Browsing by Subject "cognitive deficits"

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    A common molecular mechanism for cognitive deficits and craving in alcoholism
    (Cold Spring Harbor Laboratory Press, 2020) Meinhardt, Marcus W.; Pfarr, Simone; Rohleder, Cathrin; Vengeliene, Valentina; Barroso-Flores, Janet; Hoffmann, Rebecca; Meinhardt, Manuela L.; Paul, Elisabeth; Hansson, Anita C.; Köhr, Georg; Meier, Nils; von Bohlen und Halbach, Oliver; Bell, Richard L.; Endepols, Heike; Neumaier, Bernd; Schönig, Kai; Bartsch, Dusan; Spanagel, Rainer; Sommer, Wolfgang H.; Psychiatry, School of Medicine
    Alcohol-dependent patients commonly show impairments in executive functions that facilitate craving and can lead to relapse. The medial prefrontal cortex, a key brain region for executive control, is prone to alcohol-induced neuroadaptations. However, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood. Here using a bi-directional neuromodulation approach we demonstrate a causal link for reduced prefrontal mGluR2 function and both impaired executive control and alcohol craving. By neuron-specific prefrontal knockdown of mGluR2 in rats, we generated a phenotype of reduced cognitive flexibility and excessive alcohol-seeking. Conversely, restoring prefrontal mGluR2 levels in alcohol-dependent rats rescued these pathological behaviors. Also targeting mGluR2 pharmacologically reduced relapse behavior. Finally, we developed a FDG-PET biomarker to identify those individuals that respond to mGluR2-based interventions. In conclusion, we identified a common molecular pathological mechanism for both executive dysfunction and alcohol craving, and provide a personalized mGluR2-mechanism-based intervention strategy for medication development of alcoholism.
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    A Double-Blind Trial of Adjunctive Valacyclovir to Improve Cognition in Early Phase Schizophrenia
    (Office of the Vice Chancellor for Research, 2015-04-17) Walters, Kamilah; Mehdiyoun, Nicole; Francis, Michael; Breier, Alan
    Schizophrenia is a chronic and debilitating neuropsychiatric disease that occurs in approximately one percent of the population and is characterized by cognitive deficits, including difficulties with abstract thinking, discerning reality from fiction, and communication. Cognitive deficits are a prominent feature of the illness and contribute to significant occupational and social disabilities. Additionally, there are no clinically effective treatments for cognitive deficits in schizophrenia. Although the etiology of these symptoms is unknown, recent studies have shown an association between Herpes Simplex Virus 1 (HSV-1) exposure and the severity of cognitive deficits in the schizophrenic population. Valacyclovir is an oral antiviral medication approved by the United States Food and Drug Administration for treatment of herpes virus infections, including HSV-1. Results from a pilot study at the University of Pittsburgh show that treatment with adjunctive valacyclovir improved working and visual memory in comparison to placebo in a population of older adults with chronic phase schizophrenia. The primary goal of the main study is to determine the efficacy of adjunctive valacyclovir to improve cognition by studying visual and working memory in HSV-1 positive early phase schizophrenia patients in a multi-site clinical trial coordinated by the Indiana University Psychotic Disorders Program. The aim of this research is to present a comprehensive review of recent findings regarding the importance of HSV-1 exposure and inflammatory markers in schizophrenia, and to discuss the methods and expected outcomes of our ongoing study.
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    Effects of EGCG Treatment of Ts65Dn Down Syndrome Mice on a Balance Beam Task
    (Office of the Vice Chancellor for Research, 2015-04-17) Taboada, Maria Fatima Delgado; Stringer, Megan; Roper, Randall J.; Goodlett, Charles R.
    Down syndrome (DS) is caused by trisomy of chromosome 21, and affects 1/700 live births. DS results in about 80 clinical phenotypes, including cognitive impairment. DYRK1A, a chromosome 21 gene, has been linked to alterations in morphology and function of the brain resulting in cognitive impairment. Epigallocatechin-3-gallate (EGCG), an inhibitor of DYRK1A activity, has been proposed as a possible treatment for cognitive deficits seen in individuals with DS. Using the Ts65Dn DS mouse model, we examined the effects of EGCG treatment on cerebellum dependent tasks using a balance beam test. We hypothesized that treatment with EGCG would improve Ts65Dn performance on the balance beam. In a first experiment, mice were given a dose of ~30 mg/kg/day EGCG, which showed no significant improvement in the balance beam task. In a second experiment, mice were given a dose of 100 mg/kg/day EGCG or water (control) starting at 3 weeks of age. The mice were handled two days before testing and then underwent a series of behavioral tasks including the balance beam test. The mice traversed three beams of differing widths (12, 9 and 6 mm), and three consecutive trials for each were recorded for further analysis. The balance beam recordings were scored by three independent scorers, blind to genotype and treatment, and the number of hind paw slips for each trial were scored. Our preliminary results indicate that the Ts65Dn mice are impaired at this task and have more hind paw slips compared to euploid controls. A larger number of animals should help to distinguish any differences in Ts65Dn mice due to EGCG treatment.