Browsing by Subject "Prefrontal cortex"
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Item Alcohol-induced temporal transcriptome remodeling in the prefrontal cortex in a mouse model of alcohol dependence(2006-08) Lodowski, Kerrie Hall; Bergeson Susan E.Alcohol dependence (alcoholism) is a complex disease influenced by both environmental factors and genetic predisposition. Mouse models have been used to study many alcohol dependence-related traits and the genetics that underlie them. Two of the most commonly used mice in alcohol research are the C57BL/6J (B6) and DBA/2J (D2) inbred strains, which diverge on several alcohol-related traits including the development of acute physical dependence. Here we utilized the B6 and D2 mice as a genetic model of acute physical dependence, coupled with mRNA Differential Display (DD) and cDNA microarray analysis, to uncover the transcriptional response of the brain to an acute dose of alcohol as a function of time. About 150 genetically divergent and alcohol-responsive genes were identified between the whole brains of B6 and D2 mice using DD and were added as additional targets to the mouse microarrays. Microarray analysis of the prefrontal cortex of B6 and D2 mice revealed strain-specific, acute alcohol-responsive transcriptome remodeling manifested as temporal patterns of gene expression. Distinct expression patterns were identified for physiologically relevant alcohol-related consequences including intoxication, withdrawal and neuroadaptation. In silico characterization of the differentially expressed genes showed genotype dependent and independent transcriptional regulation and functional classification. In addition, categorization of differentially expressed genes by their cellular profiles revealed that some of the genes were known to be more highly expressed in either excitatory or inhibitory neuronal cell types. Our results indicate that the B6 and D2 prefrontal cortices have very different cellular and molecular responses to acute alcohol exposure. The specific roles that the genes identified in this study may play in mediating the divergent alcohol-related behavior between the strains warrant further study.Item Gene Expression in Brain and Liver Produced by Three Different Regimens of Alcohol Consumption in Mice: Comparison with Immune Activation(Public Library of Science, 2013-03-29) Osterndorff-Kahanek, Elizabeth; Ponomarev, Igor; Blednov, Yuri A.; Harris, R. AdronChronically available alcohol escalates drinking in mice and a single injection of the immune activator lipopolysaccharide can mimic this effect and result in a persistent increase in alcohol consumption. We hypothesized that chronic alcohol drinking and lipopolysaccharide injections will produce some similar molecular changes that play a role in regulation of alcohol intake. We investigated the molecular mechanisms of chronic alcohol consumption or lipopolysaccharide insult by gene expression profiling in prefrontal cortex and liver of C57BL/6J mice. We identified similar patterns of transcriptional changes among four groups of animals, three consuming alcohol (vs water) in different consumption tests and one injected with lipopolysaccharide (vs. vehicle). The three tests of alcohol consumption are the continuous chronic two bottle choice (Chronic), two bottle choice available every other day (Chronic Intermittent) and limited access to one bottle of ethanol (Drinking in the Dark). Gene expression changes were more numerous and marked in liver than in prefrontal cortex for the alcohol treatments and similar in the two tissues for lipopolysaccharide. Many of the changes were unique to each treatment, but there was significant overlap in prefrontal cortex for Chronic-Chronic Intermittent and for Chronic Intermittent-lipopolysaccharide and in liver all pairs showed overlap. In silico cell-type analysis indicated that lipopolysaccharide had strongest effects on brain microglia and liver Kupffer cells. Pathway analysis detected a prefrontal cortex-based dopamine-related (PPP1R1B, DRD1, DRD2, FOSB, PDNY) network that was highly over-represented in the Chronic Intermittent group, with several genes from the network being also regulated in the Chronic and lipopolysaccharide (but not Drinking in the Dark) groups. Liver showed a CYP and GST centered metabolic network shared in part by all four treatments. We demonstrate common consequences of chronic alcohol consumption and immune activation in both liver and brain and show distinct genomic consequences of different types of alcohol consumption.Item Medial prefrontal cortical extracellular dopamine responses after acutely experimenter-administered or orally self-administered ethanol(2012-12) Schier, Christina Joanne; Gonzales, Rueben AnthonyDopamine signaling in the prefrontal cortex is thought to play a role in ethanol abuse. However, little is known about how ethanol affects dopamine signaling in the region. There are a few rodent studies regarding the matter, but both the pharmacological effects of ethanol and the effects of self-administered ethanol on extracellular dopamine in the medial prefrontal cortex remain unclear. The goal of the studies conducted for this dissertation is to clarify these relationships. To accomplish this, we monitored both dialysate dopamine and ethanol