NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: Genotype and sex interactions

Abstract

Because the transcription factor neuronal Per-Arnt-Sim-type signal-sensor protein-domain protein 2 (NPAS2) acts both as a sensor and an effector of intracellular energy balance, and because sleep is thought to correct an energy imbalance incurred during waking, we examined NPAS2's role in sleep homeostasis using npas2 knockout (npas2 ؊/؊ ) mice. We found that, under conditions of increased sleep need, i.e., at the end of the active period or after sleep deprivation (SD), NPAS2 allows for sleep to occur at times when mice are normally awake. Lack of npas2 affected electroencephalogram activity of thalamocortical origin; during non-rapid eye movement sleep (NREMS), activity in the spindle range (10 -15 Hz) was reduced, and within the delta range (1-4 Hz), activity shifted toward faster frequencies. In addition, the increase in the cortical expression of the NPAS2 target gene period2 (per2) after SD was attenuated in npas2 ؊/؊ mice. This implies that NPAS2 importantly contributes to the previously documented wake-dependent increase in cortical per2 expression. The data also revealed numerous sex differences in sleep; in females, sleep need accumulated at a slower rate, and REMS loss was not recovered after SD. In contrast, the rebound in NREMS time after SD was compromised only in npas2 ؊/؊ males. We conclude that NPAS2 plays a role in sleep homeostasis, most likely at the level of the thalamus and cortex, where NPAS2 is abundantly expressed.circadian ͉ clock genes ͉ metabolism ͉ sleep homeostasis N euronal Per-Arnt-Sim-type signal-sensor protein (PAS)-domain protein 2 (NPAS2) is a transcription factor that is highly expressed in the CNS (1). Many PAS-domain proteins can sense oxygen, redox, voltage, or light and are implicated in environmental and developmental signaling pathways (2). NPAS2 senses cellular energy state, in that both the dimerization of NPAS2 to its obligatory partner brain and muscle arnt-like 1 (BMAL1) and the specific DNA binding of NPAS2:BMAL1 heterodimers depend on intracellular redox potential (3). NPAS2 can also affect cellular metabolism by activating transcription of lactate dehydrogenase-1 (ldh1), which encodes the LDH subunit A (3). LDH catalyzes the reduction of pyruvate to lactate, an important neuronal energy substrate. NPAS2 thus uniquely combines sensor and effector functions and might be an important regulator of cellular metabolism in the CNS.Sleep is governed by both circadian and homeostatic processes (4). The notion of the homeostatic regulation of sleep is based on the observation that sleep loss is compensated by an increase in sleep time and intensity that is proportional to the sleep time lost. Such observations indicate that a need for sleep accumulates during waking, although the nature of this need, i.e., the neurophysiological function of sleep, remains unknown. One prominent hypothesis states that sleep corrects a metabolic imbalance imposed upon the brain during wakefulness (5). This imbalance is thought to result in increased hyperpolarization of thalamocortical and ...

Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome

“…Our observation that IL6, STAT3, and PER2 were up-regulated in response to total sleep deprivation after sleep restriction is in accordance with total sleep deprivation studies that have implicated these genes in sleep homeostasis (33,43). The fact that these genes were not detected as being up-regulated in the control condition underlines how 1 wk of restricted sleep has exacerbated the effects of acute total sleep deprivation, which is a well-documented phenomenon for cognitive performance measures (44).…”

Sex differences in sleep: impact of biological sex and sex steroids

“…In general, gonadally intact female rodents spend less time in sleep states compared with males. In mice, females accumulate less total sleep and NREMS compared with males [107,110,112], whereas in intact rats only REMS is reported to be significantly less in female rats compared with males [111,113]. Comparison of sleep architecture in mice suggests that females, despite accumulating less total sleep, have more consolidated sleep bouts, consisting of longer bout durations with less state transitions and fewer arousals [110].…”

Hypocretin (orexin) is critical in sustaining theta/gamma-rich waking behaviors that drive sleep need

“…KO, black symbols, n = 8; WT, gray symbols, n = 7) are expressed as the percentage of each mouse's mean SWS δ power in baseline ZT8 to 12. Solid curves (KO, black; WT, gray) represent process-S simulations calculated using published equation parameters (17). (A, Bottom) SWS (min/h) time course across the 3 d. (B) EEG δ power dynamics at state transitions to SWS, in the minute preceding and the 2 min following, SWS onset (time 0) in four baseline intervals (Left) and four recovery intervals (Right).…”