Browsing by Subject "addiction"

Now showing 1 - 9 of 9
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    Beyond Simple Tests of Value: A neuroeconomic, translational, disease-relevant, and circuit-based approach to resolve the computational complexity of decision making
    (2018-07) Sweis, Brian
    How the brain processes information when making decisions depends on how that information is stored. Distinct neural circuits are capable of storing information in many different ways that are better suited for different situations. The decision-making processes that access those different bits of stored information are not singular and occupy separable neural circuits, each of which can operate in parallel with one another, and each of which can confer different information processing properties based on the neural constraints within which a given computation resides. Such is the framework of recent theories in neuroeconomics, which suggest that decisions are multi-faceted and action-selection processes can arise from fundamentally distinct circuit-specific neural computations. In this thesis, I present a body of work that takes a neuroeconomics approach through a series of experiments that reveal the complexities of multiple, parallel decision-making systems through complex behaviors by moving beyond simple tests of value. In the first half of this thesis, I demonstrate how complex behavioral computations can resolve fundamentally distinct valuation algorithms thought to reside in separable neural circuits. I then translate this approach between human and non-human rodent animal models in order to reveal how multiple, parallel decision-making systems are conserved across species over evolution. In the second half of this thesis, I demonstrate the utility of behavioral economics in disease-relevant and circuit-based studies. If multiple, parallel decision-making processes are thought to be intimately related to the heterogeneous ways in which information can be stored in separable neural circuits, I examine how addiction – a disease which is thought to be a disorder of the neurobiological mechanisms of learning and memory – might alter how stored information is processed in separable decision-making systems uniquely using a mouse model of two different forms of addiction. In doing so, I demonstrate how different forms of addiction give rise to unique, lasting vulnerabilities in fundamentally distinct decision-making computations. These discoveries can aid in resolving neuropsychiatric disease heterogeneity by moving beyond simple tests of value where complex behaviors that are measured can more accurately reflect the neurally distinct computations that underlie those behaviors. Finally, I take a neuromodulation approach and directly alter the strength of synaptic transmission in a circuit-specific manner using optogenetics in mice tested in this neuroeconomic framework. I demonstrate how plasticity alterations in projections between the infralimbic cortex and the nucleus accumbens are capable of giving rise to long-lasting disruptions of self-control related decision processes in a foraging valuation algorithm independent of and separate from a deliberative valuation algorithm measured within the same trial. Furthermore, I developed a novel plasticity measurement tool that is assayed at the neuronal population ensemble level and reveals individual differences in separable decision processes. The second half of the thesis demonstrates a potential biomarker to target as a circuit-computation-specific therapeutic intervention tailored to those types of decision-making dysfunctions. Taken together, I present a body of work in this thesis that demonstrates the utility of moving beyond simple tests of value in order to resolve the computational complexity of decision making.
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    Characterization of a novel opioid combination for the treatment of chronic pain
    (2020-08) Bruce, Daniel
    The peripherally-restricted combination of loperamide and oxymorphindole is a potent and efficacious preclinical analgesic treatment that relieves the behavioral hyperalgesia caused by inflammatory, post-operative and neuropathic pain states. The combination displayed analgesic synergy across all assays, pain conditions and species tested here, and was also effective in a non-evoked measure of spontaneous pain. From a clinical translation standpoint, the combination confers a protective phenotype relative to clinically approved opioids, demonstrated by the lack of constipation at therapeutic doses, no respiratory depression even at supratherapeutic doses, chronic therapeutic dosing that is devoid of analgesic tolerance, and significantly limited risk for self-administration. Mechanistically, the combination exerts its analgesic action by binding to opioid receptors¬—specifically MOR-DOR heteromers—on peripheral sensory afferent neurons, preferentially activating G protein-dependent signaling cascades to reduce neuronal excitability. Taken together, this thesis provides strong support for the continued investigation into peripheral opioid mechanisms and analgesic synergy as a path forward in our continued fight to develop better pharmacological pain treatment paradigms.
