Control of sleep and wakefulness

Abstract

This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making.

FIGURE 1

Electroencephalographic (EEG) recordings in the human and rat capture differences between vigilance states (wakefulness, NREM sleep, and REM sleep). Wakefulness in both species is characterized by low-amplitude/high-frequency activity. Note that high-frequency beta and gamma activity is not easily visible at this slow timescale. In the human, NREM sleep begins in stage 1, the prevalent EEG frequency begins to slow, with strong alpha activity at posterior sites and theta activity at anterior sites. In NREM sleep stages 2/3, both sleep spindles (7–14 Hz) and K-complexes are seen, as the EEG amplitude increases and frequency further slows. In NREM sleep stage 4, also known as slow wave sleep, strong delta (0.5–4 Hz) activity is evident, accompanied by a large increase in amplitude. During REM sleep, the EEG returns to a profile similar to wakefulness, with low-amplitude and high-frequency activity. In the rodent, NREM sleep is usually not parsed into separate stages. NREM sleep exhibits a significant increase of delta range activity, as well as an increase in amplitude. REM sleep is defined by the strong synchronous theta range (7–9 Hz) activity, probably generated in the hippocampus. Human EEG recordings are adapted from Purves et al. (1028). Note the voltage scales are not matched between species.

FIGURE 2

Location of brain nuclei controlling the sleep-wake cycle (see sects. II–IV) in sagittal (A) and coronal (B) schematics of the rat brain. Location of sections in B are represented as vertical dashed lines in A. Medulla oblongata: DPGi, dorsal aspect of the paragigantocellular reticular nucleus; GiV, ventral gigantocellular nucleus. Pons/midbrain: DR, dorsal raphe nucleus; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; LPB, lateral parabrachial nucleus; LPT, lateral pontine tegmental region; MPB, medial parabrachial nucleus; MR, median raphe nucleus; PB, parabrachial nucleus; PnC, nucleus pontine caudalis; PnO, nucleus pontine oralis; PPT, pedunculopontine tegmental nucleus; SubCA, subcoeruleus nucleus, alpha; SubCD, subcoeruleus nucleus, dorsal; SubCV, subcoeruleus nucleus, ventral; SN, substantia nigra; vlPAG, ventrolateral aspect of the periaqueductal gray; VTA, ventral tegmental area; VTG, ventral tegmental nucleus of Gudden. Hypothalamus: DMH, dorsomedial nucleus of the hypothalamus; LH, lateral hypothalamus; MM, medial mammillary nucleus; MnPO, median preoptic nucleus; MPO, medial preoptic nucleus; PeF, perifornical region of the hypothalamus; PH, posterior hypothalamus; PO, preoptic region (including VLPO); SCN, suprachiasmatic nucleus; SUM, supramammillary nucleus; TMN, tuberomammillary nucleus; VLPO, ventrolateral preoptic nucleus. Forebrain: BF, basal forebrain (including HDB, horizontal limb of the diagonal band; MCPO, magnocellular preoptic nucleus; SI, substantia innominata; VP, ventral pallidum); AMY, amygdala; CPu, caudate putamen; GP, globus pallidus. Thalamus: CM, thalamic centromedial nucleus; LGN, lateral geniculate nucleus; PV, thalamic paraventricular nucleus; RE, nucleus reuniens; RT, thalamic reticular nucleus VL, thalamic ventrolateral nucleus; VM, thalamic ventromedial nucleus; VMPO, ventromedial preoptic nucleus. Hippocampus: CA1, CA1 region of the hippocampus; CA3, CA3 region of the hippocampus; DG, dentate gyrus of the hippocampus. Neocortex: AC, anterior cingulate cortex; IL, infralimbic cortex; PrL, prelimbic cortex. [Adapted from Paxinos and Watson (989), with permission from Elsevier.]

FIGURE 3

Simplified model of cortical circuitry generating gamma oscillations. Cortical circuits consist primarily of excitatory pyramidal neurons and inhibitory GABAergic interneurons. Inhibitory drive generated by interneurons plays an important role in the generation of oscillatory output. Fast spiking interneurons containing parvalbumin (PV) that synapse onto the cell bodies of pyramidal neurons are particularly important in generating gamma oscillations. Recurrent glutamatergic synapses onto GABAergic interneurons provide excitatory drive to the fast spiking interneurons. Both chemical and electrical synapses between PV-positive interneurons enhance synchrony and the coupling of gamma rhythms to theta rhythms.

FIGURE 4

A simplified structural model of hippocampal theta rhythm control. Tonic neuronal activity of the reticular formation, largely originating in the nucleus pontine oralis (PnO), excites the supramammillary nucleus (SUM) by means of glutamatergic projections. Pontine tonic activity is converted to rhythmic firing in SUM, indicated by the wave symbol. Glutamatergic SUM output then excites GABAergic and cholinergic neurons of the medial septum/vertical limb of the diagonal band (MS/vDB), which serves as the pacemaker of the hippocampal theta rhythm.

