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- Genre: Doctoral Dissertation
Description
Intermittent social defeat stress induces cross-sensitization to psychostimulants and escalation of drug self-administration. These behaviors could result from the stress-induced neuroadaptation in the mesocorticolimbic dopamine circuit. Brain-derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA) is persistently elevated after social defeat stress, and may contribute to the stress-induced neuroadaptation in the mesocorticolimbic dopamine circuit. BDNF modulates synaptic plasticity, and facilitates stress- and drug-induced neuroadaptations in the mesocorticolimbic system. The present research examined the role of mesolimbic BDNF signaling in social defeat stress-induced cross-sensitization to psychostimulants and the escalation of cocaine self-administration in rats. We measured drug taking behavior with the acquisition, progressive ratio, and binge paradigms during self-administration. With BDNF overexpression in the ventral tegmental area (VTA), single social defeat stress-induced cross-sensitization to amphetamine (AMPH) was significantly potentiated. VTA-BDNF overexpression also facilitates acquisition of cocaine self-administration, and a positive correlation between the level of VTA BDNF and drug intake during 12 hour binge was observed. We also found significant increase of DeltaFosB expression in the nucleus accumbens (NAc), the projection area of the VTA, in rats received intra-VTA BDNF overexpression. We therefore examined whether BDNF signaling in the NAc is important for social defeat stress-induced cross-sensitization by knockdown of the receptor of BDNF (neurotrophin tyrosine kinase receptor type 2, TrkB) there. NAc TrkB knockdown prevented social defeat stress-induced cross-sensitization to psychostimulant. Also social defeat stress-induced increase of DeltaFosB in the NAc was prevented by TrkB knockdown. Several other factors up-regulated by stress, such as the GluA1 subunit of Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and BDNF in the VTA were also prevented. We conclude that BDNF signaling in the VTA increases social defeat stress-induced vulnerability to psychostimulants, manifested as potentiated cross-sensitization/sensitization to AMPH and escalation of cocaine self-administration. Also BDNF signaling in the NAc is necessary for the stress-induced neuroadaptation and behavioral sensitization to psychostimulants. Therefore, TrkB in the NAc could be a therapeutic target to prevent stress-induced vulnerability to drugs of abuse in the future. DeltaFosB in the NAc shell could be a neural substrate underlying persistent cross-sensitization and augmented cocaine self-administration induced by social defeat stress.
ContributorsWang, Junshi (Author) / Hammer, Ronald (Thesis advisor) / Feuerstein, Burt (Committee member) / Nikulina, Ella (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2013
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
ABSTRACT
Auditory hallucinations are a characteristic symptom of schizophrenia. Research has documented that the auditory cortex is metabolically activated when this process occurs, and that imbalances in the dopaminergic transmission in the striatum contribute to its physiopathology. Most animal models have focused the effort on pharmacological approaches like non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists to produce activation of the auditory cortex, or dopamine antagonists to alleviate it. I hypothesize that these perceptual phenomena can be explained by an imbalance activation of spiny projecting neurons in the striatal pathways, whereby supersensitive postsynaptic D2-like receptor, signaling in the posterior caudatoputamen generates activation of the auditory cortex. Therefore, I characterized the neuroanatomical component involved in the activation of the auditory cortex. I evaluated the participation of dopamine D2-like receptor using selective dopamine antagonist manipulations and identified the circuits related to the auditory cortex by retrograde trans-synaptic tracing using pseudorabies virus (PRV-152). My results show that dopamine infused in the posterior caudatoputamen dose dependently increases the transcription of the immediate early gene, zif268 in the auditory cortex, predominantly in layers III and IV, but also in cortical columns, suggesting enhanced functional auditory activity. This indicates the participation of the posterior striatum in the modulation of the secondary auditory cortex. I was able to demonstrate also that a coinfusion of a selective dopamine D2-like receptor antagonist, eticlopride and dopamine, attenuate the activation of the auditory cortex. Furthermore, using PRV-152 I delineate the distinctive circuit by axial mapping of the infected neurons. Thus, I found secondary projections from the posterior caudatoputamen that synapse in the thalamus before reaching the auditory cortex. These striatal projections correspond to the same brain region affected by dopamine during auditory cortical activation. My results further characterized a mechanism to generate intrinsic perception of sound that may be responsible for auditory hallucinations. I propose this paradigm may elucidate insight on the biological basis of psychotic behavior.
