Matching Items (75)
Description
The maternal separation (MS) paradigm is an animal model of early life stress. Animals subjected to MS during the first two weeks of life display altered behavioral and neuroendocrinological stress responses as adults. MS also produces altered responsiveness to and self-administration (SA) of various drugs of abuse including cocaine, ethanol, opioids, and amphetamine. Methamphetamine (METH) causes great harm to both the individual user and to society; yet, no studies have examined the effects of MS on METH SA. This study was performed to examine the effects of MS on the acquisition of METH SA, extinction, and reinstatement of METH-seeking behavior in adulthood. Given the known influence of early life stress and drug exposure on epigenetic processes, group differences in levels of the epigenetic marker methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) core were also investigated. Long-Evans pups and dams were separated on postnatal days (PND) 2-14 for either 180 (MS180) or 15 min (MS15). Male offspring were allowed to acquire METH SA (0.05 mg/kg/infusion) in 15 2-hr daily sessions starting at PND67, followed by extinction training and cue-induced reinstatement of METH-seeking behavior. Rats were then assessed for MeCP2 levels in the NAc core by immunohistochemistry. The MS180 group self-administered significantly more METH and acquired SA earlier than the MS15 group. No group differences in extinction or cue-induced reinstatement were observed. MS15 rats had significantly elevated MeCP2-immunoreactive cells in the NAc core as compared to MS180 rats. Together, these data suggest that MS has lasting influences on METH SA as well as epigenetic processes in the brain reward circuitry.
ContributorsLewis, Candace (Author) / Olive, Micheal F (Thesis advisor) / Conrad, Cheryl (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2013
Description
Glioblastoma multiforme is associated with a very low survival rate and is recognized as the most vicious form of intracranial cancer. The Akt gene pathway has three different isoforms, each of which has a different role in the tumors of GBM. Preliminary data suggests that Akt3 may work to decrease tumorigenicity. A produced image that visualizes the subcellular localization of Akt3 led the author to believe that Akt3 may reduce tumorigenicity by decreasing genomic instability caused by the cancer. To explore this, flow cytometry was performed on GBM cell lines with Akt3v1 over-expression, Akt3v2 over-expression, and a control glioma cell line.
ContributorsGhorayeb, Antoine (Author) / Neisewander, Janet (Thesis director) / Diehnelt, Chris (Committee member) / Moussallem, Suzan (Committee member) / Barrett, The Honors College (Contributor) / College of Liberal Arts and Sciences (Contributor)
Created2012-12
Description
Previous findings from our lab have demonstrated that nicotine and social reward have synergistic effects when experienced together versus when experienced separately. The purpose of this experiment is to understand the neural mechanisms underlying this synergistic effect by quantifying Fos protein, a marker for neural activation, in various brain regions. We utilized the conditioning place preference (CPP) model to assess reward. Four groups of adolescent male rats (n=120) were given either nicotine (Nic) (0.1 mg/kg/mL) or saline (Sal) and were placed in the CPP apparatus either with a social partner (Soc) or alone (Iso). Thus, groups were: 1.)Sal+Iso, 2).Sal+Soc, 3).Nic+Iso, 4).Nic+Soc. Brains of some the rats (n=40) were collected for Fos staining 90 minutes after the last conditioning session to obtain Fos data in response to direct exposure to the stimuli. The following regions were analyzed for Fos expression: central amygdala (CeA), medial amygdala (MeA), basolateral amygdala (BLA), nucleus accumbens core (NAcCore), and nucleus accumbens shell (NAcShell). Place preference changes occurred in socially-conditioned groups reflecting social reward and in nicotine-conditioned groups reflecting nicotine reward. As expected, the Sal+Iso control group failed to display a preference change. Fos data revealed a significant increase in Fos expression in the CeA, MeA, NAcCore and NAcShell for socially-conditioned animals and a significant decrease in the NAcCore for nicotine-conditioned groups. Experiencing both social and nicotine rewards together appeared to produce greater activation in the BLA. However, there was an increase in Fos expression in the negative control group relative to Nic+Iso group. The results of CPP suggest that social, nicotine and their combination are rewarding. The combination of the nicotine and social reward could have been more rewarding than social and nicotine separately, but the test was not sensitive to reward magnitude. The increase in Fos expression in the negative control group in the BLA could be due to isolation stress. Overall, these results suggest that these brain regions had greater activation to social reward.
