The ascending reticular activating system is a concept originally proposed by Moruzzi & Magoun in 1949 on the basis of the effects of electrical stimulation of the BRAINSTEM on the cortical ELECTROENCEPHALOGRAM (EEG) in anaesthetized cats. These investigators found that high-frequency stimulation at the core of the RETICULAR FORMATION throughout the brainstem is effective in inducing the activated pattern (so-called desynchronization) of the EEG. Stimulation at the MIDBRAIN level was the most effective. The core region of the reticular formation was thought to be activated by COLLATERALS of specific sensory pathways and send a powerful excitatory drive to the THALAMUS, which in turn activates the CEREBRAL CORTEX. Subscquent studies showed that a LESION of the reticular core does indeed produce chronic EEG inactivation and SOMNOLENCE; the activation of the EEG and behavioural AROUSAL were still possible with strong sensory stimulation, but did not outlast the stimulation. These results provided a new interpretation to the earlier finding by Bremer of continuous EEG inactivation in the CERVEAU ISOLÉ (isolated FOREBRAIN) preparation; this was due to the isolation of the reticular formation from the forebrain, rather than sensory deafferentation as originally interpreted. Theoretically, the work by Moruzzi & Magoun introduced the concept that a ‘nonspecific’ (see NONSPECIFIC PROJECTIONS) rather than ‘specific’ sensory system is responsible for EEG activation. The proposal by Moruzzi & Magoun that the excitatory drive generated in the brainstem core is mediated by the thalamus en route to the cortex was later confirmed, and expanded further by Steriade and other investigators using more sophisticated cellular techniques. The seminal studies by Moruzzi & Magoun conceptualized, for the first time, that cortical activation was actively maintained by the tonic activation of brainstem core neurons, and defined the beginning of the modern era of studies on the states of vigilance, stimulating a great deal of research.
Because the anatomy of the reticular formation was poorly understood, the anatomical substrate of the ascending reticular activating system remained an enigma for three decades. It was once thought that the key anatomical feature of the reticular formation was the highly collateralizing axons of so-called isodendritic neurons, but subsequent studies failed to support this idea; cells with such extensive collaterals were the exception rather than the rule. However, the advances in neuroanatomical techniques in the 1980s, in particular TRACT TRACERS and IMMUNOHISTOCHEMISTRY, have delineated the anatomical substrate of the ascending reticular activating system. Interestingly, the sites in the midbrain that were found to be most effective in evoking cortical EEG activation upon stimulation exactly corresponded to an area ventrolateral to the midbrain PERIAQUEDUCTAL GREY where bundles of CHOLINERGIC and MONOAMINERGIC fibres ascend. Thus, it is now commonly held that the reticular activating system is composed of several ascending pathways that use different neurotransmitters and innervate distinct forebrain structures.
These pathways include ascending cholinergic, NORADRENERGIC and serotonergic projections as well as reticular projections using unidentified NEUROTRANSMITTERS, possibly GLUTAMATE.
The cholinergic pathway originates from the PEDUNCULOPONTINE TEGMENTAL NUCLEUS and the LATERODORSAL TEGMENTAL NUCLEUS (see also CH1–CH8). These neurons heavily innervate the thalamic nuclei in a topographic manner. The same cholinergic neurons also project to other forebrain structures including the BASAL FOREBRAIN, but their cortical projec-tion is limited to the MEDIAL PREFRONTAL CORTEX. The thalamus, in particular its association nuclei, also receives massive projections from non-cholinergic, probably GLUTAMATERGIC, neurons in the rostral midbrain reticular formation. The noradrenergic pathway arises from the LOCUS COERULEUS, whereas the serotonergic pathway originates in the dorsal and median RAPHE NUCLEI. These monoaminergic pathways reach not only the thalamus but also the cerebral cortex directly. In the thalamus, ACETYLCHOLINE, NORADRENALINE and SEROTONIN block SLEEP SPINDLES and facilitate sensory transmission. Two structures in the forebrain may be regarded as rostral extensions of the ascending retieular activating: the posterior HYPOTHALAMUS containing HISTAMINERGIC neurons innervating the cortex, and the basal forebrain containing cholinergic, GABAERGIC and other neurons innervating the cortex as well as neurons that become selectively active during wakefulness and REM SLEEP (rapid eye movement sleep) or during NON-REM SLEEP.
From both anatomical and functional studies, it is now clear that the neurochemically coded ascending projections with distinct projection patterns can be viewed as the anatomical substrate of the ascending reticular activating system proposed by Moruzzi & Magoun in 1949. The effects of activation of each of these pathways in cortical activation and sensory transmission are being characterized, further defining the role of each component of the system in the mechanisms of EEG and behavioural arousal.
References
Moruzzi G. & Magoun H.W. (1949) Brain stem reticular formation and activation of the EEG. Electroencephalography and Clinical Neurophysiology 1:455–473.
Steriade M. & McCarley R.W. (1990) Brainstem Control of Wakefulness and Sleep, Plenum Press: New York.
KAZUE SEMBA
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