Auditory hallucinations are a characteristic symptom of schizophrenia. Research has documented that the auditory cortex is metabolically activated when this process occurs, and that imbalances in the dopaminergic transmission in the striatum contribute to its physiopathology. Most animal models have focused the effort on pharmacological approaches like non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists to produce activation of the auditory cortex, or dopamine antagonists to alleviate it. I hypothesize that these perceptual phenomena can be explained by an imbalance activation of spiny projecting neurons in the striatal pathways, whereby supersensitive postsynaptic D2-like receptor, signaling in the posterior caudatoputamen generates activation of the auditory cortex. Therefore, I characterized the neuroanatomical component involved in the activation of the auditory cortex. I evaluated the participation of dopamine D2-like receptor using selective dopamine antagonist manipulations and identified the circuits related to the auditory cortex by retrograde trans-synaptic tracing using pseudorabies virus (PRV-152). My results show that dopamine infused in the posterior caudatoputamen dose dependently increases the transcription of the immediate early gene, zif268 in the auditory cortex, predominantly in layers III and IV, but also in cortical columns, suggesting enhanced functional auditory activity. This indicates the participation of the posterior striatum in the modulation of the secondary auditory cortex. I was able to demonstrate also that a coinfusion of a selective dopamine D2-like receptor antagonist, eticlopride and dopamine, attenuate the activation of the auditory cortex. Furthermore, using PRV-152 I delineate the distinctive circuit by axial mapping of the infected neurons. Thus, I found secondary projections from the posterior caudatoputamen that synapse in the thalamus before reaching the auditory cortex. These striatal projections correspond to the same brain region affected by dopamine during auditory cortical activation. My results further characterized a mechanism to generate intrinsic perception of sound that may be responsible for auditory hallucinations. I propose this paradigm may elucidate insight on the biological basis of psychotic behavior.
ContributorsParga Becerra, Alejandro (Author) / Neisewander, Janet (Thesis advisor) / Hammer, Ronald (Thesis advisor) / Gallitano-Mendel, Amelia (Committee member) / McLoone, Jim (Committee member) / Vu, Jie (Committee member) / Arizona State University (Publisher)
Created2014
Description
The thrill of a live performance can enhance endorphin, serotonin, dopamine, and adrenaline levels in the body. This mixture of heightened chemical levels is a result of "performance adrenaline." This phenomenon can positively and/or negatively affect a performing singer. A singer's body is her instrument, and therefore, any bodily change can alter the singing voice. The uptake of these chemicals can especially influence a central aspect of singing: breath. "Performance adrenaline" can induce shallow or clavicular breathing, alter phonation, and affect vibrato. To optimize the positive effects and counteract the negative, diaphragmatic breathing, yoga, and beta-blockers are explored as viable management tools. When managed properly, the boost offered by "performance adrenaline" can aid the singer in performing and singing. After a review of medical and psychological studies that reveal the physiological and emotional effects of endorphins, serotonin, dopamine, and adrenaline, this paper will explore the biological changes specific to vocalists and methods to optimize these effects in performance.
ContributorsPaige, Belinda Roseann (Author) / FitzPatrick, Carole (Thesis advisor) / Dreyfoos, Dale (Committee member) / Norton, Kay (Committee member) / Arizona State University (Publisher)
Created2015
Description
Fibromyalgia (FM) is a chronic musculoskeletal disorder characterized by widespread pain, fatigue, and a variety of other comorbid physiological and psychological characteristics, including a deficit of positive affect. Recently, the focus of research on the pathophysiology of FM has considered the role of a number of genomic variants. In the current manuscript, case-control analyses did not support the hypothesis that FM patients would differ from other chronic pain groups in catechol-O-methyltransferase (COMT) and mu-opioid receptor (OPRM1) genotype. However, evidence is provided in support of the hypothesis that functional single nucleotide polymorphisms on the COMT and OPRM1 genes would be associated with risk and resilience, respectively, in a dual processing model of pain-related positive affective regulation in FM. Forty-six female patients with a physician-confirmed diagnosis of FM completed an electronic diary that included once-daily assessments of positive affect and soft tissue pain. Multilevel modeling yielded a significant gene X environment interaction, such that individuals with met/met genotype on COMT experienced a greater decline in positive affect as daily pain increased than did either val/met or val/val individuals. A gene X environment interaction for OPRM1 also emerged, indicating that individuals with at least one asp allele were more resilient to elevations in daily pain than those homozygous for the asn allele. In sum, the findings offer researchers ample reason to further investigate the contribution of the catecholamine and opioid systems, and their associated genomic variants, to the still poorly understood experience of FM.
