Cyclic AMP response element-binding protein is required in excitatory neurons in the forebrain to sustain wakefulness

The molecular and intracellular signaling processes that control sleep and wake states remain largely unknown. A consistent observation is that the cyclic adenosine monophosphate (AMP) response element-binding protein (CREB), an activity-dependent transcription factor, is differentially activated during sleep and wakefulness. CREB is phosphorylated by the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway as well as other kinases, and phosphorylated CREB promotes the transcription of target genes. Genetic studies in flies and mice suggest that CREB signaling influences sleep/wake states by promoting and stabilizing wakefulness. However, it remains unclear where in the brain CREB is required to drive wakefulness. In rats, CREB phosphorylation increases in the cerebral cortex during wakefulness and decreases during sleep, but it is not known if this change is functionally relevant to the maintenance of wakefulness. Here, we used the Cre/lox system to conditionally delete CREB in the forebrain (FB) and in the locus coeruleus (LC), two regions known to be important for the production of arousal and wakefulness. We used polysomnography to measure sleep/wake levels and sleep architecture in conditional CREB mutant mice and control littermates. We found that FB-specific deletion of CREB decreased wakefulness and increased non-rapid eye movement sleep. Mice lacking CREB in the FB were unable to sustain normal periods of wakefulness. On the other hand, deletion of CREB from LC neurons did not change sleep/wake levels or sleep/wake architecture. Taken together, these results suggest that CREB is required in neurons within the FB but not in the LC to promote and stabilize wakefulness.