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- Creators: Neisewander, Janet
Description
Food is an essential driver of animal behavior. For social organisms, the acquisition of food guides interactions with the environment and with group-mates. Studies have focused on how social individuals find and choose food sources, and share both food and information with group-mates. However, it is often not clear how experiences throughout an individual's life influence such interactions. The core question of this thesis is how individuals’ experience contributes to within-caste behavioral variation in a social group. I investigate the effects of individual history, including physical injury and food-related experience, on individuals' social food sharing behavior, responses to food-related stimuli, and the associated neural biogenic amine signaling pathways. I use the eusocial honey bee (Apis mellifera) system, one in which individuals exhibit a high degree of plasticity in responses to environmental stimuli and there is a richness of communicatory pathways for food-related information. Foraging exposes honey bees to aversive experiences such as predation, con-specific competition, and environmental toxins. I show that foraging experience changes individuals' response thresholds to sucrose, a main component of adults’ diets, depending on whether foraging conditions are benign or aversive. Bodily injury is demonstrated to reduce individuals' appetitive responses to new, potentially food-predictive odors. Aversive conditions also impact an individual's social food sharing behavior; mouth-to-mouse trophallaxis with particular groupmates is modulated by aversive foraging conditions both for foragers who directly experienced these conditions and non-foragers who were influenced via social contact with foragers. Although the mechanisms underlying these behavioral changes have yet to be resolved, my results implicate biogenic amine signaling pathways as a potential component. Serotonin and octopamine concentrations are shown to undergo long-term change due to distinct foraging experiences. My work serves to highlight the malleability of a social individual's food-related behavior, suggesting that environmental conditions shape how individuals respond to food and share information with group-mates. This thesis contributes to a deeper understanding of inter-individual variation in animal behavior.
ContributorsFinkelstein, Abigail (Author) / Amdam, Gro V (Thesis advisor) / Conrad, Cheryl (Committee member) / Smith, Brian (Committee member) / Neisewander, Janet (Committee member) / Bimonte-Nelson, Heather A. (Committee member) / Arizona State University (Publisher)
Created2017
Description
Approximately 2.8 million Americans seek medical care for traumatic brain injury (TBI) each year. Of this population, the majority are sufferers of diffuse TBI, or concussion. It is unknown how many more individuals decline to seek medical care following mild TBI. This likely sizeable population of un- or self-treated individuals combined with a lack of definitive biomarkers or objective post-injury diagnostics creates a unique need for practical therapies among diffuse TBI sufferers. Practical therapies stand to decrease the burden of TBI among those who would otherwise not seek treatment or do not meet clinical diagnostic criteria upon examination. For this unique treatment niche, practical therapies for TBI are defined as having one or more of the following qualities: common availability, easy administration, excellent safety profile, and cost-effectiveness. This dissertation identifies and critically examines the efficacy of four classes of practical treatments in improving rodent outcome from experimental diffuse traumatic brain injury.
Over-the-counter (OTC) analgesics, omega-3 fatty acids, specialized pro-resolving mediators (SPMs), and remote ischemic conditioning (RIC) were administered before or following midline fluid percussion injury. Behavioral, histological, and molecular analyses were used to assess treatment effects on functional outcome and secondary injury progression. Acute administration of common OTC analgesics had little effect on post-injury outcome in mice. Dietary supplementation with omega-3 fatty acid docosahexaenoic acid (DHA) prior to or following diffuse TBI significantly reduced injury-induced sensory sensitivity and markers of neuroinflammation with no effect on spatial learning. Intraperitoneal administration of omega-3 fatty acid-derived SPM resolvin E1 significantly increased post-injury sleep and suppressed microglial activation. Aspirin-triggered (AT) resolvin D1 administration improved both motor and cognitive outcome following diffuse TBI. RIC treatment in mice demonstrated little effect on functional outcome from diffuse TBI. Untargeted proteomic analysis of plasma samples from RIC-treated mice was used to identify candidate molecular correlates of RIC. Identification of these candidates represents a vital first step in elucidating the neuroprotective mechanisms underlying RIC. The overall findings suggest that omega-3 fatty acid supplementation, SPM administration, and RIC may serve as effective practical therapies to reduce the somatic, cognitive, and neurological burden of diffuse TBI felt by millions of Americans.
