Associative learning is driven by prediction errors. Dopamine transients correlate with these errors, which current interpretations limit to endowing cues with a scalar quantity reflecting the value of future rewards. Here, we tested whether dopamine might act more broadly to support learning of an associative model of the environment. Using sensory preconditioning, we show that prediction errors underlying stimulus-stimulus learning can be blocked behaviorally and reinstated by optogenetically activating dopamine neurons. We further show that suppressing the firing of these neurons across t transition prevents normal stimulus-stimulus learning. These results establish that the acquisition of model-based information about transitions between non-rewarding events is also driven by prediction errors, and that contrary to existing canon, dopamine transients are both sufficient and necessary to support this type of learning. Our findings open new possibilities for how these biological signals might support associative learning in the mammalian brain in these and other contexts.
Quercetin, a member of the flavonoid family, is one of the most prominent dietary antioxidants. This study investigates the mechanisms for the effects of quercetin on cultured human RPE cells and in Ccl2/Cx3cr1 double knock-out (DKO) mice, which spontaneously develop progressive retinal lesions mimicking age-related macular degeneration (AMD). In the in vitro experiment, cultured ARPE-19 cells were exposed to 1mM H 2 O 2 with or without 50μM quercetin for 2 hours. Cellular viability, mitochondrial function, and apoptosis were assessed using crystal violet staining, MTT assay, and comet assay, respectively. Apoptotic molecular transcripts of BCL-2, BAX, FADD, CASPASE-3 and CASPASE-9 were measured by RQ-PCR. COX activity and nitric oxide (NO) level were determined in the supernatant of the culture medium. Quercetin treatment protected ARPE-19 cells from H 2 O 2 -induced oxidative injury, enhanced BCL-2 transcript levels, increased the BCL-2/ BAX ratio, suppressed the transcription of pro-apoptotic factors such as BAX, FADD, CASPASE-3 and CASPASE-9, inhibited the transcription of inflammatory factors such as TNF-α, COX-2 and INOS, and decreased the levels of COX and NO in the culture medium. In the in vivo experiment, DKO and C57/B6 mice were treated with 25mg/kg/day quercetin by intraperitoneal injection daily for two months. Funduscopy was performed monthly. After two months, serum was collected to measure NADP + /NADPH, COX, PGE-2, and NO levels. The eyes were harvested for histology and A2E measurement. Ocular transcripts of Bax, Inos, Fas, were detected by RQ-PCR. Quercetin treatment did not reverse the progression of retinal lesions in DKO mice funduscopically or histologically. Although quercetin treatment could recover systemic anti-oxidative capacity, suppress the systemic expression of NO, COX and PGE-2, and decrease ocular A2E levels, it could not effectively suppress the transcripts of the ocular inflammatory factors Tnf-α, Cox-2 and Inos, or the pro-apoptotic factors Fas, FasL and Caspase-3 in DKO mice. Our data demonstrate that quercetin can protect human RPE cells from oxidative stress in vitro via inhibition of pro-inflammatory molecules and direct inhibition of the intrinsic apoptosis pathway. However, quercetin (25mg/kg/day) does not improve the retinal AMD-like lesions in the Ccl2 −/− /Cx3cr1 −/− mice, likely due to its insufficient suppression of the inflammatory and apoptosis pathways in the eye.
There is little known about the impact of nonalcoholic fatty liver disease (NAFLD) on drug metabolism and transport. We examined the pharmacokinetics of oral apixaban (2.5 mg) and rosuvastatin (5 mg) when administered simultaneously in subjects with magnetic resonance imaging-confirmed NAFLD ( = 22) and healthy control subjects ( = 12). The area under the concentration-time curve to the last sampling time (AUC) values for apixaban were not different between control and NAFLD subjects (671 and 545 ng/ml × hour, respectively; = 0.15). Similarly, the AUC values for rosuvastatin did not differ between the control and NAFLD groups (25.4 and 20.1 ng/ml × hour, respectively; = 0.28). Furthermore, hepatic fibrosis in NAFLD subjects was not associated with differences in apixaban or rosuvastatin pharmacokinetics. Decreased systemic exposures for both apixaban and rosuvastatin were associated with increased body weight ( < 0.001 and < 0.05, respectively). In multivariable linear regression analyses, only participant weight but not NAFLD, age, or // genotypes, was associated with apixaban and rosuvastatin AUC ( < 0.001 and = 0.06, respectively). NAFLD does not appear to affect the pharmacokinetics of apixaban or rosuvastatin.
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