We examined how implicit and explicit memories contribute to sensorimotor adaptation of movement extent during goal-directed reaching. Twenty subjects grasped the handle of a horizontal planar robot that rendered spring-like resistance to movement. Subjects made rapid “out-and-back” reaches to capture a remembered visual target at the point of maximal reach extent. The robot’s resistance changed unpredictably between reaches, inducing target capture errors that subjects attempted to correct from one trial to the next. Each subject performed over 400 goal-directed reaching trials. Some trials were performed without concurrent visual cursor feedback of hand motion. Some trials required self-assessment of performance between trials, whereby subjects reported peak reach extent on the most recent trial. This was done by either moving a cursor on a horizontal display (visual self-assessment), or by moving the robot’s handle back to the recalled location (proprioceptive self-assessment). Control condition trials performed either without or with concurrent visual cursor feedback of hand motion did not require self-assessments. We used step-wise linear regression analyses to quantify the extent to which prior reach errors and explicit memories of reach extent contribute to subsequent reach performance. Consistent with prior reports, providing concurrent visual feedback of hand motion increased reach accuracy and reduced the impact of past performance errors on future performance, relative to the corresponding no-vision control condition. By contrast, we found no impact of interposed self-assessment on subsequent reach performance or on how prior target capture errors influence subsequent reach performance. Self-assessments were biased toward the remembered target location and they spanned a compressed range of values relative to actual reach extents, demonstrating that declarative memories of reach performance systematically differed from actual performances. We found that multilinear regression could best account for observed data variability when the regression model included only implicit memories of prior reach performance; including explicit memories (self-assessments) in the model did not improve its predictive accuracy. We conclude therefore that explicit memories of prior reach performance do not contribute to implicit sensorimotor adaptation of movement extent during goal-directed reaching under conditions of environmental uncertainty.

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Loss-of-function mutations in the deoxyguanosine kinase (DGUOK) gene result in a mitochondrial DNA (mtDNA) depletion syndrome. DGUOK plays an important role in converting deoxyribonucleosides to deoxyribonucleoside monophosphates via the salvage pathway for mtDNA synthesis. DGUOK deficiency manifests predominantly in the liver; the most common cause of death is liver failure within the first year of life and no therapeutic options are currently available. in vitro supplementation with deoxyguanosine or deoxyguanosine monophosphate (dGMP) were reported to rescue mtDNA depletion in DGUOK-deficient, patient-derived fibroblasts and myoblasts. CERC-913, a novel ProTide prodrug of dGMP, was designed to bypass defective DGUOK while improving permeability and stability relative to nucleoside monophosphates. To evaluate CERC-913 for its ability to rescue mtDNA depletion, we developed a primary hepatocyte culture model using liver tissue from DGUOK-deficient rats. DGUOK knockout rat hepatocyte cultures exhibit severely reduced mtDNA copy number (10%) relative to wild type by qPCR and mtDNA content remains stable for up to 8 days in culture. CERC-913 increased mtDNA content in DGUOK-deficient hepatocytes up to 2.4-fold after 4 days of treatment in a dose-dependent fashion, which was significantly more effective than dGMP at similar concentrations. These early results suggest primary hepatocyte culture is a useful model for the study of mtDNA depletion syndromes and that CERC-913 treatment can improve mtDNA content in this model. K E Y W O R D S deoxyguanosine kinase, deoxyguanosine kinase deficiency, mtDNA depletion syndrome, primary hepatocyte cell culture, ProTide † Please note that we are requesting co-first authorship for authors Mark Vanden Avond and Hui Meng as they both did extensive proportions of the work at all levels.