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    The Codification Of The Cultural Health Belief Model Among The Southwestern Ojibwe
    (2019-06) St. Germaine, Rebecca
    ABSTRACT The Cultural Specific Approach to Health Model codifies an a priori approach to reconstruction of the health belief theory and significantly impacts medication experiences. The objective was to codify the Cultural Specific Approach to Health Model as an a priori construct to establish and explain a responsive framework of healthcare modeling demonstrated by the relationship of the Anishinaabe peoples’ Cultural Specific Approach construct of Bimaadiziwin. Propositions are: (1) why are phenological or traditional practices important to understand with the Cultural Specific Approach; (2) why is the relationship of spiritual and healing practices significant to the contribution of the Cultural Specific Approach; (3) what role does happiness discriminate in the psychosocial relationship to Cultural Specific Approach; and lastly, (4) what best defines professional cultural competency for practitioners to enhance patient’s perceptions of health and reported outcomes? The nomothetic study included eight providers, twenty-six healthcare administrators and 455 self-identified Ojibwe adults with a diagnosis of a substance use disorder, and other chronic illnesses, living on five Ojibwe rural reservations designated as medically underserved areas in the Midwest region of the United States between 2014 and 2018. Two areas were examined within three case study units: 1) the methodological initiation; and, 2) a novel pharmaceutical practice care approach based on the Cultural Specific Approach to Health Model. The results of the study showed positive changes in behaviors within a population that demonstrated the highest prevalence of substance use disorder and highlighted the integrated role of the pharmacists’ practice to combat opioid addiction.
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    Connect [Winter 2017]
    (University of Minnesota: College of Education and Human Development, 2016-12) University of Minnesota: College of Education and Human Development
    The gratitude factor: New findings on what works in addiction recovery. Motivation to move: A kinesiology lab explores how technology can help promote health. Launchpad for ideas that work: A new team is speeding up the transmission of knowledge and innovation to users and markets. First up - an online community for reading educators.
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    Does substance use during youth cause lasting changes in resting-state neurophysiology and brain functional connectivity? A co-twin control investigation
    (2017-08) Burwell, Scott
    This dissertation comprises two studies aimed at disentangling potential causal effects of recreational substance use (alcohol, cannabis, tobacco) on resting-state electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) brain outcomes in a community sample of young adults. As noted by the introductory text for each study, there is a dearth of causally-informative research designs in published literature regarding whether drug and alcohol use has lasting effects on human EEG and fMRI. These two studies intend to bridge this gap by utilizing a causally-informative co-twin control (CTC) research design which utilizes the fact that twins reared in the same home are matched on many factors (e.g., genes, parental substance use, SES) that contribute to confounding in the hypothetical causal link between substance use and brain outcomes in extant cross-sectional research. As such, within twin-pair differences in use can be exploited to study within twin-pair differences in brain outcome (e.g., EEG, fMRI) to understand possible causal effects.
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    Modulation of Adult Neurogenesis in Opioid Addiction
    (2016-05) ZHANG, YUE
    One of the major problems in treatment of opioid addiction is the repeated reuse and long-term memory of the drug-experience even after prolonged periods of abstinence. During the past decades, there has been enormous expansion in our understanding of how opioid drugs act on the nervous system. A complex brain network including the mesolimbic dopamine system, ventral striatum, extended amygdala, prefrontal cortex and hippocampus is suggested to be associated with the addiction cycle, in particular, the adult neurogenesis taken place in the dentate gyrus (DG) of the hippocampus has a functional implication in opioid addiction. It is intriguing to study the convergence between the modulation of adult neurogenesis and opioid addiction, since the adult-born granule cells were shown to play a role in neuroplasticity of hippocampus function and in the development and retention of drug-contextual memory. In the first part of my study, I attempted to define the temporal window of morphine’s inhibitory effect on adult neurogenesis with a transgenic mouse model. Four days of conditioned place preference (CPP) training with morphine significantly reduced the number of late stage progenitors and immature neurons in the sub-granular zone (SGZ) of mouse hippocampus but did not affect the number of early progenitor cells. The results from colocalization of cell-type selective markers suggested that under the condition of CPP training, morphine affects the transition of neural progenitor/stem cells differentiate into immature neurons. When the transcription factor neural differentiation1 (NeuroD1) was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. Next, a synthetic small molecule KHS101 which was reported to increase NeuroD1 mRNA in cultured neural progenitors and induce neuronal differentiation in the DG of hippocampus, was utilized to mimic the effect of lentivirus-mediated NeuroD1 overexpression on morphine-primed CPP. The results indicated that subcutaneous injection of KHS101 before conditional training could enhance the retention of drug-related memory and prolong CPP extinction; while the same treatment after conditional training disrupted the drug-contextual associations and shortened CPP extinction. Such KHS101’s effect paralleled that observed when the over-expression of NeuroD1 was temporally controlled with an inducible tetracycline system. Furthermore, the KHS101’s effect could be abolished by the stereotaxic injected NeuroD1 shRNA lentivirus. These studies suggest that morphine decrease the total numbers of newborn neurons in the SGZ by interfering with neural progenitors’ differentiation via a mechanism involving NeuroD1. Since adult neurogenesis serves as an important form of neural plasticity, we assume that certain immature neurons contribute to the formation and consolidation of drug-contextual association memory, and NeuroD1 plays a key role during this process. Such assumption is supported by the observation that compounds such as KHS101 that could regulate NeuroD1 expression in the hippocampus possess the ability to manipulate the extinction of drug contextual memory. In conclusion, the regulation of NeuroD1 activity leads to modulation of adult neurogenesis, thus affecting the drug-association memory.
