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- Genre: Doctoral Dissertation
Description
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
Description
5-HT2A receptor (R) antagonists and 5-HT2CR agonists attenuate reinstatement of cocaine-seeking behavior (i.e., incentive motivation). 5-HT2Rs are distributed throughout the brain, primarily in regions involved in reward circuitry, including the prefrontal cortex (PFC), caudate putamen (CPu), and basolateral (BlA) and central (CeA) amygdala. Using animal models, we tested our hypotheses that 5-HT2ARs in the medial (m) PFC mediate the incentive motivational effects of cocaine and cocaine-paired cues; 5-HT2ARs and 5-HT2CRs interact to attenuate cocaine hyperlocomotion and functional neuronal activation (i.e, Fos protein); and 5-HT2CRs in the BlA mediate the incentive motivational effects of cocaine-paired cues and anxiety-like behavior, while 5-HT2CRs in the CeA mediate the incentive motivational effects of cocaine. In chapter 2, we infused M100907, a selective 5-HT2AR antagonist, directly into the mPFC and examined its effects on reinstatement of cocaine-seeking behavior. We found that M100907 in the mPFC dose- dependently attenuated cue-primed reinstatement, without affecting cocaine-primed reinstatement, cue-primed reinstatement of sucrose-seeking behavior, or locomotor activity. In chapter 3, we used subthreshold doses of M100907 and MK212, a 5-HT2CR agonist, to investigate whether these compounds interact to attenuate cocaine hyperlocomotion and Fos protein expression. Only the drug combination attenuated cocaine hyperlocomotion and cocaine-induced Fos expression in the CPu, but had no effect on spontaneous locomotion. Finally, in chapter 4 we investigated the effects of a 5- HT2CR agonist in the BlA and CeA on cocaine-seeking behavior and anxiety-like behavior. We found that CP809101, a selective 5-HT2CR agonist, infused into the BlA increased anxiety-like behavior on the elevated plus maze (EPM), but failed to alter cocaine-seeking behavior. CP809101 infused into the CeA attenuated cocaine-primed reinstatement and this effect was blocked by co-administration of a 5-HT2CR antagonist. Together, these results suggest that 5-HT2ARs in the mPFC are involved in cue-primed reinstatement, 5-HT2A and 5-HT2CRs may interact in the nigrostriatal pathway to attenuate cocaine hyperlocomotion and Fos expression, and 5-HT2CRs are involved in anxiety-like behavior in the BlA and cocaine-primed reinstatement in the CeA. Our findings add to the literature on the localization of 5-HT2AR antagonist and 5-HT2CR agonist effects, and suggest a potential treatment mechanism via concurrent 5-HT2AR antagonism and 5-HT2CR agonism.
ContributorsPockros, Lara Ann (Author) / Neisewander, Janet L (Thesis advisor) / Olive, Michael F (Committee member) / Conrad, Cheryl D. (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2013
Description
Patients with schizophrenia have deficits in sensorimotor gating, the ability to gate out irrelevant stimuli in order to attend to relevant stimuli. Prepulse inhibition (PPI) of the startle response is a reliable and valid model of sensorimotor gating across species. Repeated D2-like agonist treatment alleviates prior PPI deficits in rats, termed a PPI recovery, and is observable 28 days after treatment. The aim of the current project is to illuminate the underlying mechanism for this persistent change of behavior and determine the clinical relevance of repeated D2-like agonist treatment. Our results revealed a significant increase in Delta FosB, a transcription factor, in the nucleus accumbens (NAc) 10 days after repeated D2-like agonist treatment. Additionally, we investigated if Delta FosB was necessary for long-lasting PPI recovery and discovered a bilateral infusion of dominant-negative Delta JunD prevented PPI recovery after repeated D2-like agonist treatment. To further develop the underlying mechanism of PPI recovery, we observed that dominant negative mutant cyclic adenosine monophosphate (cAMP) response biding element protein (CREB) prevented repeated D2-like agonist-induced Delta FosB expression in the NAc. We then compared our previous behavioral and intracellular findings to the results of repeated aripiprazole, a novel D2-like partial agonist antipsychotic, to determine if repeated D2-like receptor agonist action is a clinically relevant pharmacological approach. As compared to previous PPI recovery and Delta FosB expression after repeated D2-like agonist treatment, we found similar PPI recovery and Delta FosB expression after repeated aripiprazole treatment in rats. We can conclude that repeated D2-like agonist treatment produces persistent PPI recovery through CREB phosphorylation and Delta FosB, which is necessary for PPI recovery. Furthermore, this pharmacological approach produces behavioral and intracellular changes similar to an effective novel antipsychotic. These findings suggest the underlying intracellular mechanism for sustained PPI recovery is clinically relevant and may be a potential target of therapeutic intervention to alleviate sensorimotor gating deficits, which are associated with cognitive symptoms of schizophrenia.
