The role of CREB and the cAMP/PKA/CREB signaling pathway in sleep and memory

Studies have demonstrated that mice with low levels of the CREB protein (CREB αΔ mice) on a mixed genetic background have impaired hip pocampus-dependent memory. One question is whether impairments of memory seen in CREB αΔ mice are due to the effects of the CREB protein on sleep/wake regulation. To examine this hypothesis, we analyzed sleep/wake regulation in CREB αΔ mice on a F1 B6/129 genetic background. CREB αΔ mice have increased levels of baseline NREM sleep and decreased levels of wakefulness over 24 hours, in the absence of changes in their circadian period length, as well as increased amounts of NREM and REM sleep rebound after 6 hours of sleep deprivation. CREB αΔ mice also have shortened REM sleep and wake periods, suggesting that they may have general impairments in maintaining an activated electroencephalogram state. To examine the function of discrete neural systems in CREB αΔ mice on a F1 B6/129 background, we examined hippocampus-dependent and amygdala-dependent learning and memory. CREB αΔ mice had impaired cued and contextual fear conditioning, but normal Moms water maze learning and memory, indicating that they had deficits in amygdala-dependent learning and memory. We propose that these deficits in amygdala function may also be responsible for the altered sleep phenotype of CREB αΔ mice. Although altered sleep in CREB αΔ mice may contribute to deficits in learning and memory, it is unclear whether these deficits are due to alterations of sleep on learning, consolidation, retrieval, or reconsolidation. To investigate the idea that sleep deprivation may be acting on memory consolidation, we sleep deprived wildtype mice at discrete times after fear conditioning. Sleep deprivation from 0–5 hours after training but not from 5–10 hours after training impaired memory consolidation for fear conditioning. These times of sensitivity to sleep loss roughly coincide with times that fear conditioning is sensitive to PKA disruption, providing support for the idea that sleep deprivation could work to disrupt memory consolidation by acting through the cAMP/PKA/CREB signaling pathway. Taken together, these results provide evidence for the role of the cAMP/PKA/CREB signaling pathway in sleep and learning and memory