-administration that takes advantage of using all data generated from individual subjects and is less arbitrary than some criteria that are currently used.
ContributorsCole, Natalie (Author) / Neisewander, Janet L (Thesis advisor) / Sanabria, Federico (Thesis advisor) / Bimonte-Nelson, Heather A. (Committee member) / Olive, Michael F (Committee member) / Arizona State University (Publisher)
Created2011
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Description
Anxiety sensitivity (AS; the fear of anxiety-related bodily sensations) has been earmarked as a significant risk factor in the development and maintenance of pathological anxiety in adults and children. Given the potential implications of heightened AS, recent research has focused on investigating the etiology and developmental course of elevated AS;

Anxiety sensitivity (AS; the fear of anxiety-related bodily sensations) has been earmarked as a significant risk factor in the development and maintenance of pathological anxiety in adults and children. Given the potential implications of heightened AS, recent research has focused on investigating the etiology and developmental course of elevated AS; however, most of this work has been conducted with adults and is retrospective in nature. Data from college students show that early anxiety-related learning experiences may be a primary source of heightened AS levels, but it remains unclear whether AS in children is linked to their learning experiences (i.e., parental reinforcement, modeling, punishment, and/or transmission of information about anxiety-related behaviors). Based on AS theory and its iterations, an emerging theoretical model was developed to aid further exploration of the putative causes and consequences of heightened AS levels. Using a sample of 70 clinic-referred youth (ages 6 to 16 years old; 51.4% Hispanic/Latino), the present study sought to further explicate the role of learning in the development of AS and anxiety symptoms. Results suggest that childhood learning experiences may be an important precursor to heightened AS levels and, subsequently, increased experiences of anxiety symptoms. Findings also indicate that some youth may be more vulnerable to anxiety-related learning experiences and suggest that culture may play a role in the relations among learning, AS, and anxiety symptoms.
ContributorsHolly, Lindsay (Author) / Pina, Armando A (Thesis advisor) / Crnic, Keith A (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2012
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Description
Social influences are important determinants of drug initiation in humans, particularly during adolescence and early adulthood. My dissertation tested three hypotheses: 1) conditioned and unconditioned nicotine and social rewards elicit unique patterns of neural signaling in the corticolimbic neurocircuitry when presented in combination versus individually; 2) play behavior is

Social influences are important determinants of drug initiation in humans, particularly during adolescence and early adulthood. My dissertation tested three hypotheses: 1) conditioned and unconditioned nicotine and social rewards elicit unique patterns of neural signaling in the corticolimbic neurocircuitry when presented in combination versus individually; 2) play behavior is not necessary for expression of social reward; and 3) social context enhances nicotine self-administration. To test the first hypothesis, Fos protein was measured in response to social and nicotine reward stimuli given alone or in combination and in response to environmental cues associated with the rewards in a conditioned place preference (CPP) test. Social-conditioned environmental stimuli attenuated Fos expression in the nucleus accumbens core. A social partner elevated Fos expression in the caudate-putamen, medial and central amygdala, and both nucleus accumbens subregions. Nicotine decreased Fos expression in the cingulate cortex, caudate-putamen, and the nucleus accumbens core. Both stimuli combined elevated Fos expression in the basolateral amygdala and ventral tegmental area, suggesting possible overlap in processing both rewards in these regions. I tested the second hypothesis with an apparatus containing compartments separated by a wire mesh barrier that allowed limited physical contact with a rat or object. While 2 pairings with a partner rat (full physical contact) produced robust CPP, additional pairings were needed for CPP with a partner behind a barrier or physical contact with an object (i.e., tennis ball). The results demonstrate that physical contact with a partner rat is not necessary to establish social-reward CPP. I tested the third hypothesis with duplex operant conditioning chambers separated either by a solid or a wire mesh barrier to allow for social interaction during self-administration sessions. Nicotine (0.015 and 0.03 mg/kg, IV) and saline self-administration were assessed in male and female young-adult rats either in the social context or isolation. Initially, a social context facilitated nicotine intake at the low dose in male rats, but suppressed intake in later sessions more strongly in female rats, suggesting that social factors exert strong sex-dependent influences on self-administration. These novel findings highlight the importance of social influences on several nicotine-related behavioral paradigms and associated neurocircuitry.
ContributorsPeartree, Natalie (Author) / Neisewander, Janet L (Thesis advisor) / Conrad, Cheryl D. (Committee member) / Nikulina, Ella M (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2015