There is an additional population of neurons in the supramammillary region and extending laterally to selleck products the subthalamic nucleus, which is

a known source of projections to the cerebral cortex and basal forebrain (Grove, 1988 and Saper, 1985). Many neurons in this region express the vesicular glutamate transporter 2 (Hur and Zaborszky, 2005 and Ziegler et al., 2002) but whether these glutamatergic neurons promote arousal remains to be determined. The most rostral population of arousal-promoting subcortical neurons is located in the basal forebrain. Many of these neurons contain either acetylcholine or gamma-amino-butyric acid (GABA), and a small number contain glutamate ( Manns et al., 2001 and Hur and Zaborszky, 2005). Basal forebrain cholinergic neurons innervate, both directly and indirectly activate cortical Bcl-2 inhibitor pyramidal cells, and probably augment cortical activation and EEG desynchronization ( Jones, 2004). GABAergic basal forebrain neurons innervate and presumably inhibit cortical GABAergic interneurons and deep layer pyramidal cells ( Freund and Meskenaite, 1992 and Henny and Jones, 2008), both of which most likely result in disinhibition of cortical circuits.

Many of these basal forebrain neurons are wake-active and fire in bursts correlated with specific EEG rhythms. Small ibotenic acid lesions of the basal forebrain result in modest slowing of the EEG without changing the amount of wake or sleep, while specific lesions of basal forebrain cholinergic neurons reduce wakefulness transiently, without affecting the EEG frequency spectrum ( Kaur et al., 2008). On the other hand, acute inactivation Calpain of the basal forebrain with the anesthetic procaine produces deep NREM sleep, whereas activation with glutamatergic agonists causes wakefulness ( Cape and Jones, 2000). A definitive understanding of the roles of the basal forebrain cell groups in arousal awaits studies that differentially eliminate the GABAergic population. The thalamic relay nuclei (such

as the anterior, ventral, and lateral thalamic cell groups; medial and lateral geniculate nuclei; mediodorsal nucleus; and pulvinar) are the most important and abundant sources of subcortical glutamatergic afferents to the cerebral cortex, and the intralaminar and midline nuclei provide a diffuse source of cortical input ( Jones and Leavitt, 1974). Surprisingly, there is little evidence that these inputs play a major role in producing wakefulness. Early electrical stimulation studies suggested that the midline and intralaminar thalamic nuclei might constitute a diffuse, nonspecific cortical activating system ( Morison and Dempsey, 1942 and Steriade, 1995), but lesions of the midline and intralaminar nuclei did not prevent cortical activation ( Moruzzi and Magoun, 1949 and Starzl et al., 1951).