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The number of action potentials evoked by the same osmotic stimulus was larger late in the sleep cycle. On the other hand, stimulating the SCN at a physiological frequency inhibited excitatory synaptic currents (EPSCs) induced in vasopressin (MNC) neurons by OVLT affer-ent activation. Electrophysiological techniques were used to explore this synaptic regulation in more detail. Recording of spontaneous EPSCs from the MNC neurons indicated that SCN stimulation reduced the EPSC frequency, but not the amplitude of these currents. Furthermore, this SCN-mediated inhibition of the OVLT-MNC synapses was associated with an increase in synaptic failure. Both of these observations suggest that OVLT activity is less likely to evoke firing in MNC neurons when the SCN is activated and argue for a pre-synaptic mechanism of action.

The SCN-induced inhibition was not associated with changes in paired-pulse facilitation (PPF) at the OVLT/MNC synapse. PPF occurs at synapses in which the response of the second of two stimuli is potentiated at interstimulus intervals of tens of milliseconds. Under these conditions, PPF provides a mea-sure of presynaptic release mechanisms and can be considered as a calcium-dependent form of short-term plasticity. Instead of altering PPF, a SCN-driven decrease in the probability of release of glutamate was more likely. The authors concluded that SCN clock neurons mediate a presynaptic ‘silencing’ of OVLT osmosensory afferent synapses onto MNC vasopressin neurons. These data suggest that this homeostatic circuit is being inhib-ited during some phases in the daily cycle. In other words, at some times during the day, the circadian system is applying the brakes on the osmosensory response. During the late sleep phase, the brake is released, as the animal isn’t drinking, and more water needs to be retained. By changing the relationship

lamina terminalis (OVLT), which are not iso-lated by the blood-brain barrier. These sensory neurons appear to function as osmometers, tracking osmotic conditions and signaling any perturbations with changes in their firing rate5,6. These osmosensory neurons, in turn, excite magnocellular neurosecretory cells (MNCs) in the supraoptic nucleus (SON) and paraventricular nucleus in the hypothalamus7 (Fig. 1). The MNCs then go on to produce and release vasopressin into the periphery, where this hormone promotes water re-absorption. As with many homeostatic processes, this mechanism is regulated by the circadian sys-tem8, and vasopressin release increases dur-ing the end of the sleep cycle9. This has the effect of helping the body to retain more water. Without this regulation, our bodies would likely have difficulty maintaining the normal balance of ions and water during the late night, when we are likely to be asleep and unlikely to be drinking water.

To study this homeostatic system, the authors developed a unique preparation in which a chunk of hypothalamic tissue con-taining the cells of this circuit was kept intact in a slice. This makes experimental manipu-lation easier, while still ensuring that the important parts of the hypothalamic circuit are still connected. This circuit therefore con-tains the osmosensory OVLT neurons and the vasopressin-releasing MNCs of the SON. As the SCN is also included, the whole circuit, complete with circadian control, is main-tained in the dish.

The authors used this preparation to explore the mechanisms underlying the temporal reg-ulation of vasopressin release. They found that synaptic excitation of rat vasopressin neurons by osmosensory OVLT afferents was facilitated during the late night. To examine this, the authors applied a local hyperosmotic stimu-lus to the OVLT while recording from MNCs.

Anyone who has ever experienced jet-lag knows that our bodies contain their own internal clock, which keeps us synchronized with the physical world and keeps our vari-ous physiological systems working together. How does this internal biological clock keep time? The core of the circadian timing sys-tem is based in the suprachiasmatic nucleus (SCN), where neurons exhibit circadian (daily) rhythms in their activity that are driven by cell-autonomous molecular feedback loops1. These neural rhythms are critical for circadian output and are perhaps required for the gen-eration of the molecular oscillations. But how do these SCN rhythms regulate other brain regions? This is a critical question, as a host of recent studies have turned up evidence that misalignment in the biological clock increases risk for cancer, metabolic diseases, cardiovas-cular dysfunction, mood disorders and cogni-tive decline2,3.

In this issue, Trudel and Bourque4 explore interactions between the SCN and a homeo-static circuit involved in osmotic balance, the process that keeps our fluids from becom-ing too dilute or too concentrated. They find that the SCN modulates a circuit involved in maintaining osmotic balance in a way that pre-vents dehydration during sleep. As students, many of us learned about the regulation of the release of vasopressin from the posterior pituitary; greater vasopressin release results in more water being retained by the body. This vasopressin release is regulated by the concentration of various ions in our blood, as monitored by osmosensory neurons located in brain regions such as the organum vasculosom

Preventing dehydration during sleepChristopher S Colwell

Vasopressin release increases late in sleep. Suprachiasmatic clock neurons modulate osmosensory synapses onto vasopressin neurons to facilitate osmoregulated vasopressin release, reports a study in this issue. This explains the increased late-night vasopressin release, and such facilitation prevents dehydration during sleep.

