Biological Psychiatry - Vol. 2

By Hugo D'Haenen; J.A. Den Boer et al. | Go to book overview

Neurotransmitter Systems Regulating Sleep-Wake States

Barbara E. Jones

Three distinct physiological and cognitive states exist in mammals: waking, slow-wave sleep (SWS) and rapid-eye-movement sleep (REMS). Waking is a multifarious state but is generally characterized by fast waves on the electroencephalographic (EEG) record in association with behavioural activity and responsiveness; SWS is characterized by slow waves on the EEG record in association with behavioural quiescence and decreased responsiveness; however, REMS, or 'paradoxical sleep' (PS), is characterized by a unique dissociation of EEG, characterized by fast waves indicative of cortical arousal, and behaviour, characterized by quiescence and diminished responsiveness, indicative of sleep. Viewed in terms of metabolism and energy expenditure, waking requires variable yet relatively high levels of energy expenditure by the brain and body; SWS requires low levels and thus allows conservation and restoration of energy stores in both brain and body; however, REMS requires high levels of energy expenditure by the brain while maintaining minimal energy use by the body. These states occur within a circadian cycle and an ultradian cycle. Depending upon the species, the active, waking phase of the circadian cycle occurs either during the day and light, as in humans, or during the night and darkness, as in cats and rats. Sleep is concentrated to differing degrees in the opposite phase, when it occurs, according to an ultradian rhythm. Across the phylogenetic scale, the period of the ultradian sleep-wake rhythm is correlated with basal metabolic rate and body weight, and thus is apparently determined in part by energy expenditure, storage, conservation and restoration. In addition to their regulation by underlying rhythms, the sleep-wake states are also regulated by homeostatic processes, such that the deprivation of sleep results in an increased drive for sleep and increased occurrence of sleep upon recovery. The rhythmic and homeostatic nature of sleep-wake states indicates the existence of underlying, alternating and accumulating processes that may depend upon changes in chemical transmitters and their receptors in the brain.

Neurotransmitters include small molecules such as glutamate and GABA, acetylcholine and the monoamines, which may act directly upon ion channels or indirectly upon them through second messengers to modify membrane potentials and activity of neurons. They may also include peptides, which function as transmitters, modulators or hormones. Although, to date, no single transmitter/modulator molecule has been found that serves a specific or exclusive function in promoting or generating waking, SWS or REMS, specific neuronal systems containing particular neurotransmitters have been shown to be integral to the promotion of each of these states.

From early physiological studies, it has been known that no specific centres are present in the brain for the generation of any one state, but that redundant neuronal systems are distributed through the brainstem and forebrain, systems which are collectively important for the promotion and maintenance of individual states (Jones, 2000). For waking (Figure XXIV-2.1), neurons distributed through the brainstem reticular formation (RF) and concentrated within the oral pontine and mesencephalic fields comprise the ascending reticular activating system, which, by lesions in humans and animals, is known to be critical for the generation and maintenance of the EEG and behavioural components of waking (Moruzzi and Magoun, 1949). This system of neurons gives rise to ascending pathways projecting dorsally into the nonspecific thalamo-cortical projection system, which in turn stimulates widespread activation of the cerebral cortex (Dempsey et al, 1941). Other fibres ascend ventrally into and through the hypothalamus up to the level of the basal forebrain (substantia innominata [SI]), from where cortical activation is also relayed in a widespread manner (Starzl et al, 1951). These systems collectively stimulate cortical activation, characterized by high-frequency (beta and gamma) EEG activity. Fibres also terminate in the posterior hypothalamus, where lesions are known in humans and animals to produce a comatose state (Ranson, 1939). As evident as well from electrical stimulation (Hess, 1957), the posterior hypothalamus is an important higher control centre for the sympathetic nervous system, thus coordinating peripheral autonomic responses (increased temperature, respiration, heart rate, blood pressure) with cortical activation. In addition, the descending projections from the brainstem reticular formation, including the caudal pontine and medullary reticular formation, serve to stimulate somatic motor activity, reactivity and postural muscle tonus (as evident in electromyographic [EMG] activity) through facilitatory reticulo-spinal influences (Magoun and Rhines, 1946).

For SWS (Figure XXIV-2.2), the medulla appears, to play a role in promoting sleep, particularly neurons in the region of the solitary and vagal, parasympathetic nuclei, which may inhibit the activating neurons located in the ponto-mesencephalic tegmentum (Batini et al, 1959; Favale et al, 1961). Within the forebrain, sleep marked by EEG slow waves may be elicited by low-frequency stimulation of the thalamo-cortical projection neurons (Akert et al, 1952). Most potent there is the influence shown to emanate from the preoptic and anterior hypothalamic (POAH) region, where lesions have produced insomnia and electrical stimulation has promoted sleep, probably in part due to inhibition of the posterior hypothalamus and ponto-mesencephalic reticular formation (von Economo, 1931; Nauta, 1946; Hess, 1954). This region serves in an antagonistic manner to the posterior hypothalamus, inhibiting sympathetic activity and facilitating parasympathetic responses (decreased temperature, respiration, heart rate, blood pressure). SWS appears to emerge from the dampening of cortical activation, somatic motor activity (as evident by decreased EMG) and sympathetic nervous activity along with a shift to a predominance of parasympathetic activity.

For REMS (or PS, as it is often also called in animals) (Figure XXIV–2.3), the brainstem appears to contain the essential structures for the generation of the state (Jouvet, 1962). The oral pontine reticular formation (PnO) is necessary for the triggering of ascending and descending parameters of the state, including


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