Memory consolidation has been proposed as a function of sleep. However, sleep is a complex phenomenon characterized by several features including duration, intensity, and continuity. Sleep continuity is disrupted in different neurological and psychiatric conditions, many of which are accompanied by memory deficits. This finding has raised the question of whether the continuity of sleep is important for memory consolidation. However, current techniques used in sleep research cannot manipulate a single sleep feature while maintaining the others constant. Here, we introduce the use of optogenetics to investigate the role of sleep continuity in memory consolidation. We optogenetically targeted hypocretin/orexin neurons, which play a key role in arousal processes. We used optogenetics to activate these neurons at different intervals in behaving mice and were able to fragment sleep without affecting its overall amount or intensity. Fragmenting sleep after the learning phase of the novel object recognition (NOR) task significantly decreased the performance of mice on the subsequent day, but memory was unaffected if the average duration of sleep episodes was maintained at 62–73% of normal. These findings demonstrate the use of optogenetic activation of arousal-related nuclei as a way to systematically manipulate a specific feature of sleep. We conclude that regardless of the total amount of sleep or sleep intensity, a minimal unit of uninterrupted sleep is crucial for memory consolidation.

Background: We have previously reported that the expression of circadian clock-genes increases in the cerebral cortex after sleep deprivation (SD) and that the sleep rebound following SD is attenuated in mice deficient for one or more clock-genes. We hypothesized that besides generating circadian rhythms, clock-genes also play a role in the homeostatic regulation of sleep. Here we follow the time course of the forebrain changes in the expression of the clock-genesperiod(per)-1, per2, and of the clock-controlled genealbumin D-binding protein(dbp) during a 6 h SD and subsequent recovery sleep in three inbred strains of mice for which the homeostatic sleep rebound following SD differs. We reasoned that if clock genes are functionally implicated in sleep homeostasis then the SD-induced changes in gene expression should vary according to the genotypic differences in the sleep rebound.Results: In all three strainsperexpression was increased when animals were kept awake but the rate of increase during the SD as well as the relative increase inperafter 6 h SD were highest in the strain for which the sleep rebound was smallest; i.e., DBA/2J (D2). Moreover, whereas in the other two strainsper1andper2reverted to control levels with recovery sleep,per2expression specifically, remained elevated in D2 mice.dbpexpression increased during the light period both during baseline and during SD although levels were reduced during the latter condition compared to baseline. In contrast toper2,dbpexpression reverted to control levels with recovery sleep in D2 only, whereas in the two other strains expression remained decreased.Conclusion: These findings support and extend our previous findings that clock genes in the forebrain are implicated in the homeostatic regulation of sleep and suggest that sustained, high levels ofper2expression may negatively impact recovery sleep.

▪ Abstract Sleep and circadian rhythms are the primary determinants of arousal state, and torpor is the most extreme state change that occurs in mammals. The view that torpor is an evolutionary extension of sleep is supported by electrophysiological studies. However, comparisons of factors that influence the expression of sleep and torpor uncover significant differences. Deep sleep immediately following torpor suggests that torpor is functionally a period of sleep deprivation. Recent studies that employ post-torpor sleep deprivation, however, show that the post-torpor intense sleep is not homeostatically regulated, but might be a reflection of synaptic loss and replacement. The circadian system regulates sleep expression in euthermic mammals in such a way that would appear to preclude multiday bouts of torpor. Indeed, the circadian system is robust in animals that show shallow torpor, but its activity in hibernators is at least damped if not absent. There is good evidence from some species, however, that the circadian system plays important roles in the timing of bouts of torpor.

Memories are consolidated and strengthened during sleep. Here we show that memories can also be weakened during sleep. We used a fear-conditioning paradigm in mice to condition footshock to an odor (conditioned stimulus (CS)). Twenty-four hours later, presentation of the CS odor during sleep resulted in an enhanced fear response when tested during subsequent wake. However, if the re-exposure of the CS odor during sleep was preceded by bilateral microinjections of a protein synthesis inhibitor into the basolateral amygdala, the subsequent fear response was attenuated. These findings demonstrate that specific fear memories can be selectively reactivated and either strengthened or attenuated during sleep, suggesting the potential for developing sleep therapies for emotional disorders.

Background and Purpose: Down's syndrome is a common genetic cause of intellectual disability, for which there are no drug therapies. Mechanistic studies in a model of Down's syndrome [Ts65Dn (TS) mice] demonstrated that impaired cognitive function was due to excessive neuronal inhibitory tone. These deficits were normalized by low doses of GABA_A receptor antagonists in adult animals. In this study, we explore the therapeutic potential of pentylenetetrazole, a GABA_A receptor antagonist with a history of safe use in humans.Experimental Approach: Long‐term memory was assessed by the novel object recognition test in different cohorts of TS mice after a delay following a short‐term chronic treatment with pentylenetetrazole. Seizure susceptibility, an index of treatment safety, was studied by means of EEG, behaviour and hippocampus morphology. EEG spectral analysis was used as a bio‐marker of the treatment.Key Results: PTZ has a wide therapeutic window (0.03–3 mg·kg⁻¹) that is >10–1000‐fold below its seizure threshold and chronic pentylenetetrazole treatment did not lower the seizure threshold. Short‐term, low, chronic dose regimens of pentylenetetrazole elicited long‐lasting (>1 week) normalization of cognitive function in young and aged mice. Pentylenetetrazole effectiveness was dependent on the time of treatment; cognitive performance improved after treatment during the light (inactive) phase, but not during the dark (active) phase. Chronic pentylenetetrazole treatment normalized EEG power spectra in TS mice.Conclusions and Implications: Low doses of pentylenetetrazole were safe, produced long‐lasting cognitive improvements and have the potential of fulfilling an unmet therapeutic need in Down's syndrome.