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    Palmitoylation of Caveolin-1 and its importance for structural and functional plasticity
    (2018-11) Eisinger, Katherine
    This dissertation examines the regulation and function of caveolin-1 (Cav1). Cav1 is an integral membrane protein that creates functional microdomains of neuronal proteins within lipid rafts. Cav1 regulates a variety of signaling pathways, including mGluR-activated G protein cascades, and is involved in membrane trafficking of proteins such as estrogen and dopamine receptors. The function of Cav1 is regulated by palmitoylation, a reversible post-translational addition of a 16-carbon lipid chain that is involved in trafficking and compartmentalizing target proteins. This regulatory mechanism is important not only for Cav1, but also for membrane association of estrogen receptors. Within the nervous system, palmitoylation of estrogen receptor alpha (ERα) is necessary for surface membrane localization and mediation of downstream signaling through the activation of metabotropic glutamate receptors (mGluRs). Mutation of the single palmitoylation site on ERα prevents its physical association with Cav1, which in turn is required for the formation of the estrogen receptor/mGluR signaling complex. Interestingly, siRNA knockdown of either of two palmitoyl acyltransferases, DHHC7 or DHHC21, also eliminates this signaling mechanism. As ERα has only one palmitoylation site, I hypothesized that one of these DHHCs palmitoylates another essential protein in this signaling complex, namely Cav1. I investigated this using an acyl-biotin exchange assay in HEK293 cells in conjunction with DHHC overexpression, and found that DHHC7 increased Cav1 palmitoylation. Mutation of the palmitoylation sites on Cav1 eliminated this effect, but did not disrupt the ability of the DHHC enzyme to associate with the protein. In contrast, siRNA knockdown of DHHC7 alone was not sufficient to decrease Cav1 palmitoylation, but rather required simultaneous knockdown of DHHC21. These findings raise questions about the overall influence of palmitoylation on the membrane-initiated estrogen signaling pathway, and highlight the importance of considering the influence of palmitoylation on other Cav1-dependent processes. Additionally, recent studies have shown that altering Cav1 expression influences neuronal plasticity and related behaviors in contexts ranging from learning and memory to chronic injury. Given this relationship between Cav1 and experience-dependent plasticity, I hypothesized that Cav1 expression would also be involved in drug-induced changes in neuronal signaling. I utilized a locomotor sensitization paradigm to test this hypothesis. Animals receiving repeated cocaine displayed behavioral sensitization and greater expression of Cav1 mRNA in the nucleus accumbens when compared to saline-treated controls. Overexpression of Cav1 in the nucleus accumbens enhanced cocaine-induced locomotor responses to cocaine, while Cav1 KO animals did not sensitize. Cultured neurons from the nucleus accumbens, a brain region critical for the development of sensitization, had enhanced dendritic complexity in Cav1 KO mice and altered responses to cocaine. Finally, I report that Cav1 palmitoylation is required for its normal function. Together, these findings suggest that (1) Cav1 KO mice may be structurally saturated such that normal drug-induced plasticity is prevented, (2) Cav1 palmitoylation plays an important role in facilitating the proper activity of signaling molecules associated with Cav1, and (3) understanding Cav1 function will be necessary for fully understanding the development of addiction.