Over-the-counter (OTC) analgesics, omega-3 fatty acids, specialized pro-resolving mediators (SPMs), and remote ischemic conditioning (RIC) were administered before or following midline fluid percussion injury. Behavioral, histological, and molecular analyses were used to assess treatment effects on functional outcome and secondary injury progression. Acute administration of common OTC analgesics had little effect on post-injury outcome in mice. Dietary supplementation with omega-3 fatty acid docosahexaenoic acid (DHA) prior to or following diffuse TBI significantly reduced injury-induced sensory sensitivity and markers of neuroinflammation with no effect on spatial learning. Intraperitoneal administration of omega-3 fatty acid-derived SPM resolvin E1 significantly increased post-injury sleep and suppressed microglial activation. Aspirin-triggered (AT) resolvin D1 administration improved both motor and cognitive outcome following diffuse TBI. RIC treatment in mice demonstrated little effect on functional outcome from diffuse TBI. Untargeted proteomic analysis of plasma samples from RIC-treated mice was used to identify candidate molecular correlates of RIC. Identification of these candidates represents a vital first step in elucidating the neuroprotective mechanisms underlying RIC. The overall findings suggest that omega-3 fatty acid supplementation, SPM administration, and RIC may serve as effective practical therapies to reduce the somatic, cognitive, and neurological burden of diffuse TBI felt by millions of Americans.
ContributorsHarrison, Jordan L (Author) / Lifshitz, Jonathan (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Willyerd, Frederick A (Committee member) / Pirrotte, Patrick (Committee member) / Arizona State University (Publisher)
Created2017
Description
Research suggests that the more positive the first drug experience, the more likely addiction will develop. Since smoking is initiated in a social setting, it is surprising how little is known about social context effects on acquisition of nicotine self-administration. We investigated this issue in rats during late adolescence using conjoined self-administration chambers that had a removable shared wall. Rats were assigned to training conditions with either a solid black plexiglass or wire mesh partition in place throughout 22 subsequent 2-hour daily training sessions. Initially, 58 day-old (late-adolescent) male and female rats received 2, 30-min habituation sessions/day over 2 consecutive days, with only an inactive lever present. Sessions began with presentation of a retractable lever and thereafter each response on that lever resulted in simultaneous delivery of saline or 1 of 2 doses of nicotine (0.015 or 0.030 mg/kg, IV) and lever retraction for a 20-second time out. The findings indicate that the social context inhibits nicotine self-administration in female rats during the development of addiction, but has little effect on the initial stages of drug acquisition. Furthermore, the data suggest that in male rats the social context enhances responding independent of nicotine, but has few effects on nicotine self-administration during the development of addiction. The findings have important implications for substance use disorders.
ContributorsDufwenberg, Martin (Author) / Neisewander, Janet (Thesis director) / Deviche, Pierre (Committee member) / Peartree, Natalie (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Statistical Sciences (Contributor) / School of Politics and Global Studies (Contributor) / School of Life Sciences (Contributor)
Created2015-05
Description
Cocaine is a powerful psychomotor stimulant that can affect serotonin (5HT), dopamine, and norepinephrine systems in the brain. Previous studies with 5HT1B receptor agonist, CP94253, have shown dose-dependent decreases in cocaine-self administration in male rats during maintenance. However, these studies do not take into consideration sex differences between male rats and female rats. Female rats introduce a new complexity because they constantly undergo an estrous cycle that consists of four phases, metestrus, diestrus, proestrus, and estrus. It was hypothesized that cocaine infusions and active lever response rates would greatly decrease during proestrus and estrus in comparison to metestrus and diestrus due to hormonal level differences of LH, FSH, progesterone, and estradiol. In this study, female rats were trained to self-administer a training dose of 0.75 mg/kg/infusion on a fixed progressive ratio (FR5). Rats were then pretreated with CP94253 to test the effects of this 5HT1B agonist on female rat cocaine self-administration during the estrous cycle. Results showed there was no three-way interaction between cycle phase, pretreatment, and cocaine dose on infusions or active lever responses. However, pretreatment with CP94253 decreased cocaine intake and active lever responses at high cocaine doses, regardless of cycle phase. Lastly, there was a two-way interaction between pretreatment and cycle phase in which active lever responses decreased during diestrus and proestrus. These results imply that CP94253 enhances cocaine's effect regardless of cycle phase. Future work can work with ovariectomized (OVX) female rats to observe cocaine self-administration during controlled cycle phases.
