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  • The CO chemosensitivity of the LH PFA has been shown


    The CO2 chemosensitivity of the LH/PFA has been shown to be dependent on sleep-wake states (B.S. Deng et al., 2007; Dias et al., 2010, 2009; Li et al., 2013). In this context, it was demonstrated that focal acidification of the LH/PFA, by microdialysis of acidic artificial cerebrospinal fluid (aCSF), increased ventilation during wakefulness, but not during sleep (Li et al., 2013). The arousal state-dependent aspect of the role that the LH/PFA plays in central chemoreception is in accordance with the activity of the putative chemosensitive neurons of this region, the orexin/hypocretin neurons, which are synchronized with the sleep-wake cycle, firing more frequently during wakefulness (Lee et al., 2005; Mileykovskiy et al., 2005). In fact, the importance of the orexinergic system on the maintenance of arousal is well established (Gestreau et al., 2008). Further, the role of the LH/PFA in central chemoreception Phosphoramidon Disodium Salt australia varies not only with arousal state, but also with the diurnal cycle, being predominant during the dark/active period (Dias et al., 2010; Nattie and Li, 2010), which is congruent with the diurnal variation of orexin levels in rat cerebrospinal fluid, where higher values are observed during the dark period compared with the light period (Desarnaud et al., 2004). Several neurotransmitters and neuromodulators have been suggested to influence orexinergic neuron activity. Studies have demonstrated the existence of glutamatergic projections to the LH/PFA and the expression of glutamate receptors in this region (Ozhan et al., 2001; van den Pol and Trombley, 1993). Evidence suggests that the source of glutamatergic inputs to the orexin neurons may be the basal forebrain, the lateral parabrachial nucleus, the LH/PFA itself, and many other Phosphoramidon Disodium Salt australia areas that have not yet been identified (Eyigor et al., 2012a; Henny and Jones, 2006; Li et al., 2002b; Ohno and Sakurai, 2008). Glutamate is suggested to affect orexin neurons and to modulate the orexinergic function in the regulation of wakefulness and feeding (Eyigor et al., 2012b; Rosin et al., 2003). Glutamate is known to provide mainly excitatory inputs on the orexinergic system (Eyigor et al., 2012b), but inhibitory modulation has also been demonstrated, which appears to involve the activation of metabotropic receptors (Acuna-goycolea et al., 2004). In fact, metabotropic glutamate receptors in LH/PFA maintain tonic presynaptic inhibition at excitatory (and inhibitory) synapses (Kuzmiski et al., 2009; Kuzmiski and Bains, 2010). In this regard, the group III of metabotropic glutamate receptor has been shown to trigger presynaptic glutamate release onto orexin cells modulating the output of the orexinergic arousal system (Acuna-Goycolea et al., 2004). Nevertheless, it is still unknown whether this glutamatergic modulation in the LH/PFA, via metabotropic receptors, is also involved in the diurnal modulation of the ventilatory response to the central chemoreflex. Thus, we investigated the glutamatergic regulation, through metabotropic receptors on the LH/PFA, on the hypercapnic ventilatory responses in conscious rats during dark and light periods of the diurnal cycle.
    Material and methods
    Discussion Glutamate is referred to as the main excitatory amino acid neurotransmitter in the hypothalamus (Eyigor et al., 2012a; van den Pol et al., 1990). In the lateral hypothalamus, the presence of glutamate, the expression of its receptors and a broad number of its functions have been demonstrated (Eyigor et al., 2012b; van den Pol and Trombley, 1993). The CO2 chemosensitive neurons of the LH/PFA, the orexin neurons, receive glutamatergic inputs (Eyigor et al., 2012b; Henny and Jones, 2006) which are suggested to influence orexin neuron activity (Li et al., 2002a). Although the main effect of glutamatergic synapses on orexin neurons appears to be excitation (Li et al., 2002a) the activation of mGluRs has been shown to attenuate the excitation of orexin neurons (Acuna-goycolea et al., 2004). Nevertheless, whether the glutamatergic neurotransmission through mGluRs on the LH/PFA affects the hypercapnic ventilatory response was not known.