concentrations in the medial prefrontal cortex of Long Evans rats while an experimenter administered or a rat operantly self-administered ethanol. In naïve rats, dopamine dose-dependently increased after the intravenous infusions of a 10% ethanol solution, while no changes were noted after saline infusions. In rats trained to orally self-administer drinking solutions, dopamine transiently increased at the initiation of consumption in both ethanol-plus-sucrose- and sucrose-solution-consuming rats. Dopamine concentrations remained significantly elevated for the entire 21-minute drinking period in the ethanol-plus-sucrose-consuming group and for the first seven minutes of the drink period in the sucrose-consuming group. Additionally, in the ethanol-plus-sucrose-consuming group, dialysate ethanol concentrations were lowest at the initiation of drinking and then slowly increased, peaking 35 minutes after drinking commenced. Taken together, these data suggest that the mesocortical dopamine system is responsive to acute, intravenous and repeatedly, orally, self-administered ethanol. It appears that direct pharmacological effects of ethanol were responsible for the dopamine increase after acute, ethanol administration. Furthermore, while is it possible that the direct pharmacological effects of ethanol also bolstered the dopamine response seen after ethanol self-administration, we cannot firmly conclude by what mechanism ethanol elicited the differences. Overall, our clarifying and novel results support a role for the mesocortical dopamine system in ethanol abuse, which deserves continued investigation. In addition to completing the two aforementioned data studies, we also published the methods we use to monitor dialysate ethanol concentrations, in a specific brain region, during ethanol self-administration in a video-methods journal. The methods are presented in both a detailed written protocol, as well as a video demonstrating how to perform the procedures.Item Neuroadaptations in Human Chronic Alcoholics: Dysregulation of the NF-κB System(Public Library of Science, 2007-09-26) Ökvist, Anna; Johansson, Sofia; Kuzmin, Alexander; Bazov, Igor; Merino-Martinez, Roxana; Ponomarev, Igor; Mayfield, R. Dayne; Harris, R. Adron; Sheedy, Donna; Garrick, Therese; Harper, Clive; Hurd, Yasmin L.; Terenius, Lars; Ekström, Tomas J.; Bakalkin, Georgy; Yakovleva, TatjanaBackground -- Alcohol dependence and associated cognitive impairments apparently result from neuroadaptations to chronic alcohol consumption involving changes in expression of multiple genes. Here we investigated whether transcription factors of Nuclear Factor-kappaB (NF-κB) family, controlling neuronal plasticity and neurodegeneration, are involved in these adaptations in human chronic alcoholics. Methods and Findings -- Analysis of DNA-binding of NF-κB (p65/p50 heterodimer) and the p50 homodimer as well as NF-κB proteins and mRNAs was performed in postmortem human brain samples from 15 chronic alcoholics and 15 control subjects. The prefrontal cortex involved in alcohol dependence and cognition was analyzed and the motor cortex was studied for comparison. The p50 homodimer was identified as dominant κB binding factor in analyzed tissues. NF-κB and p50 homodimer DNA-binding was downregulated, levels of p65 (RELA) mRNA were attenuated, and the stoichiometry of p65/p50 proteins and respective mRNAs was altered in the prefrontal cortex of alcoholics. Comparison of a number of p50 homodimer/NF-κB target DNA sites, κB elements in 479 genes, down- or upregulated in alcoholics demonstrated that genes with κB elements were generally upregulated in alcoholics. No significant differences between alcoholics and controls were observed in the motor cortex. Conclusions -- We suggest that cycles of alcohol intoxication/withdrawal, which may initially activate NF-κB, when repeated over years downregulate RELA expression and NF-κB and p50 homodimer DNA-binding. Downregulation of the dominant p50 homodimer, a potent inhibitor of gene transcription apparently resulted in derepression of κB regulated genes. Alterations in expression of p50 homodimer/NF-κB regulated genes may contribute to neuroplastic adaptation underlying alcoholism.Item Prefrontal cortex D1 receptor regulation of mesolimbic dopamine and cocaine self-administration(2004) Olsen, Christopher Mark; Duvauchelle, Christine L.The prefrontal cortex (PFC) is known to modulate mesolimbic dopamine (DA) activity and has also been implicated in drug abuse. The present study demonstrated that blockade of DA D1 receptors in the PFC had a delayed effect on mesolimbic DA activity and cocaine self-administration. Using in vivo microdialysis, nucleus accumbens (NAcc) DA was found to be elevated 24 hours, but not immediately following intra-PFC infusion of the D1 antagonist SCH 23390, but not the D1 agonist SKF 38393. Tyrosine hydroxylase (TH), phospho-TH, and dopamine transporter (DAT) levels were unchanged one and 24 hours following intra-PFC SCH 23390 or SKF 38393 in the ventral tegmental area (VTA) and NAcc. Neither intra-PFC SCH 23390 nor SKF 38393 had an immediate effect on cocaine self-administration on a progressive ratio (PR) or fixed ratio (FR) of reinforcement. SCH 23390 produced a delayed lowering of breakpoints for 0.25 mg/kg, but not 0.75 mg/kg