cGMP-Dependent Protein Kinase Type I Is Implicated in the Regulation of the Timing and Quality of Sleep and Wakefulness

Many effects of nitric oxide (NO) are mediated by the activation of guanylyl cyclases and subsequent production of the second messenger cyclic guanosine-3′,5′-monophosphate (cGMP). cGMP activates cGMP-dependent protein kinases (PRKGs), which can therefore be considered downstream effectors of NO signaling. Since NO is thought to be involved in the regulation of both sleep and circadian rhythms, we analyzed these two processes in mice deficient for cGMP-dependent protein kinase type I (PRKG1) in the brain. Prkg1 mutant mice showed a strikingly altered distribution of sleep and wakefulness over the 24 hours of a day as well as reductions in rapid-eye-movement sleep (REMS) duration and in non-REM sleep (NREMS) consolidation, and their ability to sustain waking episodes was compromised. Furthermore, they displayed a drastic decrease in electroencephalogram (EEG) power in the delta frequency range (1–4 Hz) under baseline conditions, which could be normalized after sleep deprivation. In line with the re-distribution of sleep and wakefulness, the analysis of wheel-running and drinking activity revealed more rest bouts during the activity phase and a higher percentage of daytime activity in mutant animals. No changes were observed in internal period length and phase-shifting properties of the circadian clock while chi-squared periodogram amplitude was significantly reduced, hinting at a less robust oscillator. These results indicate that PRKG1 might be involved in the stabilization and output strength of the circadian oscillator in mice. Moreover, PRKG1 deficiency results in an aberrant pattern, and consequently a reduced quality, of sleep and wakefulness, possibly due to a decreased wake-promoting output of the circadian system impinging upon sleep

The peak-flux of GRB 221009A measured with GRBAlpha

The brightest gamma-ray burst ever observed, long-duration GRB 221009A, was detected by GRBAlpha nano-satellite without saturation. We present light curves of the prompt emission in 13 energy bands, from 80 keV to 950 keV, and perform a spectral analysis to calculate the peak flux and peak isotropic-equivalent luminosity. Since the satellite's attitude information is not available for the time of this GRB, more than 200 incident directions were probed in order to find the median luminosity and its systematic uncertainty. We found that the peak flux in the $80-800$ keV range (observer frame) was $F_{\rm{ph}}^{\rm{p}}=1300_{-200}^{+1200}$ ph cm$^{-2}$s$^{-1}$ or $F_{\rm{erg}}^{\rm{p}}=5.7_{-0.7}^{+3.7}\times10^{-4}$ erg cm$^{-2}$s$^{-1}$ and the fluence in the same energy range of the first GRB episode lasting 300 s, which was observable by GRBAlpha, was $S=2.2_{-0.3}^{+1.4}\times10^{-2}$ erg cm$^{-2}$ or $S^{\rm{bol}}=4.9_{-0.5}^{+0.8}\times10^{-2}$ erg cm$^{-2}$ for the extrapolated range of $0.9-8,690$ keV. We infer the isotropic-equivalent released energy of the first GRB episode to be $E_{\rm{iso}}^{\rm{bol}}=2.8_{-0.5}^{+0.8}\times10^{54}$ erg in the $1-10,000$ keV band (rest frame at $z=0.15$). The peak isotropic-equivalent luminosity in the $92-920$ keV range (rest frame) was $L_{\rm{iso}}^{\rm{p}}=3.7_{-0.5}^{+2.5}\times10^{52}$ erg s$^{-1}$ and the bolometric peak isotropic-equivalent luminosity was $L_{\rm{iso}}^{\rm{p,bol}}=8.4_{-1.5}^{+2.5}\times10^{52}$ erg s$^{-1}$ (4 s scale) in the $1-10,000$ keV range (rest frame). The peak emitted energy is $E_p^\ast=E_p(1+z)=1120\pm470$ keV. Our measurement of $L_{\rm{iso}}^{\rm{p,bol}}$ is consistent with the Yonetoku relation. It is possible that, due to the spectral evolution of this GRB and orientation of GRBAlpha at the peak time, the true values of peak flux, fluence, $L_{\rm{iso}}$, and $E_{\rm{iso}}$ are even higher. [abridged]Comment: 7 pages, 7 figures, 1 table, accepted for publication in Astronomy & Astrophysic

Sickness behaviour pushed too far – the basis of the syndrome seen in severe protozoal, bacterial and viral diseases and post-trauma

Certain distinctive components of the severe systemic inflammatory syndrome are now well-recognized to be common to malaria, sepsis, viral infections, and post-trauma illness. While their connection with cytokines has been appreciated for some time, the constellation of changes that comprise the syndrome has simply been accepted as an empirical observation, with no theory to explain why they should coexist. New data on the effects of the main pro-inflammatory cytokines on the genetic control of sickness behaviour can be extended to provide a rationale for why this syndrome contains many of its accustomed components, such as reversible encephalopathy, gene silencing, dyserythropoiesis, seizures, coagulopathy, hypoalbuminaemia and hypertriglyceridaemia. It is thus proposed that the pattern of pathology that comprises much of the systemic inflammatory syndrome occurs when one of the usually advantageous roles of pro-inflammatory cytokines – generating sickness behaviour by moderately repressing genes (Dbp, Tef, Hlf, Per1, Per2 and Per3, and the nuclear receptor Rev-erbα) that control circadian rhythm – becomes excessive. Although reversible encephalopathy and gene silencing are severe events with potentially fatal consequences, they can be viewed as having survival advantages through lowering energy demand. In contrast, dyserythropoiesis, seizures, coagulopathy, hypoalbuminaemia and hypertriglyceridaemia may best be viewed as unfortunate consequences of extreme repression of these same genetic controls when the pro-inflammatory cytokines that cause sickness behaviour are produced excessively. As well as casting a new light on the previously unrationalized coexistence of these aspects of systemic inflammatory diseases, this concept is consistent with the case for a primary role for inflammatory cytokines in their pathogenesis across this range of diseases

Non-nociceptive roles of opioids in the CNS: opioids' effects on neurogenesis, learning, memory and affect.

Mortality due to opioid use has grown to the point where, for the first time in history, opioid-related deaths exceed those caused by car accidents in many states in the United States. Changes in the prescribing of opioids for pain and the illicit use of fentanyl (and derivatives) have contributed to the current epidemic. Less known is the impact of opioids on hippocampal neurogenesis, the functional manipulation of which may improve the deleterious effects of opioid use. We provide new insights into how the dysregulation of neurogenesis by opioids can modify learning and affect, mood and emotions, processes that have been well accepted to motivate addictive behaviours