Ramya Undamatla, Olayemi G Fagunloye, Jeffrey Chen, Lia R Edmunds, Anjana Murali, Amanda Mills, Bingxian Xie, Martha M Pangburn, Ian Sipula, Gregory Gibson, Claudette St Croix, Michael J Jurczak <<<

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies that includes steatosis, steatohepatitis (NASH) and fibrosis and is strongly associated with insulin resistance and type 2 diabetes. Changes in mitochondrial function are implicated in the pathogenesis of NAFLD, particularly in the transition from steatosis to NASH. Mitophagy is a mitochondrial quality control mechanism that allows for the selective removal of damaged mitochondria from the cell via the autophagy pathway. While past work demonstrated a negative association between liver fat content and rates of mitophagy, when changes in mitophagy occur during the pathogenesis of NAFLD and whether such changes contribute to the primary endpoints associated with the disease are currently poorly defined. We therefore undertook the studies described here to establish when alterations in mitophagy occur during the pathogenesis of NAFLD, as well as to determine the effects of genetic inhibition of mitophagy via conditional deletion of a key mitophagy regulator, PARKIN, on the development of steatosis, insulin resistance, inflammation and fibrosis. We find that loss of mitophagy occurs early in the pathogenesis of NAFLD and that loss of PARKIN hastens the onset but not severity of key NAFLD disease features. These observations suggest that loss of mitochondrial quality control in response to nutritional stress may contribute to mitochondrial dysfunction and the pathogenesis of NAFLD. <<<

Memories benefit from sleep, and sleep loss immediately following learning has a negative impact on subsequent memory storage. Several prominent hypotheses ascribe a central role to hippocampal sharp-wave ripples (SWRs), and the concurrent reactivation and replay of neuronal patterns from waking experience, in the offline memory consolidation process that occurs during sleep. However, little is known about how SWRs, reactivation, and replay are affected when animals are subjected to sleep deprivation. We performed long duration (~12 h), high-density silicon probe recordings from rat hippocampal CA1 neurons, in animals that were either sleeping or sleep deprived following exposure to a novel maze environment. We found that SWRs showed a sustained rate of activity during sleep deprivation, similar to or higher than in natural sleep, but with decreased amplitudes for the sharp-waves combined with higher frequencies for the ripples. Furthermore, while hippocampal pyramidal cells showed a log-normal distribution of firing rates during sleep, these distributions were negatively skewed with a higher mean firing rate in both pyramidal cells and interneurons during sleep deprivation. During SWRs, however, firing rates were remarkably similar between both groups. Despite the abundant quantity of SWRs and the robust firing activity during these events in both groups, we found that reactivation of neurons was either completely abolished or significantly diminished during sleep deprivation compared to sleep. Interestingly, reactivation partially rebounded upon recovery sleep, but failed to reach the levels characteristic of natural sleep. Similarly, the number of replays were significantly lower during sleep deprivation and recovery sleep compared to natural sleep. These results provide a network-level account for the negative impact of sleep loss on hippocampal function and demonstrate that sleep loss impacts memory storage by causing a dissociation between the amount of SWRs and the replays and reactivations that take place during these events. <<<