Open main menu

Wikipedia β

Ascending reticular activating system

The ascending reticular activating system (ARAS), also known as the extrathalamic control modulatory system or simply reticular activating system (RAS), is a set of connected nuclei in the brains of vertebrates that is responsible for regulating wakefulness and sleep-wake transitions. As its name implies, its most influential component is the reticular formation.

Ascending reticular activating system
Gray690.png
Deep dissection of brain-stem. Ventral view. (Reticular formation labeled near center.)
Identifiers
NeuroNames ancil-231
Dorlands
/Elsevier
s_33/12787787
Anatomical terms of neuroanatomy

Contents

History and etymologyEdit

Moruzzi and Magoun first investigated the neural components regulating the brain’s sleep-wake mechanisms in 1949. Physiologists had proposed that some structure deep within the brain controlled mental wakefulness and alertness.[1] It had been thought that wakefulness depended only on the direct reception of afferent (sensory) stimuli at the cerebral cortex.

The direct electrical stimulation of the brain could simulate electrocortical relays. Magoun used this principle to demonstrate, on two separate areas of the brainstem of a cat, how to produce wakefulness from sleep. First the ascending somatic and auditory paths; second, a series of “ascending relays from the reticular formation of the lower brain stem through the mesencephalic tegmentum, subthalamus and hypothalamus to the internal capsule.”[2] The latter was of particular interest, as this series of relays did not correspond to any known anatomical pathways for the wakefulness signal transduction and was coined the ascending reticular activating system (ARAS).

Next, the significance of this newly identified relay system was evaluated by placing lesions in the medial and lateral portions of the front of the midbrain. Cats with mesancephalic interruptions to the RAS entered into a deep sleep and displayed corresponding brain waves. In alternative fashion, cats with similarly placed interruptions to ascending auditory and somatic pathways exhibited normal sleeping and wakefulness, and could be awakened with somatic stimuli. Because these external stimuli would be blocked by the interruptions, this indicated that the ascending transmission must travel through the newly discovered RAS.

Finally, Magoun recorded potentials within the medial portion of the brain stem and discovered that auditory stimuli directly fired portions of the reticular activating system. Furthermore, single-shock stimulation of the sciatic nerve also activated the medial reticular formation, hypothalamus, and thalamus. Excitation of the RAS did not depend on further signal propagation through the cerebellar circuits, as the same results were obtained following decerebellation and decortication. The researchers proposed that a column of cells surrounding the midbrain reticular formation received input from all the ascending tracts of the brain stem and relayed these afferents to the cortex and therefore regulated wakefulness.[2][3]

Location and structureEdit

Anatomical componentsEdit

The ARAS is composed of several neuronal circuits connecting the dorsal part of the posterior midbrain and anterior pons to the cerebral cortex via distinct pathways that project through the thalamus and hypothalamus.[4] The thalamic pathway consists primarily of cholinergic neurons in the pontine tegmentum, whereas the hypothalamic pathway is composed primarily of monoamine neurons (i.e., neurons that release dopamine, norepinephrine, serotonin, and histamine).[5][6] The most significant components of the ARAS include:[5][6][7]

The RAS consists of evolutionarily ancient areas of the brain, which are crucial to survival and protected during adverse periods. As a result, the RAS still functions during inhibitory periods of hypnosis.[8]

NeurotransmittersEdit

The primary neurotransmitters involved in the ARAS are dopamine, norepinephrine, serotonin, histamine, and acetylcholine.[5][6]