The author is in the Department of Psychiatry,

University of California Los Angeles School of

Medicine, Los Angeles, California, USA.

e-mail: ccolwell@mednet.ucla.edu

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It will also be important to determine whether this regulatory mechanism of presynaptic regu-lation is a common motif in the SCN control of other brain regions. Another well stud-ied output pathway is the nightly release of melatonin from the pineal gland. This rather complicated multisynaptic pathway ultimately involves the autonomic regulation of a rate-limiting enzyme required for the production of melatonin10. Thus, there are two important control pathways by which the SCN regulates the secretion of a hormone using two very different regulatory strategies. More work is needed to find the common elements and differences in the circadian control of other physiological processes.

Answering these questions may be vital to understanding many of the symptoms that appear in both normal aging and disease states. For example, rhythms in neural activity in the SCN and in vasopressin secretion both appear to decline as we age. Could this be part of the reason for the increase in nightly trips to the bathroom that so many of us associ-ate with aging? Similarly, recent studies have linked disruptions of the circadian system with metabolic dysfunction, including type 2 diabetes11,12. Diabetes insipidus results from insufficient vasopressin signaling to concen-trate the urine for water conservation. Future work will need to address the extent to which the mis-regulation of this nightly release of vasopressin may explain the link between dis-rupted circadian rhythms and diabetes. For now, this study gives us something to ponder on the next midnight trip to the bathroom.

COMPETING FINaNCIal INTERESTSThe author declares no competing financial interests.

1. Reppert, S.M. & Weaver, D.R. Nature 418, 935–941 (2002).

2. Takahashi, J.S., Hong, H.K., Ko, C.H. & McDearmon, E.L. Nat. Rev. Genet. 9, 764–775 (2008).

3. Barnard, A.R. & Nolan, P.M. PLoS Genet. 4, e1000040 (2008).

4. Trudel, E. & Bourque, C.W. Nat. Neurosci. 13, 467– 474 (2010).

5. Ciura, S. & Bourque, C.W. J. Neurosci. 26, 9069–9075 (2006).

6. Egan, G. et al. Proc. Natl. Acad. Sci. USA 100, 15241–15246 (2003).

7. Bourque, C.W. Nat. Rev. Neurosci. 9, 519–531 (2008).

8. Bhumbra, G.S., Lombardelli, S., Gonzalez, J.A., Parsy, K.S. & Dyball, R.E. J. Neuroendocrinol. 21, 935–945 (2009).

9. Forsling, M.L. Exp. Physiol. 85 Spec No, 179S–186S (2000).

10. Karolczak, M., Korf, H.W. & Stehle, J.H. Endocrine 27, 89–100 (2005).

11. Turek, F.W. et al. Science 308, 1043–1045 (2005). 12. Woon, P.Y. et al. Proc. Natl. Acad. Sci. USA 104,

14412–14417 (2007).

tion switch work between nocturnal rats and diurnal animals such as ourselves? Also, the mechanisms underlying this SCN-driven silencing need to be delineated. Trudel and Bourque4 found that the SCN presynaptic inhibition was reduced, but not eliminated, by the presence of a broad spectrum vaso-pressin receptor antagonist, suggesting that this mechanism is not the full story. More work needs to be done to identify the recep-tors involved in the inhibition and to clarify the rest of this signaling pathway, which may involve neuropeptides such as the vasoactive intestinal peptide and prokineticin 2.

between osmolarity and vasopressin release, the SCN is effectively modulating the ‘gain’ of this homeostatic circuit, promoting the release of vasopressin so that you can sleep without the need for a drink (or a trip to the bathroom).

There are a number of questions remain-ing that will hopefully be addressed in future work. For example, the population of SCN neurons exhibit robust rhythms in electri-cal activity that peak in the day regardless of whether an organism sleeps during the day (nocturnal) or night (diurnal). So how does this basic mechanism of SCN-driven inhibi-

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Figure 1 Circadian regulation of an osmoregulatory circuit. Top, illustration of the mammalian brain that highlights one of the central circuits involved in osmotic regulation. The concentration of various ions in our blood is continuously monitored by sensory neurons located in brain regions such as the OVLT. These sensory neurons track osmotic conditions and signal any perturbations to MNCs in the SON and paraventricular nuclei (PVN) in the hypothalamus. The MNCs then go on to produce and release vasopressin (VP) into the circulation through the posterior pituitary (PP). Vasopressin is released with a daily rhythm and, among other actions, this peptide promotes water re-absorption by the kidneys. The autonomic nervous system (ANS) also regulates kidney function and probably conveys time-of-day information. Bottom, in this circuit, the MNCs are the command neurons whose electrical activity directly determines the release of vasopressin into the circulation. Hypertonic stimulation triggers action potentials in the OVLT, which in turn drives electrical activity in the MNCs through a glutaminergic connection. Data from Trudel and Bourque4 suggest that the SCN presynaptically inhibits this sensory input to the MNCs during part of the daily cycle. This inhibition is removed during the late sleep phase, resulting in an increase release of vasopressin and water retention in the kidneys. Glu, glutamate.