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Compromised frontocerebellar circuitry contributes to nonplanning impulsivity in recovering alcoholics.

ABSTRACT: RATIONALE:Degradation of frontocerebellar circuitry is a principal neural mechanism of alcoholism-related executive dysfunctions affecting impulse control and cognitive planning. OBJECTIVE:We tested the hypothesis that alcoholic patients would demonstrate compromised dorsal anterior cingulate cortex (dACC) -cerebellar functional connectivity when adjusting their strategies to accommodate uncertain conditions and would recruit compensatory brain regions to overcome ineffective response patterns. METHODS:Twenty-six alcoholics and 26 healthy participants underwent functional MRI in two sequential runs while performing a decision-making task. The first run required a response regardless of level of ambiguity of the stimuli; the second run allowed a PASS option (i.e., no response choice), which was useful on ambiguous trials. RESULTS:Healthy controls demonstrated strong synchronous activity between the dACC and cerebellum while planning and executing a behavioral strategy. By contrast, alcoholics showed synchronous activity between the dACC and the premotor cortex, perhaps enabling successful compensation for accuracy and reaction time in certain conditions; however, a negative outcome of this strategy was rigidity in modifying response strategy to accommodate uncertain conditions. Compared with the alcoholic group, the control group had lower nonplanning impulsiveness, which correlated with using the option PASS to respond in uncertain conditions. CONCLUSION:These findings suggest that compromised dACC-cerebellar functional circuitry contributes to recruitment of an alternative network-dACC-premotor cortex- to perform well under low-risk, unambiguous conditions. This compensatory network, however, was inadequate to enable the alcoholics to avert making poor choices in planning and executing an effective behavioral strategy in high-risk, uncertain conditions.

SUBMITTER: Jung YC

PROVIDER: S-EPMC4216649 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Compromised frontocerebellar circuitry contributes to nonplanning impulsivity in recovering alcoholics.

Jung Young-Chul YC Schulte Tilman T Müller-Oehring Eva M EM Namkoong Kee K Pfefferbaum Adolf A Sullivan Edith V EV

Psychopharmacology 20140501 23

<h4>Rationale</h4>Degradation of frontocerebellar circuitry is a principal neural mechanism of alcoholism-related executive dysfunctions affecting impulse control and cognitive planning.<h4>Objective</h4>We tested the hypothesis that alcoholic patients would demonstrate compromised dorsal anterior cingulate cortex (dACC) -cerebellar functional connectivity when adjusting their strategies to accommodate uncertain conditions and would recruit compensatory brain regions to overcome ineffective resp ...[more]

PMID: 24781521

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Project description:Persons with alcoholism who are abstinent exhibit persistent impairments in the capacity for response inhibition, and this form of impulsivity is significantly associated with heightened relapse risk. Brain-imaging studies implicate aberrant prefrontal cortical function in this behavioral pathology, although the underlying mechanisms are not understood. Here we present evidence that deficient activation of glycine and serine release in the ventral medial prefrontal cortex (vmPFC) contributes to increased motor impulsivity during protracted abstinence from long-term alcohol exposure. Levels of 12 neurotransmitters were monitored in the rat vmPFC during the performance of a challenging variant of the five-choice serial reaction time task (5-CSRTT) in which alcohol-exposed rats exhibit excessive premature responding. Following long-term ethanol exposure, rats showed blunted task-related recruitment of vmPFC glycine and serine release, and the loss of an inverse relationship between levels of these neurotransmitters and premature responding normally evident in alcohol-naive subjects. Intra-vmPFC administration of the glycine transport inhibitor ALX5407 prevented excessive premature responding by alcohol-exposed rats, and this was reliant on NMDA glycine site availability. Alcohol-exposed rats and controls did not differ in their premature responding and glycine and serine levels in vmPFC during the performance of the standard 5-CSRTT. Collectively, these findings provide novel insight into cortical neurochemical mechanisms contributing to increased impulsivity following long-term alcohol exposure and highlight the NMDA receptor coagonist site as a potential therapeutic target for increased impulsivity that may contribute to relapse risk.SIGNIFICANCE STATEMENT Persons with alcoholism demonstrate increased motor impulsivity during abstinence; however, the neuronal mechanisms underlying these behavioral effects remain unknown. Here, we took advantage of an animal model that shows deficiencies in inhibitory control following prolonged alcohol exposure to investigate the neurotransmitters that are potentially responsible for dysregulated motor impulsivity following long-term alcohol exposure. We found that increased motor impulsivity is associated with reduced recruitment of glycine and serine neurotransmitters in the ventromedial prefrontal cortex (vmPFC) cortex in rats following long-term alcohol exposure. Administration of glycine transport inhibitor ALX5407 in the vmPFC alleviated deficits in impulse control.

Project description:BackgroundTumor metastasis is one of the main causes of the high mortality of hepatocellular carcinoma (HCC). E-Twenty Six variant gene 6 (ETV6) is a strong transcriptional repressor, associated with the development and progression of tumors. However, the exact role and underlying mechanism of ETV6 in HCC remain unclear.MethodsWestern blotting, quantitative real-time PCR and immunohistochemistry were used to detect the expression levels of ETV6, CRKL (v-crk sarcoma virus CT10 oncogene homologue (avian)-like) and miR-429 in HCC tissues and cells; Transwell chamber and F-actin cytoskeleton staining assay to examine the effects of ETV6 and CRKL deregulation on the migration, invasion and cytoskeleton of HCC cells; Co-immunoprecipitation assay to determine the interaction between CRKL and ETV6; Chromatin immunoprecipitation assay to investigate the interaction between ETV6 and miR-429.ResultsWe established a novel ETV6-miR-429-CRKL regulatory circuitry contributes to HCC metastasis. ETV6 and CRKL were frequently increased, while miR-429 was downregulated in both hepatocarcinoma tissues and hepatocarcinoma cells. Moreover, ETV6 upregulation was positively correlated with CRKL upregulation, and two negative correlations were also established for ETV6 and CRKL upregulation with miR-429 downregulation in both hepatocarcinoma patients' tumorous tissues and hepatocarcinoma cells. Functional investigations revealed that overexpression and knockdown of ETV6 was remarkably effective in promoting and suppressing HCC cell migration, invasion, cytoskeleton F-actin expression and arrangement, whereas, CRKL overexpression exhibited similar effects to the overexpression of ETV6. Mechanistically, ETV6 negatively regulates miR-429 expression by directly binding to the promoter region of miR-429; miR-429 negatively regulates CRKL expression by selectively targeting CRKL-3'-UTR; ETV6 directly binds to CRKL and positively regulates its expression, which in turn CRKL positively regulates ETV6 expression.ConclusionsOur data demonstrated that ETV6 promotes migration and invasion of HCC cells by directly binding to promoter region of miR-429 via modulating CRKL expression. The newly identified ETV6-miR-429-CRKL regulatory circuitry contributes to the aggressiveness of HCC, which provides new clues for fundamental research on diagnosis and treatment parameters for HCC.

Dataset Information

Compromised frontocerebellar circuitry contributes to nonplanning impulsivity in recovering alcoholics.

Publications

Compromised frontocerebellar circuitry contributes to nonplanning impulsivity in recovering alcoholics.

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