ContributorsFinan, Patrick Hamilton (Author) / Zautra, Alex (Thesis advisor) / Davis, Mary (Committee member) / Lemery-Chalfant, Kathryn (Committee member) / Presson, Clark (Committee member) / Arizona State University (Publisher)
Created2011
Description
Externalizing behaviors are pervasive, widespread, and disruptive across a multitude of settings and developmental contexts. While the conventional diathesis-stress model typically measures the disordered end of the spectrum, studies that span the range of behavior, from externalizing to competence behaviors, are necessary to see the full picture. To that end, this study examined the additive and nonadditive relations of a dimension of parenting (ranging from warm to rejecting), and variants in dopamine, vasopressin, and neuropeptide-y receptor genes on externalizing/competence in a large sample of predominantly Caucasian twin children in toddlerhood, middle childhood, and early adolescence. Variants within each gene were hypothesized to increase biological susceptibility to both negative and positive environments. Consistent with prediction, warmth related to lower externalizing/higher competence at all ages. Earlier levels of externalizing/competence washed out the effect of parental warmth on future externalizing/competence with the exception of father warmth in toddlerhood marginally predicting change in externalizing/competence from toddlerhood to middle childhood. Warmth was a significant moderator of the heritability of behavior in middle childhood and early adolescence such that behavior was less heritable (mother report) and more heritable (father report) in low warmth environments. Interactions with warmth and the dopamine and vasopressin genes in middle childhood and early adolescence emphasize the moderational role gene variants play in relations between the rearing environment and child behavior. For dopamine, the long variant related to increased sensitivity to parent warmth such that the children displayed more externalizing behaviors when exposed to rejection but they also displayed more competence behaviors when exposed to high warmth. Vasopressin moderation was only present under conditions of parental warmth, not rejection. Interactions with neuropeptide-y and warmth were not significant. The picture that emerges is one of gene-environment interplay, wherein the influence of both parenting and child genotype each depend on the level of the other. As genetic research moves forward, gene variants previously implicated as conferring risk for disorder should be reexamined in conjunction with salient aspects of the environment on the full range of the behavioral outcome of interest.
ContributorsO'Brien, T. Caitlin (Author) / Lemery-Chalfant, Kathryn (Thesis advisor) / Eisenberg, Nancy (Committee member) / Enders, Craig (Committee member) / Nagoshi, Craig (Committee member) / Arizona State University (Publisher)
Created2011
Description
Dopamine (DA) is a neurotransmitter involved in attention, goal oriented behavior, movement, reward learning, and short term and working memory. For the past four decades, mathematical and computational modeling approaches have been useful in DA research, and although every modeling approach has limitations, a model is an efficient way to generate and explore hypotheses. This work develops a model of DA dynamics in a representative, single DA neuron by integrating previous experimental, theoretical and computational research. The model consists of three compartments: the cytosol, the vesicles, and the extracellular space and forms the basis of a new mathematical paradigm for examining the dynamics of DA synthesis, storage, release and reuptake. The model can be driven by action potentials generated by any model of excitable membrane potential or even from experimentally induced depolarization voltage recordings. Here the model is forced by a previously published model of the excitable membrane of a mesencephalic DA neuron in order to study the biochemical processes involved in extracellular DA production. After demonstrating that the model exhibits realistic dynamics resembling those observed experimentally, the model is used to examine the functional changes in presynaptic mechanisms due to application of cocaine. Sensitivity analysis and numerical studies that focus on various possible mechanisms for the inhibition of DAT by cocaine provide insight for the complex interactions involved in DA dynamics. In particular, comparing numerical results for a mixed inhibition mechanism to those for competitive, non-competitive and uncompetitive inhibition mechanisms reveals many behavioral similarities for these different types of inhibition that depend on inhibition parameters and levels of cocaine. Placing experimental results within this context of mixed inhibition provides a possible explanation for the conflicting views of uptake inhibition mechanisms found in experimental neuroscience literature.