ContributorsGoenaga, Julianna Gloria (Author) / Neisewander, Janet (Thesis director) / Orchinik, Miles (Committee member) / Olive, Michael (Committee member) / Barrett, The Honors College (Contributor) / School of Historical, Philosophical and Religious Studies (Contributor) / School of Life Sciences (Contributor)
Created2013-05
Description
As the incidence of dementia continues to rise, the need for an effective and non-invasive method of intervention has become increasingly imperative. Music therapy has exhibited these qualities in addition to relatively low implementation costs, therefore establishing itself as a promising means of therapeutic intervention. In this review, current research was investigated in order to determine its effectiveness and uncover the neurochemical mechanisms that lead to positive manifestations such as improved memory recall, increased social affiliation, increased motivation, and decreased anxiety. Music therapy has been found to improve several aspects of memory recall. One proposed mechanism involves temporal entrainment, during which the melodic structures present in music provide a framework for chunking information. Although entrainment's role in the treatment of motor defects has been thoroughly studied, its role in treating cognitive disorders is still relatively new. Musicians have also been shown to demonstrate extensive plastic changes; therefore, it is hypothesized that non-musicians may also glean some benefits from engaging in music. Social affiliation has been found to increase due to increases in endogenous oxytocin. Oxytocin has also been shown to strengthen hippocampal spike transmission, a promising outcome for Alzheimer's patients. An increase in motivation has also been found to occur due to music's ability to tap into the reward center of the brain. Dopaminergic transmission between the VTA, NAc and higher functioning regions such as the OFC and hypothalamus has been revealed. Additionally, relaxing music decreases stress levels and modifies associated autonomic processes, i.e. heart rate, blood pressure, and respiratory rate. On the contrary, stimulating music has been found to initiate sympathetic nervous system activity. This is thought to occur by either a reflexive brainstem response or stimulus interpretation by the amygdala.
ContributorsFlores, Catalina Nicole (Author) / Redding, Kevin (Thesis director) / Hoffer, Julie (Committee member) / Neisewander, Janet (Committee member) / School of Molecular Sciences (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
In 2014 alone, 40% of all drug abuse-related emergency department visits involved cocaine, and despite the detrimental effects there is still no FDA approved treatment for cocaine use disorders (CUDs; Dawn, 2014). Studies show that serotonin 1B receptor (5HT1BR) agonists modulate cocaine abuse-related behaviors in opposite directions depending on the phase of the addiction cycle in male rats. In particular, the selective 5HT1BR agonist, CP94,253, facilitates cocaine intake during maintenance of daily cocaine self-administration. Paradoxically, after 21 days of abstinence, CP94,253 attenuates cocaine intake in male rats on a low effort fixed ratio 5 (FR5) and a high effort progressive ratio (PR) schedule of reinforcement. PR measures motivation as it requires an exponentially increasing number of lever responses to obtain the next reinforcer after a successful reinforcer. In contrast to male rats, we recently found CP94,253 attenuates cocaine intake before and after abstinence on an FR5 schedule of reinforcement in female rats, suggesting the attenuating effects of CP94,253 on cocaine intake is not dependent on a period of abstinence in females. However, the effect of CP94,253 on motivation for cocaine has not yet been examined in female rats. Therefore, we addressed this gap in the present study. Female Sprague-Dawley rats were trained to self-administer 0.375 mg/kg, IV cocaine or to obtain sucrose pellets (45 mg) on a PR schedule of reinforcement and were then pretreated with vehicle or CP94,253 (3.2, 5.6 and 10 mg/kg, SC) prior to their self-administration session. A separate cohort was pretreated with CP94,253 to examine the effects of CP94,253 on cocaine-seeking behavior (i.e., operant responses when cocaine is no longer available) and spontaneous locomotion after 21 or 60 days of abstinence. The preliminary findings show that CP94,253 has minimal impacts on decreasing cocaine intake on a PR schedule in female rats but decreases cue reactivity up to 60 days after abstinence in female rats. These findings suggest that 5-HT1BR agonists may be useful treatments for cocaine craving.
ContributorsRuscitti, Brielle Allesandra (Author) / Neisewander, Janet (Thesis director) / Powell, Gregory (Committee member) / Scott, Samantha (Committee member) / School of Life Sciences (Contributor, Contributor) / School of Human Evolution & Social Change (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Traumatic brain injury involves a primary mechanical injury that is followed by a secondary<br/>inflammatory cascade. The inflammatory cascade in the CNS releases cytokines which are<br/>associated with leukocytosis and a systemic immune response. Acute changes to peripheral<br/>immune cell populations post-TBI include a 4.5-fold increase of neutrophils 3 hours post-injury,<br/>and 2.7-fold or higher increase of monocytes 24 hours post-injury. Flow Cytometry is a<br/>technique that integrates fluidics, optics, and electronics to characterize cells based on their light<br/>scatter and antigen expression via monoclonal antibodies conjugated to fluorochromes. Flow<br/>cytometry is a valuable tool in cell characterization however the standard technique for data<br/>analysis, manual gating, is associated with inefficiency, subjectivity, and irreproducibility.<br/>Unsupervised analysis that uses algorithms packaged as plug-ins for flow cytometry analysis<br/>software has been discussed as a solution to the limits of manual gating and as an alternative<br/>method of data visualization and exploration. This investigation evaluated the use of tSNE<br/>(dimensionality reduction algorithm) and FlowSOM (population clustering algorithm)<br/>unsupervised flow cytometry analysis of immune cell population changes in female mice that<br/>have been exposed to a LPS-induced systemic inflammatory challenge, results were compared to<br/>those of manual gating. Flow cytometry data was obtained from blood samples taken prior to and<br/>24 hours after LPS injection. Unsupervised analysis was able to identify populations of<br/>neutrophils and pro-inflammatory/anti-inflammatory monocytes, it also identified several more<br/>populations however further inquiry with a more specific fluorescent panel would be required to<br/>establish the specificity and validity of these populations. Unsupervised analysis with tSNE and<br/>FlowSOM demonstrated the efficient and intuitive nature of the technique, however it also<br/>illustrated the importance of the investigator in preparing data and modulating plug-in settings.
ContributorsDudic, Ahmed (Author) / Stabenfeldt, Sarah (Thesis director) / Lifshitz, Jonathan (Committee member) / Rojas, Luisa (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Free coenzyme A (CoASH) carries acyl groups for the tricarboxylic acid (TCA) cycle and fatty acid metabolism, and donates acyl groups for protein posttranslational modifications. Cellular de novo CoASH synthesis starts with a pantothenate kinase (PANK1-3) phosphorylating pantothenate (vitamin B5). Mutations in PANK2 cause a subtype of neurodegeneration with brain iron accumulation (NBIA). The PANKs have differential subcellular distribution and regulatory properties. However, the purpose of each PANK has remained obscure, with knockout mouse models presenting with mild phenotypes unless challenged with a high-fat diet. Based on PANK2’s known activation by palmitoylcarnitine, the PANK2-deficient cells were challenged with palmitic acid (PAL) added to glucose-containing media. The high nutrient mixture generated a surprising “starvation” profile of reduced proliferation, low ATP, AMPK activation, and autophagy upregulation in PANK2-deficient PAL-challenged cells. Further experiments showed that fatty acids accumulated and that PANK2-deficient cells had reduced respiration when provided with palmitoylcarnitine as a substrate, seemingly due to an impaired ability to oxidize fatty acids during PAL-induced Randle Cycle activation. Intriguingly, whole-cell CoASH levels remained stable despite the PAL-induced starvation phenotype, and increasing CoASH via PANK1β overexpression did not rescue the phenotype, demonstrating a unique role for PANK2 in fatty acid metabolism. Even though a direct CoASH deficiency was not detected, there were changes in short chain CoA-derivatives, including acetyl-CoA, succinyl-CoA, and butyryl-CoA, as well as evidence of impaired TCA cycle function. These impairments in both the TCA cycle and fatty acid oxidation implicate a role for PANK2 in regulating mitochondria CoA dynamics.
ContributorsNordlie, Sandra Maria (Author) / Kruer, Michael C (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Padilla Lopez, Sergio (Committee member) / Katsanos, Christos (Committee member) / Arizona State University (Publisher)
Created2022
Description
Serotonin 1B receptors (5-HT1BRs) are a novel target for developing pharmacological therapies to reduce psychostimulant craving. 5-HT1BRs are expressed in the mesolimbic pathway projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), which is involved in reward and motivation. 5-HT1BR agonists modulate both cocaine- and methamphetamine-seeking behaviors in rat models of psychostimulant craving. In this dissertation, I tested the central hypothesis that 5-HT1BRs regulate cocaine and methamphetamine stimulant and rewarding effects in mice. I injected mice daily with cocaine for 20 days and then tested them 20 days after their last injection. The results showed that the 5-HT1BR agonist CP94253 attenuated sensitization of cocaine-induced locomotion and cocaine-seeking behavior, measured as a decrease in the ability of a cocaine priming injection to reinstate extinguished cocaine-conditioned place preference (CPP). Subsequent experiments showed that CP94253 given prior to conditioning sessions had no effect on acquisition of methamphetamine-CPP, a measure of drug reward; however, CP94253 given prior to testing attenuated expression of methamphetamine-CPP, a measure of drug seeking. To examine brain regions and cell types involved in CP94253 attenuation of methamphetamine-seeking, I examined changes in the immediate early gene product, Fos, which is a marker of brain activity involving gene transcription changes. Mice expressing methamphetamine-CPP showed elevated Fos expression in the VTA and basolateral amygdala (BlA), and reduced Fos in the central nucleus of the amygdala (CeA). In mice showing CP94253-induced attenuation of methamphetamine-CPP expression, Fos was increased in the VTA, NAc shell and core, and the dorsal medial caudate-putamen. CP94253 also reversed the methamphetamine-conditioned decrease in Fos expression in the CeA and the increase in the BlA. In drug-naïve, non-conditioned control mice, CP94253 only increased Fos in the CeA, suggesting that the increases observed in methamphetamine-conditioned mice were due to conditioning rather than an unconditioned effect of CP94253 on Fos expression. In conclusion, 5-HT1BR stimulation attenuates both cocaine and methamphetamine seeking in mice, and that the latter effect may involve normalizing activity in the amygdala and increasing activity in the mesolimbic pathway. These findings further support the potential efficacy of 5-HT1BR agonists as pharmacological interventions for psychostimulant craving in humans.