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    Relapse to opioids facilitated by witnessing the distress of another is mediated by the activity of oxytocin: a preclinical model of the neural substrates of the relationship between secondary trauma and addiction
    (2020-11) Matveeva, Tatyana
    Abstract Opioid abuse poses a grave danger to human life and has been declared a Public Health Emergency in the US. In 2018 alone, prescription opioids were the most commonly reported substance exposure to poison control centers, with cases soaring to near 300 000. 44% of cases were of children under the age of 5, with over 5000 exposures to heroin and fentanyl. These trends increased since 2018 and accounted for a reduced life expectancy in the US. Indeed, in the US alone, 2.5 million adults are afflicted by opioid addiction, which claims close to 50,000 deaths per year. Efforts to quit are frequently short-lived at best, while the incidence of relapse over the longer term is considerable. Psychosocial stress and addiction liabilitySevere stress plays a powerful role in the vulnerability to both addiction and relapse, perhaps contributing to the marked rates of relapse (75%) to opioid addiction. Indeed, it is well established in both preclinical and human studies that stress confers vulnerability to drug use and the perpetuation of abusing drugs, as well as relapse to addiction. Despite the abundance of data exposing stress as a critical factor in drug seeking and relapse to drug taking, the underlying neural circuitry implicated in the relationship between stress and relapse to drugs remains poorly understood. Animal models of addiction are useful tools in attempting to elucidate mechanisms responsible for drug-seeking habits. Animal models are also widely used to examine the biological and physiological underpinnings of behavior in health and disease as it pertains to humans. Critically, however, much of this research fails to capture a key stressor in humans: witnessing the trauma of another, especially of a familiar or close person. The significance of such forms of stress in humans is evident by the increased vulnerability to and prevalence of PTSD and drug addiction among those who have witnessed the suffering or death of others. Here, we propose a novel paradigm to attempt to model social stressors as contributing to reinstatement of drug seeking in mice . A Novel paradigm for the study of Observational Distress and reinstatement of opioid-seekingI propose that the susceptibility to PTSD, addiction, and addiction relapse conferred through observing another’s distress is mediated by the assumption in the witness of an affective state that closely matches that of the one in distress. This tendency to match the emotional state of another, also called “Affective State Matching” (ASM) is central to human empathy. Although vicarious emotional experiences underlie prosocial behaviors and the development of compassion in humans (as well as prosocial and consolation behaviors in other mammals), they also enable the development of stress-induced disorders if the witnessed distress is sufficiently potent. Previous work in our lab has focused on understanding the neural underpinnings of vicarious fear using mouse dyads. We have demonstrated that fear-associated ASM can be elicited in experimental settings and shown that this phenomenon is dependent on the activity of oxytocin- a neuropeptide involved in sociality, empathy, and affiliation. Since vicarious distress is known to precipitate relapse to drug addiction, is a common precursor to PTSD in humans, and drug addiction and PTSD are often comorbid, it is possible that oxytocin facilitates relapse to drug addiction following vicarious distress. Does observational distress facilitate reinstatement of morphine-conditioned place preference? Effects of familiarity and sex.To establish whether witnessing another’s distress can reliable predict reinstatement to opioid seeking, I expose male and female mice to a biased design morphine-conditioned place preference CPP) task to first elicit the preference for morphine. Mice readily acquire a preference for the morphine-paired context relative to a compartment associated with the administration of a vehicle. Once CPP is established, mice undergo an extinction phase, the aim of which is to reverse the acquired morphine preference. This allows the testing of reinstatement of morphine seeking following observational distress. Again, male and female mice successfully extinguished mCPP. Same-sex mice were then randomly assigned to one of two roles: Observer or Demonstrator. The Demonstrator was placed in a compartment adjacent to a natural predator, a large male rat, who had been administered cocaine (20mg.kg) to enhance locomotive activity. The Observer lacked visual access to the rat and was only exposed to the behaviors exhibited by the Demonstrator during this task. Since previous studies in our lab have revealed that mice show a familiarity bias which may affect behavior in response to the distressed Demonstrator, we included both familiar (cage mates) and unfamiliar (non-cage mates) Observer-Demonstrator dyads. Demonstrators and Observers exhibited distinct, coordinated threat-associated behaviors, with Demonstrators showing increased territorial defensive aggression, attempts to escape, and threat assessment, while the Observer attempted approaching the distressed conspecific.We found that exposure to predator threat was sufficient to produce reinstatement of CPP in Demonstrators. Male Observers, however, reinstated CPP only if they were familiar with the distressed Demonstrator. Such a familiarity bias was lacking