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Spatiotemporal processing in the mammalian olfactory bulb (OB), and its analog, the invertebrate antennal lobe (AL), is subject to plasticity driven by biogenic amines. I study plasticity using honey bees, which have been extensively studied with respect to nonassociative and associative based olfactory learning and memory. Octopamine (OA) release in

Spatiotemporal processing in the mammalian olfactory bulb (OB), and its analog, the invertebrate antennal lobe (AL), is subject to plasticity driven by biogenic amines. I study plasticity using honey bees, which have been extensively studied with respect to nonassociative and associative based olfactory learning and memory. Octopamine (OA) release in the AL is the functional analog to epinephrine in the OB. Blockade of OA receptors in the AL blocks plasticity induced changes in behavior. I have now begun to test specific hypotheses related to how this biogenic amine might be involved in plasticity in neural circuits within the AL. OA acts via different receptor subtypes, AmOA1, which gates calcium release from intracellular stores, and AmOA-beta, which results in an increase of cAMP. Calcium also enters AL interneurons via nicotinic acetylcholine receptors, which are driven by acetylcholine release from sensory neuron terminals, as well as through voltage-gated calcium channels. I employ 2-photon excitation (2PE) microscopy using fluorescent calcium indicators to investigate potential sources of plasticity as revealed by calcium fluctuations in AL projection neuron (PN) dendrites in vivo. PNs are analogous to mitral cells in the OB and have dendritic processes that show calcium increases in response to odor stimulation. These calcium signals frequently change after association of odor with appetitive reinforcement. However, it is unclear whether the reported plasticity in calcium signals are due to changes intrinsic to the PNs or to changes in other neural components of the network. My studies were aimed toward understanding the role of OA for establishing associative plasticity in the AL network. Accordingly, I developed a treatment that isolates intact, functioning PNs in vivo. A second study revealed that cAMP is a likely component of plasticity in the AL, thus implicating the AmOA-beta; receptors. Finally, I developed a method for loading calcium indicators into neural components of the AL that have yet to be studied in detail. These manipulations are now revealing the molecular mechanisms contributing to associative plasticity in the AL. These studies will allow for a greater understanding of plasticity in several neural components of the honey bee AL and mammalian OB.
ContributorsProtas, Danielle (Author) / Smith, Brian H. (Thesis advisor) / Neisewander, Janet (Committee member) / Anderson, Trent (Committee member) / Tyler, William (Committee member) / Vu, Eric (Committee member) / Arizona State University (Publisher)
Created2014
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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

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
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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
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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
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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
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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