ContributorsTello-Bravo, David (Author) / Crook, Sharon M (Thesis advisor) / Greenwood, Priscilla E (Thesis advisor) / Baer, Steven M. (Committee member) / Castaneda, Edward (Committee member) / Castillo-Chavez, Carlos (Committee member) / Arizona State University (Publisher)
Created2012
Description
Capacity limits of the human nervous system require important or rewarding information to be prioritized and encoded over less important or rewarding information. The present dissertation aims to identify structural and functional neural correlates of reward-motivated memory encoding. Chapter 1 reviews studies of reward-motivated memory encoding and their neural correlates, as well as the structure and function of dopaminergic midbrain circuits. Chapter 2 presents a study that utilizes electroencephalography (EEG) to determine which of two hypothesized processes underly the influence of reward value on episodic memory. One hypothesis is that value engages prefrontal executive control processes, so that valuable stimuli engage an elaborative rehearsal strategy that benefits memory. A second hypothesis is that value acts through the reward-related midbrain dopamine system to modulate synaptic plasticity in hippocampal and cortical efferents, thereby benefiting memory encoding. The results revealed that EEG signals thought to index dopamine-driven attention allocation were modulated by reward value and were positively correlated with individual differences in behavioral measures of memory prioritization. Chapter 3 employs diffusion-weighted magnetic resonance imaging (MRI) to dissociate heterogenous functional circuits of the midbrain reward system. The results comport with primate histology and show that midbrain circuits are differentially predictive of impulsivity and of attention-deficit hyperactivity disorder (ADHD). Chapter 4 presents a study that also employs diffusion-weighted MRI. The findings replicate Chapter 3 in dissociating heterogenous functional circuits of the midbrain reward system. Additionally, the structural integrity of midbrain-hippocampus circuits was quantified. Structural integrity of these circuits was positively correlated to behavioral measures of memory prioritization. These findings suggest that structural and functional measures of the dopaminergic reward system may underlie reward-motivated memory encoding in humans.
ContributorsElliott, Blake Louis (Author) / Brewer, Gene A (Thesis advisor) / McClure, Samuel M (Committee member) / Sanabria, Federico (Committee member) / Bae, Gi-Yeul (Committee member) / Arizona State University (Publisher)
Created2021
Description
This dissertation research project developed as an urgent response to physical inactivity, which has resulted in increased rates of obesity, diabetes, and metabolic disease worldwide. Incorporating enough daily physical activity (PA) is challenging for most people. This research aims to modulate the brain's reward systems to increase motivation for PA and, thus, slow the rapid increase in sedentary lifestyles. Transcranial direct current stimulation (tDCS) involves brain neuromodulation by facilitating or inhibiting spontaneous neural activity. tDCS applied to the dorsolateral prefrontal cortex (DLPFC) increases dopamine release in the striatum, an area of the brain involved in the reward–motivation pathways. I propose that a repeated intervention, consisting of tDCS applied to the DLPFC followed by a short walking exercise stimulus, enhances motivation for PA and daily PA levels in healthy adults. Results showed that using tDCS followed by short-duration walking exercise may enhance daily PA levels in low-physically active participants but may not have similar effects on those with higher levels of daily PA. Moreover, there was a significant effect on increasing intrinsic motivation for PA in males, but there were no sex-related differences in PA. These effects were not observed during a 2-week follow-up period of the study after the intervention was discontinued. Further research is needed to confirm and continue exploring the effects of tDCS on motivation for PA in larger cohorts of sedentary populations. This novel research will lead to a cascade of new evidence-based technological applications that increase PA by employing approaches rooted in biology.
ContributorsRuiz Tejada, Anaissa (Author) / Katsanos, Christos (Thesis advisor) / Neisewander, Janet (Committee member) / Sadleir, Rosalind (Committee member) / Buman, Matthew (Committee member) / Arizona State University (Publisher)
Created2023