Trigeminal, Visceral and Vestibular Inputs May Improve Cognitive Functions by Acting through the Locus Coeruleus and the Ascending Reticular Activating System: A New Hypothesis

Abstract

It is known that sensory signals sustain the background discharge of the ascending reticular activating system (ARAS) which includes the noradrenergic locus coeruleus (LC) neurons and controls the level of attention and alertness. Moreover, LC neurons influence brain metabolic activity, gene expression and brain inflammatory processes. As a consequence of the sensory control of ARAS/LC, stimulation of a sensory channel may potential influence neuronal activity and trophic state all over the brain, supporting cognitive functions and exerting a neuroprotective action. On the other hand, an imbalance of the same input on the two sides may lead to an asymmetric hemispheric excitability, leading to an impairment in cognitive functions. Among the inputs that may drive LC neurons and ARAS, those arising from the trigeminal region, from visceral organs and, possibly, from the vestibular system seem to be particularly relevant in regulating their activity. The trigeminal, visceral and vestibular control of ARAS/LC activity may explain why these input signals: (1) affect sensorimotor and cognitive functions which are not directly related to their specific informational content; and (2) are effective in relieving the symptoms of some brain pathologies, thus prompting peripheral activation of these input systems as a complementary approach for the treatment of cognitive impairments and neurodegenerative disorders.

Keywords: ascending reticular activating system; hemispheric imbalance; locus coeruleus; performance; pupil size; trigeminal nerve; vestibular input; visceral input.

Figure 1

Connections of different ascending reticular activating system (ARAS) structures to the thalamo-cortical system. Only the principal connections of ARAS structures (indicated by textured circles) have been shown. PPT and LTD act on the specific thalamic relay nuclei and, together with the RF and the LC, on the diffuse thalamic system. DR, LC, VTA, lateral hypothalamus (LH) and tuberomammillary nucleus (TMN) have a direct access to the cerebral cortex. All ARAS structures connect to basal forebrain neurons, which are the source of cholinergic projections to the cerebral cortex. DR, dorsal raphe; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; LH, lateral hypothalamus; PPT, pedunculopontine nucleus; RF, reticular formation; SNc, substantia nigra pars compacta; TMN, tuberomammillary nucleus; VTA, ventral tegmental area.

Figure 2

Summary of the main effects of LC activation on the brain and of their consequences. (A) Behavioral effects. (B) Other effects.

Figure 3

Trigeminal Pathways to ARAS’s structures. Muscle spindles and periodontal ligament receptors, through the Me5, project to five ARAS’s structures, indicated by the textured circles: LC, RF, PPT, LDT and TMN. Orofacial somatosensory/periodontal ligament afferents reach the trigeminal principal/spinal nuclei and the RF through the ganglion of Gasser. The trigeminal principal/spinal nuclei project to both LC and RF, as well as to PPT and LTD. Indirect pathways from trigeminal nuclei to the LC may run through the PH, the PGI, the NTS and the RF. LC, Locus Coeruleus; LTD, laterodorsalis tegmental nucleus; Me5, mesencephalic trigeminal nucleus; NTS, nucleus of the tractus solitarius; PGI, nucleus paragigantocellularis; PH, prepositus hypoglossi; PPT, pedunculopontine nucleus; RF, reticular formation; TMN, tuberomammilary nucleus.

Figure 4

Visceral and vestibular pathways to ARAS’s structures. (A) Visceral pathways. (B) Vestibular pathways. ARAS structures are indicated by textured circles. CE, cerebellar cortex; FN, fastigial nucleus; LC, Locus Coeruleus; LTD, nucleus laterodorsalis tegmenti pontis; NTS, nucleus of the tractus solitarius; PGI, nucleus paragigantocellularis; PH, prepositus hypoglossi; PPT, pedunculopontine nucleus; RF, reticular formation; VN, vestibular nuclei.