ContributorsMaple, Amanda (Author) / Hammer, Ronald P. (Thesis advisor) / Olive, Michael F (Committee member) / Gallitano, Amelia L (Committee member) / Conrad, Cheryl D. (Committee member) / Nikulina, Ella M (Committee member) / Arizona State University (Publisher)
Created2013
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 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
Description
Substance use disorders (SUDs) are difficult to treat, in part because drug craving can be elicited by exposure to drug-associated environments and cues within the environment. Furthermore, this craving becomes more pronounced as abstinence progresses and it can take months to years for cue-elicited craving to finally wane. This important hallmark of addiction is modeled in rodents by exposing them to light/tone cues associated with the self-administration (SA) of cocaine. Cue exposure results in drug-seeking behavior, an animal analogue for drug craving. The overarching goal of this dissertation was to use the rodent SA model to explore the nucleus accumbens (NAc), a key brain region in the neural pathway of craving, and examine ribonucleic acid (RNA) expression that may underlie cocaine-seeking behavior. This includes messenger RNAs (mRNAs), which encode directly for proteins, and non-coding RNAs, which are important regulators of mRNA expression and cellular function. My first experiment aimed to identify non-coding microRNAs, which directly target and suppress mRNA expression, that are differentially expressed in animals with high or low cocaine-seeking behavior. In the second study, I compared RNA-sequencing (RNA-seq) datasets from rodent models of cocaine abstinence and developed a novel workflow to narrow candidate genes. In the final experiment, I utilized RNA-seq and reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) to identify and explore non-coding, circular RNAs that may influence gene regulatory networks and impact drug-seeking behavior. Overall, these studies promote our understanding of the neurogenetic mechanisms of craving and they suggest recommendations for improving the experimental design of future neurogenomic studies.
ContributorsVannan, Annika (Author) / Neisewander, Janet L (Thesis advisor) / Wilson, Melissa A (Thesis advisor) / Ferguson, Deveroux (Committee member) / Olive, Michael F (Committee member) / Perrone-Bizzozero, Nora I (Committee member) / Arizona State University (Publisher)
Created2022
Description
Opioid use rates and related deaths continue to be a public health crisis; while there are many contributing factors to opioid use disorders, criteria for diagnosis include problems related to social functioning. Previous research indicates that laboratory rats, which are frequently used as animal models of addiction-related behaviors, are capable of prosocial behavior. The following collection of studies were performed to determine the effects of heroin on prosocial behavior in rats, as well as the role of the insula in both self-administration of heroin and prosocial behaviors. All of the experiments were conducted utilizing an established model of prosocial behavior in rats in which a performing rat releases a cagemate from a restrainer. The occurrence of and latency to free the confined rat was recorded. After baseline rescuing behavior was established, rats were allowed to self-administer heroin (0.06 mg/kg/infusion i.v.), and subsequent experimental conditions were imposed.
Experimental conditions, in a series of different studies, included comparing heroin reinforcers with sucrose, chemogenetically modulating the insular cortex (both stimulatory and inhibitory processes) and administering excitotoxic lesions in the insula. There were significant differences in saving behaviors between heroin and sucrose groups demonstrating an opioid induced loss of prosocial behavior. Modulating the insula chemogenetically resulted in some restoration of these opioid related deficits, and insular lesions did not significantly impact prosocial behaviors, however, there were significant differences between rates of heroin intake in lesioned animals versus non-lesioned controls. Taken together, these results demonstrate the deleterious effects of heroin on prosocial behaviors and offer further support for the role of the insula in both addiction and social constructs.
Experimental conditions, in a series of different studies, included comparing heroin reinforcers with sucrose, chemogenetically modulating the insular cortex (both stimulatory and inhibitory processes) and administering excitotoxic lesions in the insula. There were significant differences in saving behaviors between heroin and sucrose groups demonstrating an opioid induced loss of prosocial behavior. Modulating the insula chemogenetically resulted in some restoration of these opioid related deficits, and insular lesions did not significantly impact prosocial behaviors, however, there were significant differences between rates of heroin intake in lesioned animals versus non-lesioned controls. Taken together, these results demonstrate the deleterious effects of heroin on prosocial behaviors and offer further support for the role of the insula in both addiction and social constructs.