ContributorsNguyen, Toan Thai Tran (Author) / Neisewander, Janet (Thesis director) / Gipson-Reichardt, Cassandra (Committee member) / Scott, Samantha (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Substance abuse disorders affect 15.3 million people worldwide. The field has primarily focused on dopaminergic drugs as treatments for substance use disorders. However, recent work has demonstrated the potential of serotonergic compounds to treat substance abuse. Specifically, the serotonin 1B receptor (5-HT1BR), a Gi-coupled receptor located throughout the mesocorticolimbic dopamine system, has been implicated in the incentive motivational and rewarding effects of cocaine. Our research suggests that the stimulation of 5-HT1BRs produces different effects at various time points in the addiction cycle. During maintenance of chronic cocaine administration, 5-HT1BR stimulation has a facilitative effect on the reinforcing properties of cocaine. However 5-HT1BR stimulation exhibits inhibitory effects on reinforcement during prolonged abstinence from cocaine. The aim of this study was to examine the possibility of a switch in the functional role of 5-HT1BRs in the locomotor effects of cocaine at different time points of chronic cocaine administration in mice. We found that the 5-HT1BR agonist CP 94,253 increased locomotor activity in mice tested one day after the last chronic cocaine administration session regardless of whether the chronic treatment was cocaine or saline and regardless of challenge injection (i.e., cocaine or saline). Yet after abstinence, CP 94,253 induced a decrease in locomotor activity in mice challenged with saline and attenuated cocaine-induced locomotion relative to cocaine challenge after vehicle pretreatment. These findings suggest that a switch in the functional role of 5-HT1BR is observed at different stages of the addiction cycle and further suggest that clinical applications of drugs acting on 5-HT1BR should consider these effects.
ContributorsBrunwasser, Samuel Joshua (Author) / Neisewander, Janet (Thesis director) / Pentkowski, Nathan (Committee member) / Der-Ghazarian, Taleen (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / Department of Psychology (Contributor)
Created2014-05
Description
The serotonin (5-hydroxytryptamine, 5-HT) system is implicated in the study of drug addiction. Of the 14 known serotonin receptor subtypes, the 5-HT7R is the most recently discovered and, therefore, one of the least rigorously studied. However, the 5-HT7R has been shown to play a role in multiple psychiatric conditions, including depression, anxiety, and alcoholism. This is not surprising, as the 5-HT7R is expressed in brain regions associated with emotion and reward, such as the amygdala, dorsal raphe nucleus, and striatum. MC-RG19 is a novel 5-HT7R antagonist which has >114-fold selectivity for the 5-HT7 over other serotonin receptors. This compound was developed by our collaborators at the Temple University School of Pharmacy. Due to this specificity, and the implications of the 5-HT7 in behavior, we hypothesized that MC-RG19 would have an effect on addiction-related behaviors. We investigated the effects of MC-RG19 on spontaneous locomotion, cue-induced reinstatement, and cocaine/sucrose multiple schedule self-administration. We observed a dose-dependent decrease in spontaneous locomotor activity with significance at a MC-RG19 dose of 10 mg/kg. A dose of 5.6 mg/kg, which did not significantly decrease locomotion, significantly reduces cocaine-seeking behavior (active lever pressing) in response to the reintroduction of drug-paired cues after a period of extinction. No dose (3, 5.6, or 10 mg/kg) produced a significant effect on a multiple schedule of self-administration with alternating availability of sucrose and cocaine as the reinforcer. These results indicate that MC-RG19 has an effect on the incentive \u2014 motivational properties of reward-paired cues.
ContributorsCarlson, Andrew Kenneth (Author) / Neisewander, Janet (Thesis director) / Gipson-Reichardt, Cassandra (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Abstract White matter thickness correlates with various mental illness. Commissure white matter tracts are responsible for interconnecting the same cortical area in both hemispheres. Injury to the brain can result in thinning and shrinkage even collapsing and detachment of the white matter tracts' myelin sheaths. Injury can affect cognitive function and time points are essential for therapeutic intervention. Research is beginning to identify gradual long-term neurodegenerative effects. With the advancement of brain imaging technology, we know that Wallerian degeneration has a significant negative impact on the white matter tracts throughout the brain (Johnson, Stewart, & Smith, 2013). If major tracts become injured like, the corpus callosum, then it can affect interhemispheric communication. Once myelin is damaged the axon becomes vulnerable, and the mechanisms of nerve recovery are not well known. Myelin sheath recovery has been studied in hopes to proliferate the oligodendrocytes that make up for the atrophied myelin. Neurotoxic chemicals released at activation of macrophages which hinders the brains ability to proliferate myelin protein needed for myelin differentiation adequately. In the central nervous system myelin has mechanisms to recover. Neurogenesis is a naturally occurring recovery mechanism seen after brain injury. Understanding the time points in which brain recovery occurs is important for treatment of diffuse injuries that cannot be identified through some imaging techniques. To better understand critical timepoints of natural recovery after brain injury can allow further investigation for early intervention to promote adequate recovery.
