Sleep fragmentation (SF), unlike prolonged sleep deprivation, is a common consequence of many sleep disorders in humans [
1,
2], of narcolepsy [
3], and of suboptimal sleeping conditions, such as noisy environments. A minimum period of uninterrupted sleep is essential for optimal daytime vigilance and neurocognitive and behavioral functions [
4‐
6]. Cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1beta are multifunctional pro-inflammatory cytokines, which have been recognized not only as crucial inflammatory mediators, but also as important mechanisms involved in the regulation of sleep[
7], aging and neurodegenerative diseases associated with aging [
8,
9], and learning[
10,
11]. TNF-α can be synthesized and released in the brain by both neurons and glial cells, and exerts multiple functions by binding to two different TNF receptors (p55 (TNFR1) and p75 (TNFR2)), which are constitutively expressed in the nervous system [
12]. TNF-α and IL-1β enhance slow wave sleep (SWS), and inhibition of TNF-α or IL-1β reduces spontaneous sleep. Exogenous injection of TNF-α or IL-1β into animals and/or humans induces sleepiness and elicits excess sleep [
7], whereas prolonged wakefulness upregulates both TNF-α and IL-1β in the brain [
7]. Interestingly, pathological concentrations of TNF-α inhibit long-term potentiation (LTP), a surrogate reporter of learning and memory in the hippocampus [
12‐
16], and impair cognitive function [
17].
In the brain, expression of Homer1a is increased after sleep loss, suggesting a role for sleep in the regulation of intracellular calcium homeostasis, particularly in protection and recovery from the calcium-pool changes induced by the prolonged neuronal activation imposed by extended wakefulness [
18]. According to Tononi and Cirelli, the plastic processes occurring during wakefulness result in increased synaptic strength, whereas the role of sleep is to downscale synaptic strength to a basal level while the newly acquired information is retained. Both environmental and pharmacological stressors upregulate Homer1a mRNA in key structures involving higher brain functions [
19]. Spontaneous wakefulness has been shown to be associated with the diffuse induction of molecular changes usually associated with LTP [
20,
21], including the phosphorylation of cyclic AMP response element-binding protein (CREB) and the induction of genes such as Arc, brain-derived neurotrophic factor, nerve growth factor-induced gene A , Homer, and neuronal activity-regulated pentraxin [
22‐
24]. Type 4 cAMP phosphodiesterase (PDE)4, a PDE enzyme that hydrolyzes cAMP, is known to play an important role in memory processes. PDE4 inhibition increases intracellular availability of cAMP, which is known to activate the downstream target CREB protein after activation of protein kinase A. This signaling cascade is important in the consolidation of memory processes and synaptic plasticity [
25‐
27]. Furthermore, rolipram, a selective inhibitor of PDE4, was shown to completely reverse the amnesic effects of MK-801 on working and reference memory [
28] via increased cAMP/CREB signaling in the hippocampus [
29]. The sensory, motor, or cognitive activities that occur during active wakefulness are often associated, in a small subset of neurons, with high peak firing rates that are likely to give rise to LTP-related plastic changes [
30]. This induction of LTP-related genes during spontaneous wakefulness can increase further if animals are kept awake longer by gentle handling, or if they engage in extensive exploration of their environment [
31]. By contrast, during sleep the expression of LTP-related genes is severely reduced or abolished [
20,
21,
32]. Support for the notion that synaptic strength may increase during wakefulness also comes from experiments in humans [
33]and mice [
34,
35] showing that brain metabolism, which is mostly due to synaptic activity, increases from early to late wakefulness.
SF is one of the hallmark characteristics of sleep apnea. Experimentally induced short-term SF, even in the absence of any reductions in total sleep duration, will lead to the emergence of excessive daytime sleepiness and cognitive impairments in humans [
4,
6]. However, the vast majority of the studies aiming to unravel the role of sleep in the homeostatic regulation of biological systems has focused on sleep deprivation [
36‐
38], or alternatively has used SF procedures only for short periods [
39‐
42]. To examine the effects of long-term SF in mice, thereby mimicking the long-standing clinical course of sleep apnea preceding its diagnosis, we took advantage of a newly designed and validated device that does not require increments in locomotion, precludes the need for tethering or social isolation, and is not associated with increase in corticosterone levels [
43].