cocaine on a PR schedule and had no effect on responding for 0.25 mg/kg cocaine on an FR schedule. The present study demonstrates that PFC D1 receptors modulate mesolimbic activity and sensitivity to the reinforcing properties of cocaine.Item Prefrontal-based cognitive processing and exploratory behavior(2016-08) Blanco, Nathaniel Joseph; Gonzalez-Lima, Francisco, 1955-; Love, Bradley C.; Schnyer, David M.; Beevers, Christopher G.Exploration (performing actions to obtain information) is a critical cognitive function necessary for learning and decision-making. Effective decision-making requires finding the right balance between exploration and exploitation (taking action to obtain immediate reward). We can distinguish two types of learning and decision-making that differ crucially in how they approach exploratory behavior that are thought to be served by partially distinct neural systems. Reflexive decision-making is thought to be more habitual or automatic, computationally cheap, and mediated largely by processing in the striatum. Reflective decision-making is more goal-directed, relatively computationally expensive, depends on executive processing, and is thought to crucially depend on the prefrontal cortex. Reflective learning involves building a rich mental representation of the environment. This representation can allow the learner to use uncertainty in the environment to direct exploratory choices when they will be most valuable. To be most effective, one should explore when and where there is more uncertainty in the environment in order to gain more information to guide future choices. In contrast, reflexive strategies lead to “random” exploration. In a series of studies I examined the involvement of prefrontal cortex in reflective learning and the role of reflective processing in exploratory decision-making. In two studies, I investigated the contribution of prefrontal cortex to reflective and reflexive learning by examining the effects of prefrontal transcranial infrared laser stimulation on category learning. Reflective, but not reflexive, category learning was improved by laser stimulation. In three studies, I investigated factors influencing reflective and reflexive processing in exploratory decision-making. Study 3 found that greater levels of depression symptoms were associated with less frequent reflective strategy use. Study 4 found that genotype on a gene modulating prefrontal dopamine levels (COMT) was associated with reflective strategy use under cognitive load. Study 5 investigated reflective exploratory behavior in older (>60 years) and younger (<30 years) populations, finding that rather than a reflective processing deficit, older adults’ performance suffered (relative to younger adults) due to applying the wrong reflective strategy. These findings advance our understanding of the mechanisms of exploratory behavior and suggest a critical role for the prefrontal-based learning system.Item The pharmacological effects of acute ethanol on catecholamines in the medial prefrontal cortex and dorsal striatum(2016-12) Vena, Ashley; Gonzales, Rueben Anthony; Dominguez, Juan; Harris, Adron; Duvauchelle, Christine; Morrisett, RichardThe dorsal striatum and the medial prefrontal cortex are part of a neurocircuitry that is affected by acute and chronic drug use. In the present studies, we sought to characterize the pharmacological effects of ethanol on extracellular catecholamine concentrations in the dorsal striatum and medial prefrontal cortex. To this end, we utilized two different routes of administration to quantify ethanol’s actions. We performed in vivo microdialysis in adult, male Long Evans rats as they received single or repeated intravenous infusions of ethanol. Following infusion of a 1-g/kg dose of ethanol, we observed no significant effects on extracellular dopamine in either the dorsomedial or dorsolateral striatum, but in a separate group of animals, we observed significant stimulation of extracellular norepinephrine in the medial prefrontal cortex. However, following a cumulative intravenous dosing protocol, we observed a gradual ramping up of tonic dopamine activity in the dorsal striatal subregions, which was more robust in the dorsomedial striatum. Subsequently, we performed in vivo microdialysis in separate groups of rats during an operant self-administration session to quantify the time course of extracellular dopamine and norepinephrine in the medial prefrontal cortex. In the seven operant sessions prior to the microdialysis test session, each group of rats had been assigned to a separate treatment group: one that received a sweetened ethanol solution, one that received a sucrose solution, and a handling control group that did not receive any drinking solutions. In the ethanol-experienced animals, we report a reduction in basal dopamine and norepinephrine in the medial prefrontal cortex, relative to control groups. However, there were no significant differences in the temporal profile of extracellular norepinephrine across the three treatment groups. These studies demonstrate that limited voluntary ethanol consumption appears to be sufficient to alter tonic catecholamine signaling in the medial prefrontal cortex. Additionally, we conclude that central catecholamine signaling pathways are a target for ethanol.