FIGURE 5

Dorsal and ventral pathways of the ascending reticular activating system (ARAS). The dorsal pathway (blue) originates in pontine and midbrain reticular formation, most prominently cholinergic (LDT/PPT) and glutamatergic neurons which project to the “nonspecific” intralaminar and midline thalamic nuclei which diffusely innervate many areas of the cerebral cortex as well as thalamic relay neurons with more selective projections patterns. The ventral pathway also originates in pontine/midbrain regions and projects to the lateral hypothalamic (LH) and tuberomammillary (TMN) nuclei of the hypothalamus, as well as the basal forebrain (BF). Output of LH and TMN also ascend to BF, which in turn projects to the cortex. Noradrenergic neurons of the locus coeruleus (LC) and serotonergic neurons in the dorsal raphe (DR) contribute to both pathways and send direct projections to the cortex as do histamine neurons of the TMN and orexinergic neurons in the LH. LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine nucleus. [Adapted from Paxinos and Watson (989), with permission from Elsevier.]

FIGURE 6

Functional interactions between wake-promoting neuromodulatory systems projecting to the cortex. Wake-promoting neuromodulatory systems are interconnected mainly in a mutually excitatory network. Cholinergic (ACh) basal forebrain, orexinergic (OX) lateral hypothalamic, serotonergic (5–HT) raphe, noradrenergic (NA) locus coeruleus, and histaminergic (HA) tuberomammillary neurons all interact to promote wakefulness. Thus, if one region is experimentally lesioned, other systems remain and maintain cortical activation and wakefulness. The main exceptions to this pattern are inhibitory serotonergic and norepinephrine projections to cholinergic and orexin neurons. Cortically projecting glutamatergic and GABAergic systems are also important in cortical activation and wakefulness (see text). Note: adrenergic projections to the histamine neurons act by disinhibition (inhibition of GABAergic synaptic inputs), whereas other effects shown are postsynaptic. Receptors involved are as follows: α1, alpha adrenergic type 1; α2, alpha adrenergic type 2; H1, histaminergic type 1; M3, muscarinic cholinergic; OxR1, orexin receptor type 1; OxR2, orexin receptor type 2.

FIGURE 7

The “flip-flop” switch model of transitions between sleep and wakefulness (1117). The wake state is stabilized by lateral hypothalamic (LH) excitatory orexinergic input to wake-related nuclei, including GABAergic/ histaminergic neurons of the tuberomammillary nucleus (TMN), serotonergic neurons of the dorsal raphe nucleus (DR), and noradrenergic neurons of the locus coeruleus (LC). During sleep, GABAergic/galaninergic ventrolateral preoptic (VLPO) neurons inhibit wake-promoting nuclei, including LH. Transitions between wake and sleep are due to mutual inhibition between these sleep- and wake-related nuclei. (Adapted from Saper et al. Nature 437: 1257–1263, 2005, with permission from MacMillan Publishers Ltd.

FIGURE 8

Investigations of the role of adenosine (AD) as a neuromodulatory sleep factor. A: extracellular AD concentrations in the feline basal forebrain (BF) for 10-min consecutive samples from an individual animal, showing elevated levels during wakefulness. Labels indicate behavioral state: W, wakefulness; S, slow wave (NREM) sleep; R, REM sleep. [Adapted from Porkka-Heiskanen et al. (1018). Reprinted with permission from AAAS.] B: AD concentrations in the feline BF rise during 6 h of sleep deprivation (SD) and decrease towards baseline levels during 3 h of spontaneous recovery sleep. [Adapted from Porkka-Heiskanen et al. (1018). Reprinted with permission from AAAS.] C: AD and nitric oxide (NOx, red) concentrations in the rat BF rise during 11 h of SD. The rise of NOx during SD precedes the rise of AD. AD levels are significantly elevated by hour 2 of SD and remain elevated until recovery sleep, when levels fall towards baseline levels. Levels are normalized to baseline levels in the 2 h preceding SD. [Adapted from Kalinchuk et al. (591), with permission from John Wiley and Sons.] D: AD and NOx levels in the rat frontal cortex also rise during SD. Again, the rise of NOx during SD precedes the rise of AD. The rise of AD is significant by hour 6 of SD and is delayed compared with the rise seen in BF, as shown in C. Levels are normalized to baseline levels in the 2 h preceding SD. [Adapted from Kalinchuk et al. (591), with permission from John Wiley and Sons.] E: graphic depiction of the intracellular signaling pathway of the AD A1 receptor in BF observed following sleep deprivation in rats. Steps of the pathway: 1) AD binds to the A1 receptor; 2) activation of PLC pathway, releasing inositol 1,4,5-trisphosphate (IP₃); 3) IP₃ receptor-mediated intracellular calcium mobilization and activation of protein kinase C; 4) phosphorylation of Iκ-B and release of nuclear factor-κB (NF-κB) dimer; 5) nuclear translocation of NF-κB dimer; 6) promoter DNA binding of NF-κB and transcriptional activation of target genes including A1 receptor; 7) protein synthesis (A₁ receptor synthesis). This signaling cascade appears to be confined to cholinergic neurons of BF. (Adapted from Basheer et al. Neuroscience 104: 731–739, 2001, with permission from Elsevier.

FIGURE 9

Sleep and energy metabolism. The interaction between state-dependent changes in ATP, AMPK, and AMPK-regulated anabolic and catabolic pathways is shown. Wakefulness and sleep deprivation are both characterized by increased neuronal activity and increased consumption of ATP. A higher AMP/ATP ratio results in and leads to increased phosphorylated-AMPK (P-AMPK), promoting catabolic processes. Sleep states are characterized by increased NREM delta activity, low neuronal activity, and a rise in ATP levels. The resulting lower AMP/ATP ratio leads to decreased phosphorylated AMPK, promoting anabolic processes, such as synthesis of proteins, glycogen, and fatty acids. [Adapted from Dworak et al. (323).]

FIGURE 10

Pontine tegmental membrane depolarization and action potential activity increases prior to and during REM sleep. A: first trace is nuchal (neck) EMG in the cat, showing a lack of muscle tone during REM sleep; second trace is frontal cortex EEG, showing low-amplitude activity during REM sleep; third trace is lateral geniculate nucleus (LGN) neuronal activity, revealing PGO waves immediately preceding and during REM sleep; fourth trace is extraocular muscle EOG, showing eye movement during REM sleep; and fifth trace is the membrane potential record for one pontine tegmental neuron (MP). B: oscilloscope photographs depict the changes of action potential frequency that accompany MP depolarization. Arrows in the MP trace of A correspond to the eight oscilloscope photographs of B showing tonic neuronal firing during transition into REM sleep, the REM sleep episode, and transition out of REM sleep. REM, REM sleep; NREM, NREM sleep; T, transition; W, wake; Wm, wake with movement. [Adapted from Ito et al. (550).]

FIGURE 11

Descending circuitry responsible for muscle atonia during REM sleep. During REM sleep, descending pontine subcoeruleus (SubC) glutamatergic projections excite diffusely organized glycinergic neurons of the bulbar reticular formation, including the medullary ventral gigantocellular nucleus (GiV). GABAergic/glycinergic output from the GiV inhibits spinal motoneurons, producing muscle atonia. An alternative pathway consists of a direct SubC glutamatergic projection to the spinal cord, directly synapsing on inhibitory interneurons of the ventral horn. When activated, these interneurons inhibit the spinal cord motor neurons, again producing muscle atonia. Red lines denote excitation; black, inhibition. [Adapted from Pakinos and Watson (989), with permission from Elsevier.]

FIGURE 12

The original (A) and modified (B) reciprocal interaction models of REM sleep control, originally proposed by McCarley and Hobson (819). A: the original reciprocal interaction model demonstrates increased REM activity as positive feedback of REM-on neuronal populations occurs. This activity leads to excitation of REM-off neuronal populations, which then inhibit REM-on activity. REM-off activity is self-inhibiting, and eventually wanes, releasing REM-on neurons as REM sleep again occurs. [Adapted from McCarley and Hobson (819). Reprinted with permission from AAAS.] B: LDT/PPT REM-on activity excites pontine reticular formation (PRF) glutamatergic REM-on cells, promoting REM sleep. LDT/PPT REM-on neurons also excite GABAergic interneurons adjacent to REM-off neurons, inhibiting REM-off neuronal activity. REM-on output also inhibits GABAergic REM-off interneurons, which in turn inhibit REM-on PRF neurons. As REM sleep progresses, REM-on cells begin to excite REM-off cells, leading to REM sleep cessation. Dorsal raphe (DR) and locus coeruleus (LC) REM-off neurons inhibit laterodorsal/pedunculopontine tegmental nuclei (LDT/PPT) REM-on neurons during waking and NREM sleep. Self-inhibition of these REM-off neurons leads to disinhibition of REM-on neurons, again allowing REM sleep. (Adapted from McCarley. Sleep Med 8: 302–330, 2007, with permission from Elsevier.)

FIGURE 13

Pontine generation of REM sleep phenomena. Interaction between the pontine/mesencephalic reticular formation (PRF Glutamatergic) and cholinergic laterodorsal/pedunculopontine tegmental nuclei (LDT/PPT ACh) produces ascending and descending activation, resulting in REM sleep phenomena, including PGO waves, rapid eye movements, muscle atonia, hippocampal theta oscillations, and cortical activation. GiV, ventral gigantocellular nucleus; HDB, horizontal limb of the diagonal band; MCPO, magnocellular preoptic nucleus; MRF, medullary reticular formation; MS/vDB, medial septum/vertical limb of the diagonal band; PRF, pontine reticular formation; SI, substantia innominata.