in female mice. Does Demonstrator distress predict magnitude of Observer reinstatement of CPP? Effects of familiarity and sex.We found that behavioral manifestations of ethologically relevant threat responses in Demonstrators predicted the magnitude of reinstatement of CPP in familiar but not unfamiliar Observers. Female Observers reinstated CPP regardless of their familiarity with the Demonstrator-a finding consistent with our previous reports. Does Oxytocin modulate observational distress and subsequent reinstatement? To examine the aforementioned hypothesis that oxytocin is implicated in the social transmission of distress, we administered either intranasal oxytocin, or an oxytocin antagonist, to observer animals. Since we expected oxytocin to reverse the effect of familiarity, we administered oxytocin to Unfamiliar Observers (male). Similarly, to establish whether familiar Observers’ distress behaviors were dependent on oxytocinergic activity, we administered the oxytocin antagonist in familiar Observers. Oxytocin administration reliably induced reinstatement in Unfamiliar male Observers, thus rescuing the familiarity bias, while oxytocin antagonism blocked reinstatement of CPP in familiar male Observers. These effects of oxytocin activity on Observational Distress were reflected in reduced stress-related behaviors in the familiar Observer cohort. Control experiments are described. Since female Observers reinstated the previously extinguished preference for morphine regardless of familiarity with the conspecific, we investigated whether administration of an oxytocin antagonist would rescue this effect. Indeed, both familiar and unfamiliar female Observers failed to reinstate morphine-CPP, lending further support to the hypothesis that oxytocin is implicated in mounting a stress response to the distress of a fellow conspecific. Similarly, behavioral indexes of stress-responsivity were altered in both Observer cohorts. Once again, control manipulations are described. Does witnessing the distress of another impact social interactions between Observer and Demonstrator?Bearing witness of the plight of another is associated with an elevated risk of PTSD in humans. In turn, PTSD following such exposure is frequently comorbid with altered, often aggressive, social interactions, especially against familiar individuals, such as family members or friends. To examine whether Observational Distress in our task was sufficient to alter social interactions in participating animals, we assessed social interaction between Observers, Demonstrators, and mice who were not included in the experiment. We find that familiar, but not unfamiliar male Observers exhibited consistent aggression toward the Demonstrator, indicated by numerous attacks, bites, and chasing. Interestingly, Observers did not act aggressively toward the naïve conspecific in the home cage, indicating that aggression was related to the experience of observing distress in the Demonstrator and exhibiting defensive aggression as a result. Oxytocin antagonism eliminated social aggression in familiar Observer males, further confirming a role of oxytocin in the acquisition of and responding to social distress cues. Unlike male Observers, neither familiar nor unfamiliar female Observer mice acted aggressively following Observational Distress. Does social aggression following observational distress coincide with social rank in males?Cohabiting mice quickly form social hierarchies of dominance and subordination. Social dominance or subordination can affect the propensity of a mouse to act aggressively or flee to signal subordination and terminate attacks quickly. Thus, it is possible that mouse social aggression following Observational Distress coincided with dominant status in Familiar male Observers, and that the two are thereby confounded. To disambiguate social rank and aggression, we assessed social dominance status in a randomly selected group of males using a variant of the Tube Test. This task afforded the determination of rank in mice housed in groups of four relative to each member of the home cage. Mice were then assigned blindly to an Observer or Demonstrator role and subsequently assessed for social interaction. We found that Familiar Observers acted aggressively toward Demonstrators regardless of social rank and concluded that social aggression after witnessing a Demonstrator in distress was not confounded by social status. The implications, caveats, and findings of these experiments are discussed, and directions for future work are proposed.
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    The role of astrocytic adenosine monophosphate-activated protein kinase in cocaine-related behaviors
    (2022-01) Buczek, Laura
    Cocaine use induces changes in the brain’s structure and function inducing long-lasting changes in behavior and cognition. There are no FDA approved treatments for cocaine use disorder. Investigating cocaine-induced neuroadaptations, specifically changes in brain protein expression and function, will inform molecular targets for future therapeutic drug development. Two proteins, glial glutamate transporter 1 (GLT-1) and phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) are downregulated upon cocaine exposure. It is unknown whether AMPK, expressed in neurons and astrocytes, regulates GLT-1 in the striatum in a cell-specific manner. I will first determine how astrocyte-specific manipulation of striatal AMPK impacts GLT-1 expression and function in the striatum. I will then determine whether the same astrocytic AMPK manipulations influence cocaine locomotor sensitization and acquisition of cocaine self-administration.