State-Dependent Modulation of Breathing in Urethane-Anesthetized Rats

Abstract

Respiratory activity is most fragile during sleep, in particular during paradoxical [or rapid eye movement (REM)] sleep and sleep state transitions. Rats are commonly used to study respiratory neuromodulation, but rodent sleep is characterized by a highly fragmented sleep pattern, thus making it very challenging to examine different sleep states and potential pharmacological manipulations within them. Sleep-like brain-state alternations occur in rats under urethane anesthesia and may be an effective and efficient model for sleep itself. The present study assessed state-dependent changes in breathing and respiratory muscle modulation under urethane anesthesia to determine their similarity to those occurring during natural sleep. Rats were anesthetized with urethane and respiratory airflow, as well as electromyographic activity in respiratory muscles were recorded in combination with local field potentials in neocortex and hippocampus to determine how breathing pattern and muscle activity are modulated with brain state. Measurements were made in normoxic, hypoxic, and hypercapnic conditions. Results were compared with recordings made from rats during natural sleep. Brain-state alternations under urethane anesthesia were closely correlated with changes in breathing rate and variability and with modulation of respiratory muscle tone. These changes closely mimicked those observed in natural sleep. Of great interest was that, during both REM and REM-like states, genioglossus muscle activity was strongly depressed and abdominal muscle activity showed potent expiratory modulation. We demonstrate that, in urethane-anesthetized rats, respiratory airflow and muscle activity are closely correlated with brain-state transitions and parallel those shown in natural sleep, providing a useful model to systematically study sleep-related changes in respiratory control.

α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea

“…Again, spontaneous REM sleep resulted in marked decreases in not only baseline HM activity (29), but also obstructive apnea-induced hLTF ( Figure 2, C and D), severely blunting (but not abolishing) both these first-and second-line motor defenses against OSA. Indeed, compared with cholinergic-induced REM-like, spontaneous REM sleep exerted even greater and more persistent depressant effects on HM activity and hLTF, lasting up to >20 minutes after episodic obstructive apnea ( Figure 2D).…”

“…To verify that the depressant effect of cholinergic-induced REM-like sleep on hLTF was not an artifact of the cholinergic agent per se, similar measurements were made in a separate group of rats (n = 5) after transition to spontaneous REM sleep, a condition that is attainable in rats under urethane anesthesia (29). Again, spontaneous REM sleep resulted in marked decreases in not only baseline HM activity (29), but also obstructive apnea-induced hLTF ( Figure 2, C and D), severely blunting (but not abolishing) both these first-and second-line motor defenses against OSA.…”

“…Another limitation of the present study is the necessary use of urethane anesthesia in order to avoid arousal during obstructive apnea in tracheostomized rats, which is typical of such studies (24). Unlike other anesthetics, urethane anesthesia retains the sleep-like alterations in brain state, GG activity, breathing pattern, and chemosensitivity similar to those seen during natural sleep in unanesthetized rats (29,62,63). Our finding that yohimbine had similar beneficial effects under both cholinergic-induced REM-like sleep and spontaneous REM sleep in urethane-anesthetized rats (Figure 3) further substantiated the suggested robustness of yohimbine therapy in potentially mitigating obstructive apnea -particularly those occurring predominantly during REM sleep, a common yet often under-diagnosed form of OSA (64).…”

Lack of Respiratory Coupling with Neocortical and Hippocampal Slow Oscillations

“…Conversely, the spontaneous coordination of neural activity occurring in offline states such as sleep has also been suggested to be important for the modulation and consolidation of neuroplastic changes occurring during prior wakefulness, which would have an impact on future online brain operations and behavior (Buzsáki, 1989(Buzsáki, , 1998Born et al, 2006). Patterns occurring during non-rapid-eye movement (nREM) stages (especially slow-wave-sleep [SWS]) are thought to be especially important in this regard (Born et al, 2006;Tononi and Cirelli, 2006;Girardeau and Zugaro, 2011;Mölle and Born, 2011). Therefore, the mechanisms by which spontaneous globally occurring slow-wave patterns are generated and entrained are of fundamental importance.…”

“…At the cellular level, it corresponds to the synchronous fluctuation of membrane potential from relatively hyperpolarized levels (DOWN/OFF epochs) to suprathreshold levels (UP/ON epochs) (Steriade et al, 1993b). The SO, in particular, has been associated with future memory function (Marshall and Born, 2007;Mölle and Born, 2011). Although it is typically thought of as an intrinsic spontaneous rhythm of cortical networks because it is generated in the isolated forebrain, in isolated cortical slabs, and may also be a component of activity present in in vitro preparations (Sanchez-Vives and McCormick, 2000;Timofeev et al, 2000;Dickson et al, 2003), it is also elicited or influenced by sensory stimulation, electric/magnetic fields, corticocortical interconnections, and direct neural stimulation, suggesting that its global coordination is entrained by activity-dependent processes (Amzica and Steriade, 1995;Petersen et al, 2003;MacLean et al, 2005;Massimini et al, 2007;Gao et al, 2009;Vyazovskiy et al, 2009;Ozen et al, 2010;Greenberg and Dickson, 2013).…”