Parasubthalamic calretinin neurons modulate wakefulness associated with exploration in male mice.

The parasubthalamic nucleus (PSTN) is considered to be involved in motivation, feeding and hunting, all of which are highly depending on wakefulness. However, the roles and underlying neural circuits of the PSTN in wakefulness remain unclear. Neurons expressing calretinin (CR) account for the majority of PSTN neurons. In this study in male mice, fiber photometry recordings showed that the activity of PSTNCR neurons increased at the transitions from non-rapid eye movement (non-REM, NREM) sleep to either wakefulness or REM sleep, as well as exploratory behavior. Chemogenetic and optogenetic experiments demonstrated that PSTNCR neurons were necessary for initiating and/or maintaining arousal associated with exploration. Photoactivation of projections of PSTNCR neurons revealed that they regulated exploration-related wakefulness by innervating the ventral tegmental area. Collectively, our findings indicate that PSTNCR circuitry is essential for the induction and maintenance of the awake state associated with exploration.

GABAergic neurons in the rostromedial tegmental nucleus are essential for rapid eye movement sleep suppression.

Rapid eye movement (REM) sleep disturbances are prevalent in various psychiatric disorders. However, the neural circuits that regulate REM sleep remain poorly understood. Here, we found that in male mice, optogenetic activation of rostromedial tegmental nucleus (RMTg) GABAergic neurons immediately converted REM sleep to arousal and then initiated non-REM (NREM) sleep. Conversely, laser-mediated inactivation completely converted NREM to REM sleep and prolonged REM sleep duration. The activity of RMTg GABAergic neurons increased to a high discharge level at the termination of REM sleep. RMTg GABAergic neurons directly converted REM sleep to wakefulness and NREM sleep via inhibitory projections to the laterodorsal tegmentum (LDT) and lateral hypothalamus (LH), respectively. Furthermore, LDT glutamatergic neurons were responsible for the REM sleep-wake transitions following photostimulation of the RMTgGABA-LDT circuit. Thus, RMTg GABAergic neurons are essential for suppressing the induction and maintenance of REM sleep.

Trihexyphenidyl increases delta activity in non-rapid eye movement sleep without impairing cognitive function in rodent models.

Both human and rodent studies suggest the link between non-rapid eye movement (NREM) sleep and cognition. Recent study indicated that selective activation of cholinergic neurons in basal forebrain inhibits electroencephalogram (EEG) delta power and shortens NREM sleep. In the current study, we aimed to test the pharmacological effect of trihexyphenidyl (THP), a selective muscarinic M1 receptor antagonist, on EEG power spectra and sleep with or without the selective activation of basal forebrain cholinergic neurons. THP (1, 2, and 3 mg/kg) was administrated intraperitoneally in natural sleep phase. Basal forebrain cholinergic neurons expressing modified G protein-coupled muscarinic receptors (hM3Dq) were activated by intraperitoneal injection of clozapine-N-oxide in ChAT-IRES-Cre mice. EEG and electromyogram (EMG) signals were recorded in freely moving mice to analyze EEG power spectrum and sleep hypnogram. Y-maze and novel object recognition tests were used for testing cognition. THP 1 mg/kg significantly increased EEG delta power and facilitated NREM sleep in wildtype mice, while THP 3 mg/kg was required in ChAT-IRES-Cre mice treated with clozapine-N-oxide. THP with dosage up to 8 mg/kg did not induce cognitive impairments in wildtype mice. EEG delta power of NREM sleep is often used as an indicator of sleep depth or sleep quality, which tightly link with sleep-dependent cognition. Taken together, the data collected from rodents hinted that, THP could possibly be used as the NREM sleep facilitator in humans.