1). Considering the mismatch between negative intraluminal pressure and the decreased airflow arriving through the upper airways, OSA may not only result from an upper

airway obstruction, but it could also be caused by an imbalance in lung volume compared to upper airway size. Thus, various anatomical causes together with decreased XII activation are important contributors to the pharyngeal collapse and thus to the airway occlusion in OSA (Fig. 1 and Fig. 2). Multiple neuronal mechanisms contribute to a sleep-related decrease in XII activation as both neurotransmitter and neuromodulatory systems undergo drastic state dependent changes. As demonstrated in intracellular recordings, glutamatergic and GABAergic mechanisms (Chase et al., 1989, Funk et al.,

1997, Selleck MDV3100 Soja et al., 1987 and Soja et al., 1991) as well as a powerful glycinergic premotor inhibitory system likely contribute to the REM specific decrease in XII motoneuron activity (Yamuy et al., 1999). However, the degree of inhibition may only be detectable in intracellular recordings, while active inhibition is difficult to demonstrate in EMG recordings (Funk et al., 2011). This difficulty may partly explain why the relative importance of fast neurotransmission PD-1/PD-L1 inhibition remains a matter of discussion (Chan et al., 2006, Morrison et al., 2003a and Morrison et al., 2003b). In addition to increased active inhibition by fast synaptic transmitters, there is also a pronounced these sleep related decrease in the activity of noradrenergic (Aston-Jones and Bloom, 1981) and serotonergic neurons (Jacobs and Fornal, 1991 and Leung and Mason, 1999) suggesting that the loss of noradrenergic and serotonergic neuromodulatory inputs play critical roles (Fenik et al., 2005a, Funk et al., 2011, Horner, 2008, Horner, 2009, Kubin et al., 1998 and Ladewig et al., 2004). This hypothesis is consistent across various manipulations in unrestrained animals (Chan et al., 2006, Morrison

et al., 2003a, Sood et al., 2005 and Sood et al., 2007), slice preparations (Funk et al., 1994 and Viemari and Ramirez, 2006), and with research in the so-called carbachol model for rapid eye movement (REM) sleep (Fenik et al., 2004, Fenik et al., 2005a, Fenik et al., 2005b, Fenik et al., 2005c and Fenik et al., 2008). The noradrenergic neurons from the A5 and A7 regions converge at the level of the XII motoneurons (Aldes et al., 1992) and seem to have their effect through α1 adrenergic receptor activation (Parkis et al., 1995, Selvaratnam et al., 1998 and Volgin et al., 2001). Interestingly, the pre-Bötzinger complex (preBötC), an area critical for breathing also receives noradrenergic and serotonergic inputs and is activated by a variety of serotonergic and adrenergic receptors (Doi and Ramirez, 2008, Doi and Ramirez, 2010, Lalley et al., 1995, Pena and Ramirez, 2002, Ptak et al., 2009, Tryba et al., 2006, Viemari et al., 2011 and Viemari and Ramirez, 2006).