AcetylcholineEdit

Shute and Lewis first revealed the presence of a cholinergic component of the RAS,[9] composed of two ascending mesopontine tegmental pathways rostrally situated between the mesencephalon and the centrum semiovale (semioval center).[10] These pathways involve cholinergic neurons of the posterior midbrain, the pedunculopontine nucleus (PPN) and the laterodorsal tegmental nucleus (LDT), which are active during waking and REM sleep.[11] Cholinergic activity is highest when in an awake state and during REM sleep, and is minimal in non-REM sleep[12] Cholinergic projections descend throughout the reticular formation and ascend to the substantia nigra, basal forebrain, thalamus, and cerebellum;[13] cholinergic activation in the RAS results in increased acetylcholine release in these areas. Glutamate has also been suggested to play an important role in determining the firing patterns of the tegmental cholinergic neurons.[14]

It has been recently reported that significant portions of posterior PPN cells are electrically coupled. It appears that this process may help coordinate and enhance rhythmic firing across large populations of cells. This unifying activity may help facilitate signal propagation throughout the RAS and promote sleep-wake transitions. It is estimated that 10 to 15% of RAS cells may be electrically coupled.[11]

NorepinephrineEdit

The adrenergic component of the reticular activating system is closely associated with the noradrenergic neurons of the locus coeruleus. In addition to noradrenergic projections that parallel the aforementioned cholinergic paths, there are ascending projections directly to the cerebral cortex and descending projections to the spinal cord.[13] Unlike cholinergic neurons, the adrenergic neurons are active during waking and slow wave sleep but cease firing during REM sleep.[14] In addition, adrenergic neurotransmitters are destroyed much more slowly than acetylcholine. This sustained activity may account for some of the time latency during changes of consciousness.[10]

More recent work has indicated that the neuronal messenger nitric oxide (NO) may also play an important role in modulating the activity of the noradrenergic neurons in the RAS. NO diffusion from dendrites regulates regional blood flow in the thalamus, where NO concentrations are high during waking and REM sleep and significantly lower during slow-wave sleep. Furthermore, injections of NO inhibitors have been found to affect the sleep-wake cycle and arousal.[14]

Additionally, it appears that hypocretin/orexin neurons of the hypothalamus activate both the adrenergic and cholinergic components of the RAS and may coordinate activity of the entire system.[15]

DopamineEdit

HistamineEdit

SerotoninEdit

FunctionEdit

Regulating sleep-wake transitionsEdit

The main function of the RAS is to modify and potentiate thalamic and cortical function such that electroencephalogram (EEG) desynchronization ensues.[1][16] There are distinct differences in the brain’s electrical activity during periods of wakefulness and sleep: Low voltage fast burst brain waves (EEG desynchronization) are associated with wakefulness and REM sleep (which are electrophysiologically similar); high voltage slow waves are found during non-REM sleep. Generally speaking, when thalamic relay neurons are in burst mode the EEG is synchronized and when they are in tonic mode it is desynchronized.[16] Stimulation of the RAS produces EEG desynchronization by suppressing slow cortical waves (0.3–1 Hz), delta waves (1–4 Hz), and spindle wave oscillations (11–14 Hz) and by promoting gamma band (20 – 40 Hz) oscillations.[15]

The physiological change from a state of deep sleep to wakefulness is reversible and mediated by the RAS.[3] Inhibitory influence from the brain is active at sleep onset, likely coming from the preoptic area (POA) of the hypothalamus. During sleep, neurons in the RAS will have a much lower firing rate; conversely, they will have a higher activity level during the waking state.[17] Therefore, low frequency inputs (during sleep) from the RAS to the POA neurons result in an excitatory influence and higher activity levels (awake) will have inhibitory influence. In order that the brain may sleep, there must be a reduction in ascending afferent activity reaching the cortex by suppression of the RAS.[3]

AttentionEdit

The reticular activating system also helps mediate transitions from relaxed wakefulness to periods of high attention.[7] There is increased regional blood flow (presumably indicating an increased measure of neuronal activity) in the midbrain reticular formation (MRF) and thalamic intralaminar nuclei during tasks requiring increased alertness and attention.

