Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei

Abstract

The suprachiasmatic nucleus (SCN), the brain's principal circadian pacemaker, coordinates adaptive daily cycles of behavior and physiology, including the rhythm of sleep and wakefulness. The cellular mechanism sustaining SCN circadian timing is well characterized, but the neurochemical pathways by which SCN neurons coordinate circadian behaviors remain unknown. SCN transplant studies suggest a role for (unidentified) secreted factors, and one potential candidate is the SCN neuropeptide prokineticin 2 (Prok2). Prok2 and its cognate prokineticin receptor 2 (Prokr2/Gpcr73l1) are widely expressed in both the SCN and its neural targets, and Prok2 is light-regulated. Hence, they may contribute to cellular timing within the SCN, entrainment of the clock, and/or they may mediate circadian output. We show that a targeted null mutation of Prokr2 disrupts circadian coordination of the activity cycle and thermoregulation. Specifically, mice lacking Prokr2 lost precision in timing the onset of nocturnal locomotor activity; and under both a light/dark cycle and continuous darkness, there was a pronounced temporal redistribution of activity away from early to late circadian night. Moreover, the coherence of circadian behavior was significantly reduced, and nocturnal body temperature was depressed. Entrainment by light is not, however, dependent on Prokr2, and bioluminescence real-time imaging of organotypical SCN slices showed that the mutant SCN is fully competent as a circadian oscillator. We conclude that Prokr2 is not necessary for SCN cellular timekeeping or entrainment, but it is an essential link for coordination of circadian behavior and physiology by the SCN, especially in defining the onset and maintenance of circadian night.T he suprachiasmatic nucleus (SCN) of the hypothalamus constitutes an autonomous circadian pacemaker necessary for the maintenance of daily rhythms, including the cycle of sleep and wakefulness (1). The molecular basis of the cellular oscillator of the SCN is broadly characterized, but how the SCN signals circadian time to other sites in the brain and thence to peripheral tissues is unclear (2). Neuroanatomical projections from the SCN run predominantly to local hypothalamic and thalamic structures (3), including the dorsomedial nucleus (DMN), a principal site for the regulation of sleep and wakefulness and circadian arousal by behavioral cues (4, 5). How such ''hard-wired'' connections influence SCN targets remains open to question. Although electrical signaling by means of synaptic contacts is likely important (6), encapsulated SCN grafts unable to form synaptic contacts with host tissues are nevertheless able to establish circadian activity/rest cycles in previously arrhythmic, SCN-lesioned recipients (7). This finding indicates that paracrine factors from the SCN mediate circadian coordination within the brain. A small number of candidate factors have been explored, including TGF-␣ (8) and cardiotrophin-like cytokine (9). These factors are expressed by the SCN on a circadian basis, and local ...

Pharmacological Imposition of Sleep Slows Cognitive Decline and Reverses Dysregulation of Circadian Gene Expression in a Transgenic Mouse Model of Huntington's Disease

“…This is consistent with the notion that not only does the SCN control the timing of sleep, but that there is also a mechanism whereby sleep states provide feedback that influences SCN activity (Deboer et al, 2003). The most dramatic effect of Alprazolam was seen with mProk2, which acts via the Prok2 receptor to coordinate circadian behavior and physiology (Li et al, 2006;Prosser et al, 2007). The impaired expression of mProk2 in SCN from R6/2 mice offers a potential cause of the disturbed circadian behavior in these mice.…”

Maternity-related plasticity in circadian rhythms of bumble-bee queens

“…Similar dim red light illumination is commonly used for monitoring locomotor activity in circadian studies (e.g. [4,5,7,[24][25][26]). We monitored locomotor activity and analysed circadian rhythms with the CLOCKLAB data acquisition and analysis system (Actimetrics Co., Wilmette, IL, USA).…”

Circadian clocks: regulators of endocrine and metabolic rhythms

“…A screen for secreted factors of the suprachiasmatic nucleus (Kramer et al 2005) has identified transforming growth factor-a and the neuropeptide cardiotrophin-like cytokine (Kraves & Weitz 2006) as likely mediators of SCN output. More recently, loss of the genes encoding either the SCN peptide prokineticin 2 (Prok2; Li et al 2006, Hu et al 2007 or its cognate receptor Prok2R (Prosser et al 2007) has been shown to compromise circadian endocrine, behavioural and thermoregulatory rhythms, with particular effects in early night. Moreover, homeostatic regulation of sleep is compromised in mice lacking the Prok2 gene.…”