Matching Items (7)
Filtering by

Clear all filters

153899-Thumbnail Image.png
Description
Many behaviors are organized into bouts – brief periods of responding punctuated by pauses. This dissertation examines the operant bouts of the lever pressing rat. Chapter 1 provides a brief history of operant response bout analyses. Chapters 2, 3, 5, and 6 develop new probabilistic models to identify changes in

Many behaviors are organized into bouts – brief periods of responding punctuated by pauses. This dissertation examines the operant bouts of the lever pressing rat. Chapter 1 provides a brief history of operant response bout analyses. Chapters 2, 3, 5, and 6 develop new probabilistic models to identify changes in response bout parameters. The parameters of those models are demonstrated to be uniquely sensitive to different experimental manipulations, such as food deprivation (Chapters 2 and 4), response requirements (Chapters 2, 4, and 5), and reinforcer availability (Chapters 2 and 3). Chapter 6 reveals the response bout parameters that underlie the operant hyperactivity of a common rodent model of attention deficit hyperactivity disorder (ADHD), the spontaneously hypertensive rat (SHR). Chapter 6 then ameliorates the SHR’s operant hyperactivity using training procedures developed from findings in Chapters 2 and 4. Collectively, this dissertation provides new tools for the assessment of response bouts and demonstrates their utility for discerning differences between experimental preparations and animal strains that may be otherwise indistinguishable with more primitive methods.
ContributorsBrackney, Ryan J (Author) / Sanabria, Federico (Thesis advisor) / Smith, Brian H. (Thesis advisor) / Neisewander, Janet (Committee member) / Killeen, Peter (Committee member) / Arizona State University (Publisher)
Created2015
134699-Thumbnail Image.png
Description
Nicotine use is an outstanding public health problem with associated social and economic consequences. Nicotine is an active alkaloid compound in tobacco and is recognized as a psychoactive drug. Preclinically, nicotine addiction and relapse can be modeled using a self-administration-reinstatement paradigm. Here, we used a nicotine self-administration and contingent cue-induced

Nicotine use is an outstanding public health problem with associated social and economic consequences. Nicotine is an active alkaloid compound in tobacco and is recognized as a psychoactive drug. Preclinically, nicotine addiction and relapse can be modeled using a self-administration-reinstatement paradigm. Here, we used a nicotine self-administration and contingent cue-induced reinstatement model to examine rapid, transient synaptic plasticity (t-SP) induced by nicotine cue-triggered motivation. Although preliminary, treatment with the NMDA GluN2B subunit antagonist, ifenprodil, reduced reinstated nicotine seeking, and increased the percentage of spines with smaller head diameters. Thus, future studies are needed to fully parse out the role of NAcore GluN2B receptors in cued nicotine seeking and t-SP.
ContributorsMccallum, Joseph John (Author) / Gipson-Reichardt, Cassandra (Thesis director) / Neisewander, Janet (Committee member) / Olive, Michael Foster (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
153854-Thumbnail Image.png
Description
Evidence from the 20th century demonstrated that early life stress (ELS) produces long lasting neuroendocrine and behavioral effects related to an increased vulnerability towards psychiatric illnesses such as major depressive disorder, post-traumatic stress disorder, schizophrenia, and substance use disorder. Substance use disorders (SUDs) are complex neurological and behavioral psychiatric illnesses.

Evidence from the 20th century demonstrated that early life stress (ELS) produces long lasting neuroendocrine and behavioral effects related to an increased vulnerability towards psychiatric illnesses such as major depressive disorder, post-traumatic stress disorder, schizophrenia, and substance use disorder. Substance use disorders (SUDs) are complex neurological and behavioral psychiatric illnesses. The development, maintenance, and relapse of SUDs involve multiple brain systems and are affected by many variables, including socio-economic and genetic factors. Pre-clinical studies demonstrate that ELS affects many of the same systems, such as the reward circuitry and executive function involved with addiction-like behaviors. Previous research has focused on cocaine, ethanol, opiates, and amphetamine, while few studies have investigated ELS and methamphetamine (METH) vulnerability. METH is a highly addictive psychostimulant that when abused, has deleterious effects on the user and society. However, a critical unanswered question remains; how do early life experiences modulate both neural systems and behavior in adulthood? The emerging field of neuroepigenetics provides a potential answer to this question. Methyl CpG binding protein 2 (MeCP2), an epigenetic tag, has emerged as one possible mediator between initial drug use and the transition to addiction. Additionally, there are various neural systems that undergo long lasting epigenetics changes after ELS, such as the response of the hypothalamo-pituitary-adrenal (HPA) axis to stressors. Despite this, little attention has been given to the interactions between ELS, epigenetics, and addiction vulnerability. The studies described herein investigated the effects of ELS on METH self-administration (SA) in adult male rats. Next, we investigated the effects of ELS and METH SA on MeCP2 expression in the nucleus accumbens and dorsal striatum. Additionally, we investigated the effects of virally-mediated knockdown of MeCP2 expression in the nucleus accumbens core on METH SA, motivation to obtain METH under conditions of increasing behavioral demand, and reinstatement of METH-seeking in rats with and without a history of ELS. The results of these studies provide insights into potential epigenetic mechanisms by which ELS can produce an increased vulnerability to addiction in adulthood. Moreover, these studies shed light on possible novel molecular targets for treating addiction in individuals with a history of ELS.
ContributorsLewis, Candace (Author) / Olive, M. Foster (Thesis advisor) / Hammer, Ronald (Committee member) / Neisewander, Janet (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2015
155638-Thumbnail Image.png
Description
Animals must learn to ignore stimuli that are irrelevant to survival, which is a process referred to as ‘latent inhibition’. This process has been shown to be genetically heritable (Latshaw JS, Mazade R, Sinakevitch I, Mustard JA, Gadau J, Smith BH (submitted)). The locus containing the AmTYR1 gene has been

