c57bl/6j male mice ( 25 months of age ) were housed individually on a 12 hr/12 hr light / dark schedule with lights on at 7 a.m. ( zt0 ) and handled for 6 days . mice were sleep - deprived ( sd ) in their home cages for 5 hours by gentle handling beginning at zt5 or left undisturbed ( non - sleep - deprived mice , nsd ) . for contextual fear conditioning experiments , animals were placed in a novel chamber for 3 minutes , and received a 2-second , 1.5 ma footshock after 2.5 minutes . mice received intra - peritoneal injections of rolipram ( rol ; 1 mg / kg ) or vehicle ( 2% dmso in 0.9% saline ) immediately and 2.5 hours post - training . testing of contextual memory was performed 24 hours after training in the trained context and 48 hours after training in a novel chamber . 1-train ltp was induced by a single 100 hz , 1-second duration train of stimuli . 4-train ltp consisted of 4 trains applied with a 5-minute inter - train interval ; for massed 4-train ltp a 5-second inter - train interval was used . theta - burst stimulation ( tbs ) consisted of 40-ms duration , 100 hz bursts delivered at 5 hz for 3 seconds ( 15 bursts of 4 pulses per burst , for a total of 60 pulses ) . chemical ltp was induced by treatment of slices for 15 minutes with 5 m forskolin ( fsk ) in 0.1% ethanol , or a combination of 50 m forskolin and 30 m 3-isobutyl-1-methylxanthine ( ibmx , in water ) . rolipram ( 0.1 m in 0.1% dmso ) was applied for 60 minutes , beginning 30 minutes before tetanization . camp assays on ca1 regions of hippocampal slices 10 minutes after treatment for 15 minutes with forskolin ( 50 m ) , forskolin + ibmx ( 30 m ) , or vehicle ( 0.1% etoh ) were performed by radioimmunoassay according to kit instructions . camp - specific pde activity assays29 and western blots for pde4a530 were performed as previously described . full methods and any associated references are available in the online version of the paper at www.nature.com/nature .
millions of people regularly obtain insufficient sleep1 . given the impact of sleep deprivation on our lives , understanding the cellular and molecular pathways affected by sleep deprivation is clearly of social and clinical importance . 
 one of the major effects of sleep deprivation on the brain is to produce memory deficits in learning paradigms that are dependent on the hippocampus25 . in this study , we have identified a molecular mechanism by which brief sleep deprivation alters hippocampal function . 
 sleep deprivation selectively impaired camp / pka - dependent forms of synaptic plasticity6 in the hippocampus , reduced camp signaling , and increased activity and protein levels of phosphodiesterase-4 ( pde4 ) , an enzyme that degrades camp . treatment with pde inhibitors rescued the sleep deprivation - induced deficits in camp signaling , synaptic plasticity , and hippocampus - dependent memory . 
 these findings demonstrate that brief sleep deprivation disrupts hippocampal function by interfering with camp signaling through increased pde4 activity . 
 thus drugs that enhance camp signaling may provide a novel therapeutic approach to counteract the cognitive effects of sleep deprivation .