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- All Subjects: Neurosciences
- Creators: Olive, Michael F
- Resource Type: Text
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
After natural menopause in women, androstenedione becomes the primary hormone secreted by the residual follicle deplete ovaries. Two independent studies, in rodents that had undergone ovarian follicular depletion, found that higher serum androstenedione levels correlated with increased working memory errors. This led to the hypothesis that androstenedione impairs memory. The current study directly tested this hypothesis, examining the cognitive effects of androstenedione administration in a rodent model. Middle-aged ovariectomized rats received vehicle or one of two doses of androstenedione (4 or 8 mg/kg daily). Rats were tested on a spatial working and reference memory maze battery including the water radial arm maze, Morris maze, and delay-match-to-sample task. Results showed that androstenedione at the highest dose impaired reference memory and working memory, including ability to maintain performance as memory demand was elevated. The latter was true for both high temporal demand memory retention of one item of spatial information, as well as the ability to handle multiple items of spatial working memory information. Glutamic acid decarboxylase (GAD) levels were measured in multiple brain regions to determine whether the gamma-aminobutyric acid (GABA) system mediates androstenedione's cognitive impairments. Results showed that higher entorhinal cortex GAD levels were correlated with poorer Morris maze performance, regardless of androstenedione treatment. These findings suggest that androstenedione, the main hormone produced by the follicle deplete ovary, is detrimental to spatial learning, reference memory, and working memory, and that spatial reference memory performance might be related to the GABAergic system.
ContributorsCamp, Bryan Walter (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Olive, Michael F (Committee member) / Conrad, Cheryl D. (Committee member) / Arizona State University (Publisher)
Created2012
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
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
Description
The capability of cocaine-associated stimuli in eliciting craving in human addicts, even after extended periods of abstinence, is modeled in animals using cue reinstatement of extinguished cocaine-seeking behavior. This study aimed to examine brain activation in response to cocaine cues in this model apart from activation produced by test novelty using a novel cue control. Rats trained to self-administer cocaine paired with either an oscillating light or tone cue underwent daily extinction training and were then tested for reinstatement of extinguished cocaine-seeking behavior elicited by response-contingent presentations of either their assigned cocaine-paired cue or the alternate, novel cue. Additional controls received saline infusions and cue presentations yoked to a cocaine-trained rat. Brains were harvested for Fos immunohistochemistry immediately after the 90-min reinstatement test. Surprisingly, conditioned and novel cues both reinstated responding to a similar degree; however magnitude of reinstatement did vary by cue modality with the greatest reinstatement to the light cues. In most brain regions, Fos expression was enhanced in rats with a history of cocaine training regardless of cue type with the exception of the Cg1 region of the anterior cingulate cortex, which was sensitive to test cue modality. Also Fos expression within the dorsomedial caudate-putamen was correlated with responding in the novel, but not conditioned, cue groups. In subsequent experiments, we observed a similar pattern of reinstatement in rats trained and tested for sucrose-seeking behavior, whereas rats trained and tested with the cues only reinstated to a novel light and tone, but not a familiar cue. The results suggest that novel cues reinstate responding to a similar extent as conditioned cues regardless of whether animals have a history of operant-delivered drug or a natural reinforcer. Furthermore, similar brain circuits as those involved in cocaine-seeking behavior are activated by novel cues, suggesting converging processes exist to drive conditioned and novel reinforcement seeking.
ContributorsBastle, Ryan (Author) / Neisewander, Janet L (Thesis advisor) / Sanabria, Federico (Committee member) / Olive, Michael F (Committee member) / Arizona State University (Publisher)
Created2012
Description
A direct Magnetic Resonance (MR)-based neural activity mapping technique with high spatial and temporal resolution may accelerate studies of brain functional organization.
The most widely used technique for brain functional imaging is functional Magnetic Resonance Image (fMRI). The spatial resolution of fMRI is high. However, fMRI signals are highly influenced by the vasculature in each voxel and can be affected by capillary orientation and vessel size. Functional MRI analysis may, therefore, produce misleading results when voxels are nearby large vessels. Another problem in fMRI is that hemodynamic responses are slower than the neuronal activity. Therefore, temporal resolution is limited in fMRI. Furthermore, the correlation between neural activity and the hemodynamic response is not fully understood. fMRI can only be considered an indirect method of functional brain imaging.
Another MR-based method of functional brain mapping is neuronal current magnetic resonance imaging (ncMRI), which has been studied over several years. However, the amplitude of these neuronal current signals is an order of magnitude smaller than the physiological noise. Works on ncMRI include simulation, phantom experiments, and studies in tissue including isolated ganglia, optic nerves, and human brains. However, ncMRI development has been hampered due to the extremely small signal amplitude, as well as the presence of confounding signals from hemodynamic changes and other physiological noise.
Magnetic Resonance Electrical Impedance Tomography (MREIT) methods could have the potential for the detection of neuronal activity. In this technique, small external currents are applied to a body during MR scans. This current flow produces a magnetic field as well as an electric field. The altered magnetic flux density along the main magnetic field direction caused by this current flow can be obtained from phase images. When there is neural activity, the conductivity of the neural cell membrane changes and the current paths around the neurons change consequently. Neural spiking activity during external current injection, therefore, causes differential phase accumulation in MR data. Statistical analysis methods can be used to identify neuronal-current-induced magnetic field changes.
The most widely used technique for brain functional imaging is functional Magnetic Resonance Image (fMRI). The spatial resolution of fMRI is high. However, fMRI signals are highly influenced by the vasculature in each voxel and can be affected by capillary orientation and vessel size. Functional MRI analysis may, therefore, produce misleading results when voxels are nearby large vessels. Another problem in fMRI is that hemodynamic responses are slower than the neuronal activity. Therefore, temporal resolution is limited in fMRI. Furthermore, the correlation between neural activity and the hemodynamic response is not fully understood. fMRI can only be considered an indirect method of functional brain imaging.
Another MR-based method of functional brain mapping is neuronal current magnetic resonance imaging (ncMRI), which has been studied over several years. However, the amplitude of these neuronal current signals is an order of magnitude smaller than the physiological noise. Works on ncMRI include simulation, phantom experiments, and studies in tissue including isolated ganglia, optic nerves, and human brains. However, ncMRI development has been hampered due to the extremely small signal amplitude, as well as the presence of confounding signals from hemodynamic changes and other physiological noise.
Magnetic Resonance Electrical Impedance Tomography (MREIT) methods could have the potential for the detection of neuronal activity. In this technique, small external currents are applied to a body during MR scans. This current flow produces a magnetic field as well as an electric field. The altered magnetic flux density along the main magnetic field direction caused by this current flow can be obtained from phase images. When there is neural activity, the conductivity of the neural cell membrane changes and the current paths around the neurons change consequently. Neural spiking activity during external current injection, therefore, causes differential phase accumulation in MR data. Statistical analysis methods can be used to identify neuronal-current-induced magnetic field changes.
ContributorsFu, Fanrui (Author) / Sadleir, Rosalind (Thesis advisor) / Kodibagkar, Vikram (Committee member) / Kleim, Jeffrey (Committee member) / Muthuswamy, Jitendran (Committee member) / Helms Tillery, Stephen (Committee member) / Arizona State University (Publisher)
Created2019
Description
There is a critical need for creating an implantable microscale neural interface that can chronically monitor neural activity and oxygenation. These are key aspects for understating the development of impaired neural circuits and their functions. A technology with such capability would foster new insights in the studies of brain diseases and disorders. The propose is that MR-PISTOL (Proton imaging of Siloxane to Map Tissue Oxygenation Levels) imaging technique can be used for direct measurements of oxygen partial pressure at microelectrode-tissue interface. The strategy consists of coating microelectrodes with soft-silicone, a ultra-soft conductive PDMS (polydimethylsiloxane), as a carrier for liquid siloxanes MR-PISTOL contrast agents. This work presents a proof-of-concept of an injection molding technique for batch fabricate microelectrodes with such coating. Also, reports stability studies of soft-silicone loaded with liquid polydimethylsiloxane (PDMSO) in rodent brains. A batch of thirty coated carbon electrodes was achieved using candy molds. Coating uniformity was evaluated in twelve probes. They were randomly chosen and imaged with a custom image setup that allows 90o rotation of the probes. The total average coating thickness before and after rotation were 0.397 millimeters with standard deviation of 0.070 millimeters and 0.442 millimeters with standard deviation of 0.062 millimeters. Therefore, data confirms that this technique yields uniform coating. Stability of fabricated coated carbon electrodes unloaded (n= 3) and loaded with PDMSO (n= 3) was assessed. 3D X-ray imaging using Zeiss Xradia 520 machine was chosen for studying coatings mechanical stability in ex-vivo rat brain. Transmission electron microscopy (TEM) and scanning electron microscope (SEM) with an energy dispersive x-ray microanalysis (EDS) detector were used to investigate their chemical stability in in vivo mouse brain. Initial EDS analysis from TEM and SEM of acute (6 hours) and chronic (2 weeks) brain slices suggest that PDMSO does not leach into brain. More experiments should be done to confirm and endorse this finding. The mechanical study shows that coating loaded with PDMSO delaminated during insertion. This was not observed with electrodes used in the chemical stability studies. Further experiments need to be done to identify possible causes of mechanical failures.
Contributorsde Mesquita Teixeira, Livia (Author) / Muthuswamy, Jitendran (Thesis advisor, Committee member) / Kodibagkar, Vikram (Thesis advisor, Committee member) / Sridharan, Arati (Committee member) / Arizona State University (Publisher)
Created2018
Description
Compressed sensing magnetic resonance spectroscopic imaging (MRSI) is a noninvasive and in vivo potential diagnostic technique for cancer imaging. This technique undersamples the distribution of specific cancer biomarkers within an MR image as well as changes in the temporal dimension and subsequently reconstructs the missing data. This technique has been shown to retain a high level of fidelity even with an acceleration factor of 5. Currently there exist several different scanner types that each have their separate analytical methods in MATLAB. A graphical user interface (GUI) was created to facilitate a single computing platform for these different scanner types in order to improve the ease and efficiency with which researchers and clinicians interact with this technique. A GUI was successfully created for both prospective and retrospective MRSI data analysis. This GUI retained the original high fidelity of the reconstruction technique and gave the user the ability to load data, load reference images, display intensity maps, display spectra mosaics, generate a mask, display the mask, display kspace and save the corresponding spectra, reconstruction, and mask files. Parallelization of the reconstruction algorithm was explored but implementation was ultimately unsuccessful. Future work could consist of integrating this parallelization method, adding intensity overlay functionality and improving aesthetics.
ContributorsLammers, Luke Michael (Author) / Kodibagkar, Vikram (Thesis director) / Hu, Harry (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
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