Animals must learn to ignore stimuli that are irrelevant to survival, which is a process referred to as ‘latent inhibition’. This process has been shown to be genetically heritable (Latshaw JS, Mazade R, Sinakevitch I, Mustard JA, Gadau J, Smith BH (submitted)). The locus containing the AmTYR1 gene has been shown through quantitative trait loci mapping to be linked to strong latent inhibition in honey bees. The Smith lab has been able to show a correlation between learning and the AmTYR1 receptor gene through pharmacological inhibition of the receptor. In order to further confirm this finding, experiments were designed to test how honey bees learn with this receptor knocked out. Here this G-protein coupled receptor for the biogenic amine tyramine is implemented as an important factor underlying latent inhibition in honey bees. It is shown that double-stranded RNA (dsRNA) and Dicer-substrate small interfering RNA (dsiRNA) that are targeted to disrupt the tyramine receptors specifically affects latent inhibition but not excitatory associative conditioning. The results therefore identify a distinct reinforcement pathway for latent inhibition in insects.
ContributorsPetersen, Mary Margaret (Author) / Smith, Brian H. (Thesis advisor) / Wang, Ying (Committee member) / Neisewander, Janet (Committee member) / Sinakavich, Irina (Committee member) / Arizona State University (Publisher)
Created2017
151450-Thumbnail Image.png
Description
Sensory gating is a process by which the nervous system preferentially admits stimuli that are important for the organism while filtering out those that may be meaningless. An optimal sensory gate cannot be static or inflexible, but rather plastic and informed by past experiences. Learning enables sensory gates to recognize

Sensory gating is a process by which the nervous system preferentially admits stimuli that are important for the organism while filtering out those that may be meaningless. An optimal sensory gate cannot be static or inflexible, but rather plastic and informed by past experiences. Learning enables sensory gates to recognize stimuli that are emotionally salient and potentially predictive of positive or negative outcomes essential to survival. Olfaction is the only sensory modality in mammals where sensory inputs bypass conventional thalamic gating before entering higher emotional or cognitive brain regions. Thus, olfactory bulb circuits may have a heavier burden of sensory gating compared to other primary sensory circuits. How do the primary synapses in an olfactory system "learn"' in order to optimally gate or filter sensory stimuli? I hypothesize that centrifugal neuromodulator serotonin serves as a signaling mechanism by which primary olfactory circuits can experience learning informed sensory gating. To test my hypothesis, I conditioned genetically-modified mice using reward or fear olfactory-cued learning paradigms and used pharmacological, electrophysiological, immunohistochemical, and optical imaging approaches to assay changes in serotonin signaling or functional changes in primary olfactory circuits. My results indicate serotonin is a key mediator in the acquisition of olfactory fear memories through the activation of its type 2A receptors in the olfactory bulb. Functionally within the first synaptic relay of olfactory glomeruli, serotonin type 2A receptor activation decreases excitatory glutamatergic drive of olfactory sensory neurons through both presynaptic and postsynaptic mechanisms. I propose that serotonergic signaling decreases excitatory drive, thereby disconnecting olfactory sensory neurons from odor responses once information is learned and its behavioral significance is consolidated. I found that learning induced chronic changes in the density of serotonin fibers and receptors, which persisted in glomeruli encoding the conditioning odor. Such persistent changes could represent a sensory gate stabilized by memory. I hypothesize this ensures that the glomerulus encoding meaningful odors are much more sensitive to future serotonin signaling as such arousal cues arrive from centrifugal pathways originating in the dorsal raphe nucleus. The results advocate that a simple associative memory trace can be formed at primary sensory synapses to facilitate optimal sensory gating in mammalian olfaction.
ContributorsLi, Monica (Author) / Tyler, William J (Thesis advisor) / Smith, Brian H. (Thesis advisor) / Duch, Carsten (Committee member) / Neisewander, Janet (Committee member) / Vu, Eric (Committee member) / Arizona State University (Publisher)
Created2012
151807-Thumbnail Image.png
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,

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
147512-Thumbnail Image.png
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

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