Sleep and memory: Electrophysiological, genetic, and molecular studies

Sleep has been hypothesized to play a role in memory consolidation. Both sleep and memory consolidation appear to share a common pathway, the cAMP/PKA/CREB pathway. Therefore, we have examined how the effects of mutations in this pathway alter sleep as well as how learning affects sleep/wake states and gene expression. We characterized sleep in R(AB) transgenic mice that express a transgene that reduces PKA activity in neurons within the cortex and hippocampus. This mutation results in impairments in hippocampus-dependent memory, synaptic plasticity and place cell stability. Our analysis of sleep/wake states reveals that(AB) transgenic mice are a mouse model for sleep-maintenance insomnia. They share many feature of this disease, including sleep fragmentation, increased REM sleep and alterations in delta and spindle oscillations. These impairments in sleep continuity and reduced homeostatic changes in delta and sigma power are characteristic of sleep-maintenance insomnia in humans. Reductions in synaptic plasticity may cause altered sleep oscillations in R(AB) transgenic mice as predicted by computer models. This study provides further evidence that previously reported phenotypes involving memory dysfunction may be a product of impaired sleep. We also examined how contextual fear conditioning, novel context exposure, foot shock, and handling alter sleep in mice. Previous studies reported that sleep after training is important for long term memory of contextual fear conditioning. Here, we show that contextual fear conditioning can substantially increase NREM sleep during the 24 hour period after training and reduce sigma oscillations during wakefulness. The largest increases in NREM sleep were seen 12–16 hours following training. Because fear conditioned mice sleep more than mice receiving exposure to conditioned stimuli or an immediate shock, our results suggest that the learning experience of fear conditioning alters sleep/wake states. Our data provides original findings that NREM sleep is enhanced by learning and may facilitate memory consolidation. We have also investigated how sleep deprivation alters the expression of memory genes responsible for learning fear conditioning. This study provides additional insight on how sleep deprivation may impair memory at the molecular level. Together, these three studies demonstrate how the signaling pathways involved in sleep and memory interact