Clinical relevanceEdit

PainEdit

Direct electrical stimulation of the reticular activating system produces pain responses in cats and educes verbal reports of pain in humans.[citation needed] Additionally, ascending reticular activation in cats can produce mydriasis,[citation needed] which can result from prolonged pain. These results suggest some relationship between RAS circuits and physiological pain pathways.[18]

Developmental influencesEdit

There are several potential factors that may adversely influence the development of the reticular activating system:

Regardless of birth weight or weeks of gestation, premature birth induces persistent deleterious effects on pre-attentional (arousal and sleep-wake abnormalities), attentional (reaction time and sensory gating), and cortical mechanisms throughout development.
Prenatal exposure to cigarette smoke is known to produce lasting arousal, attentional and cognitive deficits in humans. This exposure can induce up-regulation of nicotinic receptors on α4b2 subunit on Pedunculopontine nucleus (PPN) cells, resulting in increased tonic activity, resting membrane potential, and hyperpolarization-activated cation current. These major disturbances of the intrinsic membrane properties of PPN neurons result in increased levels of arousal and sensory gating deficits (demonstrated by a diminished amount of habituation to repeated auditory stimuli). It is hypothesized that these physiological changes may intensify attentional dysregulation later in life.

PathologiesEdit

Given the importance of the RAS for modulating cortical changes, disorders of the RAS should result in alterations of sleep-wake cycles and disturbances in arousal.[13] Some pathologies of the RAS may be attributed to age, as there appears to be a general decline in reactivity of the RAS with advancing years.[21] Changes in electrical coupling have been suggested to account for some changes in RAS activity: If coupling were down-regulated, there would be a corresponding decrease in higher-frequency synchronization (gamma band). Conversely, up-regulated electrical coupling would increase synchronization of fast rhythms that could lead to increased arousal and REM sleep drive.[11] Specifically, disruption of the RAS has been implicated in the following disorders:

Intractable schizophrenic patients have a significant increase (> 60%) in the number of PPN neurons[13] and dysfunction of NO signaling involved in modulating cholinergic output of the RAS.[14]
Patients with these syndromes exhibit a significant (>50%) decrease in the number of locus coeruleus (LC) neurons, resulting is increased disinhibition of the PPN.[13]
Lesions along the PPT/LDT nuclei are associated with narcolepsy.[22] There is a significant down-regulation of PPN output and a loss of orexin peptides, promoting the excessive daytime sleepiness that is characteristic of this disorder.[15]
Dysfunction of NO signaling has been implicated in the development of PSP.[14]
The exact role of the RAS in each of these disorders has not yet been identified. However, it is expected that in any neurological or psychiatric disease that manifests disturbances in arousal and sleep-wake cycle regulation, there will be a corresponding dysregulation of some elements of the RAS.[13]
REM sleep disturbances are common in Parkinson's. It is mainly a dopaminergic disease, but cholinergic nuclei are depleted as well. Degeneration in the RAS begins early in the disease process.[22]
During the 1920s, an outbreak of an illness characterized by hypersomnia occurred, and was termed encephalitis lethargica. It was classed as a sleep disorder.

ReferencesEdit

  1. ^ a b Steriade, M. (1996). "Arousal: Revisiting the reticular activating system". Science. 272 (5259): 225–226. PMID 8602506. doi:10.1126/science.272.5259.225. 
  2. ^ a b Magoun, H. W. (1952). "AN ASCENDING RETICULAR ACTIVATING SYSTEM IN THE BRAIN STEM". Ama Archives of Neurology and Psychiatry. 67 (2): 145–154. PMID 14893989. doi:10.1001/archneurpsyc.1952.02320140013002. 
  3. ^ a b c Evans, B.M. (2003). "Sleep, consciousness and the spontaneous and evoked electrical activity of the brain. Is there a cortical integrating mechanism?". Neurophysiologie clinique. 33: 1–10. doi:10.1016/s0987-7053(03)00002-9. 
  4. ^ Steriade, M (1995). "NEUROMODULATORY SYSTEMS OF THALAMUS AND NEOCORTEX". Seminars in the Neurosciences. 7 (5): 361–370. doi:10.1006/smns.1995.0039. 
  5. ^ a b c Iwańczuk W, Guźniczak P (2015). "Neurophysiological foundations of sleep, arousal, awareness and consciousness phenomena. Part 1". Anaesthesiol Intensive Ther. 47 (2): 162–167. PMID 25940332. doi:10.5603/AIT.2015.0015. The ascending reticular activating system (ARAS) is responsible for a sustained wakefulness state. It receives information from sensory receptors of various modalities, transmitted through spinoreticular pathways and cranial nerves (trigeminal nerve — polymodal pathways, olfactory nerve, optic nerve and vestibulocochlear nerve — monomodal pathways). These pathways reach the thalamus directly or indirectly via the medial column of reticular formation nuclei (magnocellular nuclei and reticular nuclei of pontine tegmentum). The reticular activating system begins in the dorsal part of the posterior midbrain and anterior pons, continues into the diencephalon, and then divides into two parts reaching the thalamus and hypothalamus, which then project into the cerebral cortex (Fig. 1). The thalamic projection is dominated by cholinergic neurons originating from the pedunculopontine tegmental nucleus of pons and midbrain (PPT) and laterodorsal tegmental nucleus of pons and midbrain (LDT) nuclei [17, 18]. The hypothalamic projection involves noradrenergic neurons of the locus coeruleus (LC) and serotoninergic neurons of the dorsal and median raphe nuclei (DR), which pass through the lateral hypothalamus and reach axons of the histaminergic tubero-mamillary nucleus (TMN), together forming a pathway extending into the forebrain, cortex and hippocampus. Cortical arousal also takes advantage of dopaminergic neurons of the substantia nigra (SN), ventral tegmenti area (VTA) and the periaqueductal grey area (PAG). Fewer cholinergic neurons of the pons and midbrain send projections to the forebrain along the ventral pathway, bypassing the thalamus [19, 20]. 
  6. ^ a b c Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 12: Sleep and Arousal". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 295. ISBN 9780071481274. The ARAS is a complex structure consisting of several different circuits including the four monoaminergic pathways ... The norepinephrine pathway originates from the locus ceruleus (LC) and related brainstem nuclei; the serotonergic neurons originate from the raphe nuclei within the brainstem as well; the dopaminergic neurons originate in ventral tegmental area (VTA); and the histaminergic pathway originates from neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. As discussed in Chapter 6, these neurons project widely throughout the brain from restricted collections of cell bodies. Norepinephrine, serotonin, dopamine, and histamine have complex modulatory functions and, in general, promote wakefulness. The PT in the brain stem is also an important component of the ARAS. Activity of PT cholinergic neurons (REM-on cells) promotes REM sleep. During waking, REM-on cells are inhibited by a subset of ARAS norepinephrine and serotonin neurons called REM-off cells. 
  7. ^ a b Kinomura, S., Larsson, J., Gulyas, B., & Roland, P. E. (1996). "Activation by attention of the human reticular formation and thalamic intralaminar nuclei". Science. 271 (5248): 512–515. PMID 8560267. doi:10.1126/science.271.5248.512. 
  8. ^ Svorad, D. (1957). "RETICULAR ACTIVATING SYSTEM OF BRAIN STEM AND ANIMAL HYPNOSIS". Science. 125 (3239): 156–156. PMID 13390978. doi:10.1126/science.125.3239.156. 
  9. ^ Shute CC, Lewis PR (1967). "The ascending cholinergic reticular system: neocortical, olfactory and subcortical projections". Brain. 90 (3): 497–520. PMID 6058140. doi:10.1093/brain/90.3.497. 
  10. ^ a b Rothballer, A. B. (1956). "STUDIES ON THE ADRENALINE-SENSITIVE COMPONENT OF THE RETICULAR ACTIVATING SYSTEM". Electroencephalography and Clinical Neurophysiology. 8 (4): 603–621. PMID 13375499. doi:10.1016/0013-4694(56)90084-0. 
  11. ^ a b c Garcia-Rill E, Heister DS, Ye M, Charlesworth A, Hayar A (2007). "Electrical coupling: novel mechanism for sleep-wake control". Sleep. 30 (11): 1405–1414. PMC 2082101 . PMID 18041475. 
  12. ^ http://sleepdisorders.sleepfoundation.org/chapter-1-normal-sleep/neurobiology-of-sleep/
  13. ^ a b c d e f GarciaRill, E. (1997). "Disorders of the reticular activating system". Medical Hypotheses. 49 (5): 379–387. PMID 9421802. doi:10.1016/S0306-9877(97)90083-9. 
  14. ^ a b c d e Vincent, S. R. (2000). "The ascending reticular activating system - from aminergic neurons to nitric oxide". Journal of Chemical Neuroanatomy. 18 (1-2): 23–30. PMID 10708916. doi:10.1016/S0891-0618(99)00048-4. 
  15. ^ a b c Burlet, S., Tyler, C. J., & Leonard, C. S. (2002). "Direct and indirect excitation of laterodorsal tegmental neurons by hypocretin/orexin peptides: Implications for wakefulness and narcolepsy". Journal of Neuroscience. 22 (7): 2862–2872. PMID 11923451. 
  16. ^ a b Reiner, P. B. (1995). "ARE MESOPONTINE CHOLINERGIC NEURONS EITHER NECESSARY OR SUFFICIENT COMPONENTS OF THE ASCENDING RETICULAR ACTIVATING SYSTEM". Seminars in the Neurosciences. 7 (5): 355–359. doi:10.1006/smns.1995.0038. 
  17. ^ Kumar, V. M., Mallick, B. N., Chhina, G. S., & Singh, B. (1984). "INFLUENCE OF ASCENDING RETICULAR ACTIVATING SYSTEM ON PREOPTIC NEURONAL-ACTIVITY". Experimental Neurology. 86 (1): 40–52. PMID 6479280. doi:10.1016/0014-4886(84)90065-7. 
  18. ^ Ruth, R. E., & Rosenfeld, J. P. (1977). "TONIC RETICULAR ACTIVATING SYSTEM - RELATIONSHIP TO AVERSIVE BRAIN-STIMULATION EFFECTS". Experimental Neurology. 57 (1): 41–56. PMID 196879. doi:10.1016/0014-4886(77)90043-7. 
  19. ^ Hall, R. W., Huitt, T. W., Thapa, R., Williams, D., K., Anand, K.J.S., Garcia-Rill, E. (2008). "Long-term deficits of preterm birth: Evidence for arousal and attentional disturbances". Clinical Neurophysiology. 119 (6): 1281–1291. PMC 2670248 . PMID 18372212. doi:10.1016/j.clinph.2007.12.021. 
  20. ^ Garcia-Rill, E., Buchanan, R., McKeon, K., Skinner, R.R., Wallace, T. (2007). "Smoking during pregnancy: Postnatal effects on arousal and attentional brain systems". NeuroToxicology. 28 (5): 915–923. PMC 3320145 . PMID 17368773. doi:10.1016/j.neuro.2007.01.007. 
  21. ^ Robinson, D. (1999). "The technical, neurological and psychological significance of `alpha', `delta' and `theta' waves confounded in EEG evoked potentials: a study of peak latencies". Clinical Neurophysiology. 110 (8): 1427–1434. PMID 10454278. doi:10.1016/S1388-2457(99)00078-4. 
  22. ^ a b Schwartz JR, Roth T (December 2008). "Neurophysiology of sleep and wakefulness: basic science and clinical implications". Curr Neuropharmacol. 6: 367–78. PMC 2701283 . PMID 19587857. doi:10.2174/157015908787386050.