Browsing by Subject "Brain-Derived Neurotrophic Factor"

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    Effect of BDNFVal66Met on disease markers in dominantly inherited Alzheimer's disease
    (Wiley, 2018-09) Lim, Yen Ying; Hassenstab, Jason; Goate, Alison; Fagan, Anne M.; Benzinger, Tammie L.S.; Cruchaga, Carlos; McDade, Eric; Chhatwal, Jasmeer; Levin, Johannes; Farlow, Martin R.; GraffRadford, Neill R.; Laske, Christoph; Masters, Colin L; Salloway, Stephen; Schofield, Peter; Morris, John C.; Maruff, Paul; Bateman, Randall J.; Neurology, School of Medicine
    OBJECTIVE: Previous studies suggest that the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross-sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181 , and whether these increases are associated with accelerated brain volume loss and memory decline. METHODS: A total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network. RESULTS: In mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau181 increases (6×) than Val66 homozygotes. BDNF did not influence rates of cortical β-amyloid accumulation or change in CSF Aβ42 levels in mutation carriers. In mutation noncarriers, BDNF genotype had no effect on change in cognition, brain volume, cortical β-amyloid accumulation, or change in any CSF measures of tau, ptau181 , and CSF Aβ42 . INTERPRETATION: As in sporadic AD, the deleterious effects of β-amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. The BDNF Val66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018;84:424-435.
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    Ethanol and nicotine interaction within the posterior ventral tegmental area in male and female alcohol-preferring rats: evidence of synergy and differential gene activation in the nucleus accumbens shell
    (Springer, 2015-02) Truitt, William A.; Hauser, Sheketha R.; Deehan, Gerald A.; Toalston, Jamie E.; Wilden, Jessica A.; Bell, Richard L.; McBride, William J.; Rodd, Zachary A.; Department of Psychiatry, IU School of Medicine
    RATIONALE: Ethanol and nicotine are frequently co-abused. The biological basis for the high co-morbidity rate is not known. Alcohol-preferring (P) rats will self-administer EtOH or nicotine directly into the posterior ventral tegmental area (pVTA). OBJECTIVE: The current experiments examined whether sub-threshold concentrations of EtOH and nicotine would support the development of self-administration behaviors if the drugs were combined. METHODS: Rats were implanted with a guide cannula aimed at the pVTA. Rats were randomly assigned to groups that self-administered sub-threshold concentrations of EtOH (50 mg%) or nicotine (1 μM) or combinations of ethanol (25 or 50 mg%) and nicotine (0.5 or 1.0 μM). Alterations in gene expression downstream projections areas (nucleus accumbens shell, AcbSh) were assessed following a single, acute exposure to EtOH (50 mg%), nicotine (1 μM), or ethanol and nicotine (50 mg% + 1 μM) directly into the pVTA. RESULTS: The results indicated that P rats would co-administer EtOH and nicotine directly into the pVTA at concentrations that did not support individual self-administration. EtOH and nicotine directly administered into the pVTA resulted in alterations in gene expression in the AcbSh (50.8-fold increase in brain-derived neurotrophic factor (BDNF), 2.4-fold decrease in glial cell line-derived neurotrophic factor (GDNF), 10.3-fold increase in vesicular glutamate transporter 1 (Vglut1)) that were not observed following microinjections of equivalent concentrations/doses of ethanol or nicotine. CONCLUSION: The data indicate that ethanol and nicotine act synergistically to produce reinforcement and alter gene expression within the mesolimbic dopamine system. The high rate of co-morbidity of alcoholism and nicotine dependence could be the result of the interactions of EtOH and nicotine within the mesolimbic dopamine system.