The mammalian suprachiasmatic nucleus (SCN) is a master circadian pacemaker. It is not known which SCN neurons are autonomous pacemakers or how they synchronize their daily firing rhythms to coordinate circadian behavior. Vasoactive intestinal polypeptide (VIP) and the VIP receptor VPAC 2 (encoded by the gene Vipr2) may mediate rhythms in individual SCN neurons, synchrony between neurons, or both. We found that Vip −/− and Vipr2 −/− mice showed two daily bouts of activity in a skeleton photoperiod and multiple circadian periods in constant darkness. Loss of VIP or VPAC 2 also abolished circadian firing rhythms in approximately half of all SCN neurons and disrupted synchrony between rhythmic neurons. Critically, daily application of a VPAC 2 agonist restored rhythmicity and synchrony to VIP −/− SCN neurons, but not to Vipr2 −/− neurons. We conclude that VIP coordinates daily rhythms in the SCN and behavior by synchronizing a small population of pacemaking neurons and maintaining rhythmicity in a larger subset of neurons.The SCN of the mammalian hypothalamus coordinates diverse daily rhythms, including states of vigilance, locomotor activity and hormonal release, through rhythms in neuronal firing 1 . These rhythms 'free-run' with a circadian period in the absence of synchronizing (or entraining) cues such as environmental light cycles. When the SCN are electrically silenced or lesioned, behavioral and physiologic rhythms disappear 2 .Rhythmic circadian firing within the SCN is dependent on cyclic expression of a family of 'clock genes'. Mutations of period 1 (Per1) or Per2, cryptochrome 1 (Cry 1) or Cry2, casein kinase Iε (Csnk1e), RevErbα (Nr1d1), BMAL1 (MOP3, Arntl) or clock lead to altered or abolished circadian periodicity 3 . These results have led to a model in which circadian rhythms are generated and sustained by an intracellular transcription-translation negative feedback loop. In support of this model for cell-autonomous pacemaking, single SCN neurons dispersed at low density onto a multielectrode array (MEA) can express firing rate patterns with different circadian periods 4 , leading to the suggestion that all 20,000 SCN neurons are autonomous circadian pacemakers 4-6 . In the intact SCN, these neurons usually synchronize to one another with defined phase relationships 7-10 . How synchrony is maintained between SCN neurons is Correspondence should be addressed to E.D.H. (herzog@wustl.edu).. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. Notably, rhythmicity and synchrony were restored to Vip −/− neurons by daily application of a VPAC 2 agonist. Our data show that many SCN neurons require VIP for rhythmicity, whereas others require it for synchrony. We conclude that a minority of SCN neurons are cellautonomous circadian pacemakers, which coordinate rhythms in the majority through VIP. NIH Public Access RESULTS Mice lacking VIP or VPAC 2 show multiple circadian periodsPrevious studies of locomotor activity in Vip −/− and Vipr2 −/− mutant mice ha...

Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK-cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density.DOI: http://dx.doi.org/10.7554/eLife.13424.001

Activity in hippocampal area CA1 is essential for consolidating episodic memories, but it is unclear how CA1 activity patterns drive memory formation. We find that in the hours following single-trial contextual fear conditioning (CFC), fast-spiking interneurons (which typically express parvalbumin (PV)) show greater firing coherence with CA1 network oscillations. Post-CFC inhibition of PV+ interneurons blocks fear memory consolidation. This effect is associated with loss of two network changes associated with normal consolidation: (1) augmented sleep-associated delta (0.5–4 Hz), theta (4–12 Hz) and ripple (150–250 Hz) oscillations; and (2) stabilization of CA1 neurons’ functional connectivity patterns. Rhythmic activation of PV+ interneurons increases CA1 network coherence and leads to a sustained increase in the strength and stability of functional connections between neurons. Our results suggest that immediately following learning, PV+ interneurons drive CA1 oscillations and reactivation of CA1 ensembles, which directly promotes network plasticity and long-term memory formation.

Summary Sleep is thought to consolidate changes in synaptic strength, but the underlying mechanisms are unknown. We investigated the cellular events involved in this process in ocular dominance plasticity (ODP) - a canonical form of in vivo cortical plasticity triggered by monocular deprivation (MD) and consolidated by sleep via undetermined, activity-dependent mechanisms. We find that sleep consolidates ODP primarily by strengthening cortical responses to non-deprived eye stimulation. Consolidation is inhibited by reversible, intracortical antagonism of NMDA receptors (NMDARs) or cAMP-dependent protein kinase (PKA) during post-MD sleep. Consolidation is also associated with sleep-dependent increases in the activity of remodeling neurons, and in the phosphorylation of proteins required for potentiation of glutamatergic synapses. These findings demonstrate that synaptic strengthening via NMDAR and PKA activity is a key step in sleep-dependent consolidation of ODP.

The mammalian SCN contains a biological clock that drives remarkably precise circadian rhythms in vivo and in vitro. This study asks whether the cycle-to-cycle variability of behavioral rhythms in mice can be attributed to precision of individual circadian pacemakers within the SCN or their interactions. The authors measured the standard deviation of the cycle-to-cycle period from 7-day recordings of running wheel activity, Period1 gene expression in cultured SCN explants, and firing rate patterns of dispersed SCN neurons. Period variability of the intact tissue and animal was lower than single neurons. The median variability of running wheel and Period1 rhythms was less than 40 min per cycle compared to 2.1 h in firing rate rhythms of dispersed SCN neurons. The most precise SCN neuron, with a period deviation of 1.1 h, was 10 times noisier than the most accurate SCN explant (0.1 h) or mouse (0.1 h) but comparable to the least stable explant (2.1 h) and mouse (1.1 h). This variability correlated with intrinsic period in mice and SCN explants but not with single cells. Precision was unrelated to the amplitude of rhythms and did not change significantly with age up to 1 year after birth. Analysis of the serial correlation of cycle-to-cycle period revealed that approximately half of this variability is attributable to noise outside the pacemaker. These results indicate that cell-cell interactions within the SCN reduce pacemaker noise to determine the precision of circadian rhythms in the tissue and in behavior.