ContributorsDer-Ghazarian, Taleen (Author) / Neisewander, Janet (Thesis advisor) / Olive, Foster (Committee member) / Newbern, Jason (Committee member) / Wu, Jie (Committee member) / Arizona State University (Publisher)
Created2018
Description
LKB1/STK11 is a serine/threonine kinase first identified in C.elegans as a gene important for cell polarity and proliferation. Mutations in LKB1 are the primary cause of Peutz-Jegher’s cancer syndrome, an autosomal dominantly inherited disease, in which patients are predisposed to benign and malignant tumors. Past studies have focused on defining LKB1 functions in various tissue types, for example LKB1 regulates axonal polarization and dendritic arborization by activating downstream substrates in excitatory neurons of the developing neocortex. However, the implications of LKB1, specifically in the developing cortical inhibitory GABAergic interneurons is unknown. LKB1 deletion was achieved by using Cre-lox technology to induce LKB1 loss in cells localized in the medial ganglionic eminence (MGE) that express Nkx2.1 and generate cortical GABAergic neurons. In this research study it is suggested that LKB1 plays a role in GABAergic interneuron specification by specifically regulating the expression of parvalbumin during the development of fast-spiking interneurons. Preliminary evidence suggest LKB1 also modulates the number of Nkx2.1-derived oligodendrocytes in the cortex. By utilizing a GABAergic neuron specific LKB1 deletion mutant, we confirmed that the loss of parvalbumin expression was due to a GABAergic neuron autonomous function for LKB1. These data provide new insight into the cell specific functions of LKB1 in the developing brain.
ContributorsSebastian, Rebecca (Author) / Newbern, Jason (Thesis advisor) / Neisewander, Janet (Committee member) / Gipson-Reichardt, Cassandra (Committee member) / Arizona State University (Publisher)
Created2019
Description
MicroRNAs are small, non-coding transcripts that post-transcriptionally regulate expression of multiple genes. Recently microRNAs have been linked to the etiology of neuropsychiatric disorders, including drug addiction. Following genome-wide sequence analyses, microRNA-495 (miR-495) was found to target several genes within the Knowledgebase of Addiction-Related Genes (KARG) database and to be highly expressed in the nucleus accumbens (NAc), a pivotal brain region involved in reward and motivation. The central hypothesis of this dissertation is that NAc miR-495 regulates drug abuse-related behavior by targeting several addiction-related genes (ARGs). I tested this hypothesis in two ways: 1) by examining the effects of viral-mediated miR-495 overexpression or inhibition in the NAc of rats on cocaine abuse-related behaviors and gene expression, and 2) by examining changes in NAc miR-495 and ARG expression as a result of brief (i.e., 1 day) or prolonged (i.e., 22 days) cocaine self-administration. I found that behavioral measures known to be sensitive to motivation for cocaine were attenuated by NAc miR-495 overexpression, including resistance to extinction of cocaine conditioned place preference (CPP), cocaine self-administration on a high effort progressive ratio schedule of reinforcement, and cocaine-seeking behavior during both extinction and cocaine-primed reinstatement. These effects appeared specific to cocaine, as there was no effect of NAc miR-495 overexpression on a progressive ratio schedule of food reinforcement. In contrast, behavioral measures known to be sensitive to cocaine reward were not altered, including expression of cocaine CPP and cocaine self-administration under a low effort FR5 schedule of reinforcement. Importantly, the effects were accompanied by decreases in NAc ARG expression, consistent with my hypothesis. In further support, I found that NAc miR-495 levels were reduced and ARG levels were increased in rats following prolonged, but not brief, cocaine self-administration experience. Surprisingly, inhibition of NAc miR-495 expression also decreased both cocaine-seeking behavior during extinction and NAc ARG expression, which may reflect compensatory changes or unexplained complexities in miR-495 regulatory effects. Collectively, the findings suggest that NAc miR-495 regulates ARG expression involved in motivation for cocaine. Therefore, using microRNAs as tools to target several ARGs simultaneously may be useful for future development of addiction therapeutics.
ContributorsBastle, Ryan (Author) / Neisewander, Janet (Thesis advisor) / Newbern, Jason (Committee member) / Nikulina, Ella (Committee member) / Perrone-Bizzozero, Nora (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2016