ContributorsLiptow, Kristen Ashley (Author) / Neisewander, Janet (Thesis director) / Law, L. Matthew (Committee member) / School of Social and Behavioral Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-12
Description
Previously we found that the serotonin 1B receptor (5-HT1BR) agonist CP 94,253 (CP) enhances the reinforcing properties of cocaine when given to male rats self-administering the drug daily, however, CP had the opposite effect following a 21-day period of abstinence. Methamphetamine, like cocaine, has similar mechanisms of action on the monoamine neurotransmitter systems. Therefore, we predicted that CP would have effects on the reinforcing properties of methamphetamine similar to cocaine. Additionally, we examined effects of the FDA-approved 5-HT1B/DR agonist, zolmitriptan, on psychostimulant self-administration. We first tested the effects of CP on methamphetamine self-administration utilizing a fixed ratio or progressive ratio schedule of reinforcement and found that regardless of whether or not rats experienced abstinence, CP decreased methamphetamine intake. We next verified that the effects of CP were mediated by 5-HT1BRs by demonstrating they were reversed when paired with a 5-HT1BR antagonist. We then tested the effects of zolmitriptan on methamphetamine responding and found the same results as found with CP. Finally, we tested whether the effects of zolmitriptan generalize to female rats. Both male and female rats were given access to various doses of cocaine after treatment with zolmitriptan. We also ruled out 5-HT1BR ligands has having an effect on locomotion, to rule out motor impairment as the reason behind the decreases in drug intake. Unlike our previous findings with CP effects on cocaine self-administration, zolmitriptan attenuated cocaine intake both before and after abstinence in both male and female rats. The pre-abstinence effects of zolmitriptan in attenuating intake of different psychostimulants suggest its potential as a pharmacological treatment for psychostimulant use disorders.
ContributorsCotter, Austin Richard (Author) / Neisewander, Janet (Thesis director) / Newbern, Jason (Committee member) / Garcia, Raul (Committee member) / School of International Letters and Cultures (Contributor) / School of Life Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
ADHD is a childhood neurobehavioral disorder characterized by inordinate levels of hyperactivity, inattention and impulsivity. The inability to withhold a reinforced response, or response inhibition capacity (RIC), is one aspect of impulsivity associated with ADHD. The first goal of this dissertation was to evaluate the fixed minimum interval (FMI) schedule as a method for assessing RIC. Chapter 2 showed that latencies were substantially more sensitive than FMI-derived estimates of RIC to the effects of pre-feeding and changes in rate and magnitude of reinforcement. Chapter 3 examined the ability of the FMI to discriminate between spontaneously hypertensive rats (SHR), an animal model of ADHD, and Wistar Kyoto (WKY) controls. Results from Chapter 3 showed that RIC was not substantially different between SHR and WKY rats. However, latencies were significantly shorter for SHRs than for WKYs suggesting incentive motivation differed between strains. The second goal of this dissertation was to examine the sensitivity of the SHR to nicotine. ADHD is a risk factor for tobacco dependence. The goal of Chapters 4 and 5 was to determine whether the SHR provided a model of ADHD-related tobacco sensitivity. Chapter 4 examined nicotine's locomotor and rewarding effects in adolescent SHRs using the conditioned place preference (CPP) procedure. SHRs developed CPP to the highest nicotine dose tested and were sensitive to nicotine's locomotor-enhancing properties. WKY controls did not develop CPP to any nicotine dose tested and were not sensitive to nicotine's locomotor properties. However, it is likely that nicotine effects were obscured by a pseudo-conditioning to saline in WKYs. Chapter 5 demonstrated that SHRs were more active than WKYs in the open-field but not in the Rotorat apparatus. Results also showed that SHRs and WKYs were both sensitive to nicotine's locomotor sensitizing effects. However, WKYs were more sensitive than SHRs to nicotine's locomotor suppressing effects. Collectively, results from Chapters 4 and 5 show that SHRs are sensitive to the rewarding and locomotor-enhancing properties of nicotine. However, more research is necessary to confirm that SHRs are a suitable model for studying ADHD-related tobacco use.
ContributorsWatterson, Elizabeth (Author) / Sanabria, Federico (Thesis advisor) / Olive, Foster (Thesis advisor) / Chassin, Laurie (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2015
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 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