ContributorsTomek, Seven Eli (Author) / Olive, Michael F (Thesis advisor) / Neisewander, Janet (Committee member) / Wynne, Clive (Committee member) / Comer, Sandra (Committee member) / Arizona State University (Publisher)
Created2020
Description
Intermittent social defeat stress induces psychostimulant cross-sensitization, as well as long-lasting social avoidance behavior. Previous data reveal heightened expression of AMPA receptor (AMPAR) GluA1 subunits in rat ventral tegmental area (VTA), which occurs concurrently with social stress-induced amphetamine (AMPH) cross-sensitization. These studies described herein examined whether VTA GluA1 AMPARs are important for the behavioral consequences of social stress and investigated the role of the infralimbic (IL) to VTA pathway in the induction of these responses. Functional inactivation of GluA1 in VTA DA neurons prevented stress-induced AMPH sensitization without affecting social avoidance behavior, while GluA1 overexpression in VTA DA neurons mimicked the effects of stress on AMPH sensitization. Female rats were more sensitive to the effects of stress on AMPH administration than males, specifically during proestrus/estrus, which is characterized by higher circulating estradiol. Fluorescent immunohistochemistry revealed that females expressed higher GluA1 in VTA DA neurons as a result of intermittent social defeat stress, independent of estrus stage; by contrast, females during proestrus/estrus displayed higher tyrosine kinase receptor type 2 (TrkB) expression, which is the receptor for brain derived neurotrophic factor (BDNF), in VTA DA neurons, independent of stress exposure. Functional inactivation of GluA1 in VTA DA neurons prevented stress-induced AMPH sensitization and overexpression mimicked the effects of stress on AMPH sensitization. This suggests that BDNF-TrkB signaling may work concomitantly with GluA1 signaling in the VTA to drive sex-dependent differences in stress-induced locomotor sensitization effects. Optogenetic inhibition of the IL-VTA pathway in male rats prevented stress-induced AMPH sensitization compared to control animals. In addition, fluorescent immunohistochemistry displayed less Fos labeling in the nucleus accumbens (NAc) of rats with IL-VTA light inhibition compared to control animals. This suggests that the IL-VTA pathway plays a critical role in the induction of stress-induced sensitivity to AMPH, and blocking this pathway prevents mesolimbic DA signaling to the NAc. We conclude that IL glutamate projections onto GluA1-homomeric AMPA receptors in VTA DA neurons play a critical role in driving the stress-induced sensitization response in males and females. Therefore, GluA1 VTA DA neurons could potentially be a therapeutic target to prevent stress-induced drug susceptibility in the future.
ContributorsRudolph, Megan Leigh (Author) / Hammer, Ronald P. (Thesis advisor) / Olive, Michael F (Thesis advisor) / Nikulina, Ella M (Committee member) / Ferguson, Deveroux (Committee member) / Qiu, Shenfeng (Committee member) / Arizona State University (Publisher)
Created2020
Description
Post-Traumatic Stress Disorder (PTSD) is characterized by intrusive memories from a traumatic event. Current therapies rarely lead to complete remission. PTSD can be modeled in rodents using chronic stress (creating vulnerable phenotype) combined with fear conditioning (modeling a traumatic experience), resulting in attenuated extinction learning and impaired recall of extinction. Studies typically investigate cognition soon after chronic stress ends; however, as days and weeks pass (“rest” period) some cognitive functions may improve compared to soon after stress. Whether a rest period between chronic stress and fear conditioning/extinction would lead to improvements is unclear. In Chapter 2, male rats were chronically stressed by restraint (6hr/d/21d), a reliable method to produce cognitive changes, or assigned to a non-stressed control group (CON). After chronic stress ended, fear conditioning occurred within a day (STR-IMM), or after three (STR-R3) or six weeks (STR-R6). During the first three extinction trials, differences emerged in fear to the non-shock context: STR-R3/R6 showed significantly less fear to the context than did STR-IMM or CON. Differences were unlikely attributable to generalization or to second-order conditioning. Therefore, a rest period following chronic stress may lead to improved fear extinction and discrimination between the conditioned stimulus and environment. In Chapter 3, the infralimbic cortex (IL) was investigated due to the IL’s importance in fear extinction. Rats were infused with chemogenetics to target IL glutamatergic neurons and then assigned to CON, STR-IMM or STR-R3. During the rest period of STR-R3 and the restraint for STR-IMM, the IL was inhibited using CNO (1mg/kg BW, i.p., daily), which ended before behavioral testing. STR-R3 with IL inhibition failed to demonstrate a tone-shock association as spontaneous recovery was not observed. CON with IL inhibition behaved somewhat like STR-IMM; freezing to the extinction context was enhanced. Consequently, inhibiting IL function during the rest period following chronic stress was particularly disruptive for learning in STR-R3, impaired freezing to a safe context for CON, and had no effect in STR-IMM. These studies show that time since the end of chronic stress (recently ended or with a delay) can interact with IL functioning to modify fear learning and response.
ContributorsJudd, Jessica Michelle (Author) / Conrad, Cheryl D. (Thesis advisor) / Sanabria, Federico (Committee member) / Olive, Michael F (Committee member) / Bimonte-Nelson, Heather A. (Committee member) / Arizona State University (Publisher)
Created2020