Underlying Brain Mechanisms that Regulate Sleep–Wakefulness Cycles

Irma Gvilia*,†,‡    * Ilia State University, Tbilisi 0162, Georgia
† Research Service, Veterans Affairs Greater Los Angeles Healthcare System, North Hills, CA 91343, USA
‡ Department of Medicine, University of California, Los Angeles, CA 90024, USA

I Wakefulness-Regulating Systems

Wakefulness is generated by multiple neuronal systems extending from the brainstem reticular formation to the thalamus and through the posterior hypothalamus up to the basal forebrain. These neuronal systems, including cholinergic neurons in the brainstem and basal forebrain, monoaminergic neurons in the rostral pons, midbrain and posterior hypothalamus, and hypocretin-(orexin)-containing neurons in the perifornical lateral hypothalamus, impart a tonic background level of activity that is crucial for cortical activation on the one hand and behavioral arousal on the other hand. Each of these neuronal groups subserves distinct aspects of wakefulness-related functions of the brain.

In 1935, Bremer (1935) demonstrated that transection of the brainstem at the pontomesencephalic level (but not the spinomedullary junction) produced coma in anesthetized cats. This finding provided evidence of an “ascending arousal system” necessary for forebrain and cortical arousal. More than a decade later, Morruzzi and Magoun (1949) provided additional support for the concept of an ascending arousal system when they showed that electrical stimulation of the rostral pontine reticular formation produced a desynchronized electroencephalogram (EEG) in anesthetized cats. These findings challenged the prevailing view that wakefulness-related activity of the brain and consciousness were dependent upon sensory stimulation and eventually led to the concept that wakefulness requires critical levels of ascending activation originating in the brainstem reticular formation (Moruzzi and Magoun, 1949; Starzl et al., 1951).

Reticular formation, a diffuse system of nerve cell bodies and fibers in the brainstem, extends from the medulla oblongata to the thalamus and sends nonspecific impulses throughout the cortex to “awaken” the entire brain. In addition, brainstem reticular neurons project into the hypothalamus and basal forebrain where neurons are located that also project to the cerebral cortex and participate in the maintenance of an “alert” cerebral cortex. Neurons in the medullary and caudal pontine reticular formation are particularly important for maintaining postural muscle tone along with behavioral arousal via their descending projections to the spinal cord. Neurons in the oral pontine and midbrain reticular formation are essential for sustaining cortical activation, characterized by the low-voltage, high-frequency cortical EEG patterns. Large lesions of the rostral brainstem reticular formation result in a loss of cortical activation and a state of coma in animals and humans. Electrical stimulation of the reticular formation elicits fast cortical activity and waking. Neurons of the pontomesencephalic reticular formation discharge at high rates during waking in association with fast cortical activity, and they give rise to ascending projections by which they excite the forebrain and thus comprise what Moruzzi and Magoun called the “ascending reticular activating system.”

Studies in the 1970s and 1980s revealed that the origin of the ascending reticular activating system was not a neurochemically homogenous mass of reticular tissue in the brainstem tegmentum, but rather is comprised of a serious of well-defined cell groups with identified neurotransmitters (Saper et al., 2001, 2005). As mentioned above, these systems produce cortical arousal via two pathways: a dorsal route through the thalamus and a ventral route through the hypothalamus and basal forebrain. A key component of the dorsal branch of the ascending arousal system, which provides a major excitatory signal from the upper brainstem to the thalamus, is the cholinergic neurons in the pedunculopontine (PPT) and laterodorsal (LDT) tegmental nuclei utilizing acetylcholine, an excitatory neurotransmitter of the central nervous system (Hallanger et al., 1987; Levey et al., 1987; Rye et al., 1987). These cell groups activate the thalamic relay neurons that are crucial for transmission of information to the cerebral cortex and the reticular nucleus of the thalamus acting as a gating mechanism in providing signal transmission between the thalamus and the cerebral cortex (McCormick, 1989). The neurons in the PPT and LDT fire most rapidly during wakefulness and rapid eye movement (REM) sleep, a state characterized by cortical activation (Strecker et al., 2000). These cells are much less active during nonREM sleep, when cortical activity is slow. In this view, the thalamus is thought to function as a major relay to the cortex for the ascending arousal system with the overall activity of the thalamo-cortical system forming the origin of the cortical EEG. Indeed, thalamic relay neurons fire in patterns that correlate with cortical EEG (Steriade et al., 1993). In turn, the overall activity in the thalamo-cortical system is thought to be regulated by the ascending arousal system.

Another population of cholinergic neurons is intermixed with noncholinergic (largely GABAergic) neurons in the basal forebrain (including the nucleus basalis and magnocellular preoptic nucleus in the substantia innominata and the medial septal nucleus and nucleus of the diagonal band of Broca) that project to the cortex, hippocampus, and to a lesser extent, the thalamus. The basal forebrain cholinergic neurons are also implicated in behavioral arousal and EEG desynchronization (Berridge and Foote, 1996; Lee et al., 2005; Saper, 1984). The cholinergic basal forebrain neurons discharge at high rates in association with cortical activation during waking and REM sleep (Lee et al., 2004), whereas inhibition of these neurons can slow the EEG. Acetylcholine released in the cortex excites cortical neurons so that they discharge at high frequencies subtending cortical fast EEG activity. Lesions of the basal forebrain result in severe deficits in waking and a state of coma (Buzsaki et al., 1988).

Other functionally important arousal regulatory cell group is monoaminergic neurons in the upper brainstem and caudal hypothalamus, including the noradrenergic locus coeruleus (LC) (Jones and Yang, 1985; Loughlin et al., 1982), the serotonergic dorsal (DR) and median raphe nuclei (Sobel and Corbett, 1984; Tillet, 1992; Vertes, 1991), the dopaminergic neurons in the ventral periaqueductal grey matter, and histaminergic tuberomammillary neurons in the tuberomammillary nucleus (TMN) (Lin et al., 1988, 1994; Takeda et al., 1984). Monoaminergic cell groups project to the intralaminar and midline thalamic nuclei and also innervate...