| Brain: Reticular activating system | ||
|---|---|---|
| Deep dissection of brain-stem. Ventral view. (Reticular formation labeled near center.) | ||
| NeuroNames | ancil-231 | |
The reticular activating system (RAS) is an area of the brain (including the reticular formation and its connections) responsible for regulating arousal and sleep-wake transitions.
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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 used to be 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, so Magoun used this to demonstrate, on two separate areas of a 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 wakefullness signal transduction and was coined the ascending reticular activating system (RAS).
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]
The RAS is composed of several neuronal circuits connecting the brainstem to the cortex. These pathways originate in the upper brainstem reticular core and project through synaptic relays in the rostral intralaminar and thalamic nuclei to the cerebral cortex.[4] As a result, individuals with bilateral lesions of thalamic intralaminar nuclei are lethargic or somnolent.[1] Several areas traditionally included in the RAS are:[5][6]
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.[7]
The neuronal circuits of the RAS are modulated by complex interactions between a few main neurotransmitters. The RAS contains both cholinergic and adrenergic components, which exhibit synergic as well as competitive actions to regulate thalamocortical activity and the corresponding behavioral state.
Shute and Lewis first revealed the presence of a cholinergic component of the RAS,[8] composed of two ascending mesopontine tegmental pathways rostrally situated between the mesencephalon and the centrum ovale (semioval center).[5] 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.[9] Cholinergic projections descend throughout the reticular formation and ascend to the substantia nigra, basal forebrain, thalamus, and cerebellum;[10] 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.[11]
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.[9]
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.[10] Unlike cholinergic neurons, the adrenergic neurons are active during waking and slow wave sleep but cease firing during REM sleep.[11] 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.[5]
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.[11]
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.[12]
The main function of the RAS is to modify and potentiate thalamic and cortical function such that electroencephalogram (EEG) desynchronization ensues.[1][13] 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 identical); large 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.[13] 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.[12]
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.[14] 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]
The reticular activating system also helps mediate transitions from relaxed wakefulness to periods of high attention.[6] 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.
One intuitive hypothesis, first proposed by Magoun, is that anesthetics might achieve their potent effects by reversibly blocking neural conduction within the reticular activating system, thereby diminishing overall arousal. However, further research has suggested that selective depression of the RAS may be too simplistic of an explanation to fully account for anesthetic effects.[15] This remains a major unknown and point of contention between experts of the reticular activating system and certainly needs further research.[16]
Direct electrical stimulation of the reticular activating system produces pain responses in cats and reduces verbal reports of pain in humans. Additionally, ascending reticular activation in cats can produce mydriasis, which can result from prolonged pain. These results suggest some relationship between RAS circuits and physiological pain pathways.[17]
There are several potential factors that may adversely influence the development of the reticular activating system:
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.[10] 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.[20] 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.[9] Specifically, disruption of the RAS has been implicated in the following disorders: