assessing-pupil-linked-changes-locus-coeruleus-mediated-arousal

Assessing Pupil-linked Changes in Locus Coeruleus-mediated Arousal Elicited by Trigeminal Stimulation

Current scientific literature provides evidence that trigeminal sensorimotor activity associated with chewing may affect arousal, attention, and cognitive ...

University of Bordeaux

Cats corticocerebellar units within the anterior vermis are affected by the vestibular input and show directionally tuned responses. The aim of the study was investigating whether a similar representation of labyrinth signals was present in the rat cerebellar vermis by recording units activity during tilt and wobble rotations. The analysis of the neuronal discharge during both clockwise (CW) and counterclockwise (CCW) wobble allowed to determine the spatial (preferred direction) and temporal (response phase) response properties of the recorded neurons. Many units were affected by labyrinthine stimulation. "Bi-directional" units responded to both CW and CCW stimuli, being characterized by a direction of maximal sensitivity (theta(max)), the distribution of which covered all the sectors of the horizontal plane, with contralaterally pointing vectors more represented within the caudal part of the explored region. Differences in the amplitude of the CW and CCW responses indicated that neurons received a convergence of vestibular signals endowed with different spatial and temporal properties, a process that is expected to link their response phase with the tilt direction. Population vector analysis showed that recorded neurons coded both the amplitude and direction of head tilt during different types of rotational stimuli. In conclusion, the present results show that the processing of vestibular signals with complex spatiotemporal properties represents a general function of the mammalian cerebellar vermis, allowing accurate monitoring of head rotational movements (of the head) in vertical planes. Finally, in rats, different cerebellar regions seem to receive specific vestibular inputs.

Neuronal responses to tilt within the rat cerebellar vermis.

Excitatory responses evoked by N-methyl-d-aspartate (NMDA) in the vestibular nuclei (VN) of the rat were studied in vivo during microiontophoretic application of noradrenaline (NA) and/or its agonists and antagonists. Ejection of NA-modified excitatory responses mediated by NMDA receptors (NMDAR) in all neurons tested; the effect was enhancement in 59% of cases and depression in the remaining 41%. Enhancements prevailed in all VN with the exception of the lateral vestibular nucleus, where both effects were recorded in an equal number of cases. The enhancing action of NA on NMDAR-mediated responses was mimicked by the noradrenergic beta-receptor agonist isoproterenol, the beta1 specific agonist denopamine and the alpha2 agonist clonidine. These effects were blocked respectively by the generic beta-receptor antagonist timolol, the beta1 antagonist atenolol and the alpha2 antagonist yohimbine. In contrast, application of the alpha1 receptor agonist cirazoline and the specific alpha1 antagonist prazosin respectively mimicked and partially antagonized the depression of NMDAR-mediated excitations induced by NA. Double-labeling immunohistochemical techniques demonstrated broad colocalization of NMDAR (specifically NR1 and NR2 subunits) with noradrenergic receptors (alpha1, alpha2 and beta1) in many VN neurons; only minor differences were found between nuclei. These results indicate that NA can produce generalized modulation of NMDAR-mediated excitatory neurotransmission in VN, which may in turn modify synaptic plasticity within the nuclei. 

Noradrenergic modulation of neuronal responses to n-methyl-d-aspartate in the vestibular nuclei: an electrophysiological and immunohistochemical study.

Limb somatosensory signals modify the discharge of vestibular neurons and elicit postural reflexes, which stabilize the body position. The aim of this study was to investigate the contribution of the γ-amino-butyric-acid (GABA) to the responsiveness of vestibular neurons to somatosensory inputs. The activity of 128 vestibular units was recorded in anesthetized rats in resting conditions and during sinusoidal foreleg rotation around the elbow or shoulder joints (0.026-0.625Hz, 45° peak amplitude). None of the recorded units was influenced by elbow rotation, while 40% of them responded to shoulder rotation. The selective GABAA antagonist receptor, bicuculline methiodine (BIC), was applied by microiontophoresis on single vestibular neurons and the changes in their activity at rest and during somatosensory stimulation was studied. In about half of cells the resting activity increased after the BIC application: 75% of these neurons showed also an increased response to somatosensory inputs whereas 17% exhibited a decrease. Changes in responsiveness in both directions were detected also in the units whose resting activity was not influenced by BIC. These data suggest that the responses of vestibular neurons to somatosensory inputs are modulated by GABA through a tonic release, which modifies the membrane response to the synaptic current. It is also possible that a phasic release of GABA occurs during foreleg rotation, shaping the stimulus-elicited current passing through the membrane. If this is the case, the changes in the relative position of body segments would modify the GABA release inducing changes in the vestibular reflexes and in learning processes that modify their spatio-temporal development. 

Effects of bicuculline application on the somatosensory responses of secondary vestibular neurons.

Trigeminal input to the ascending activating system is important for the maintenance of arousal and may affect the discharge of the noradrenergic neurons of the  (LC), whose activity influences both vigilance state and pupil size, inducing mydriasis. For this reason, pupil size evaluation is now considered an indicator of LC activity. Since mastication activates trigeminal afferent neurons, the aims of the present study, conducted on healthy adult participants, were to investigate whether chewing a bolus of different hardness may: (1) differentially affect the performance on a cognitive task (consisting in the retrieval of specific target numbers within numerical matrices) and (2) increase the dilatation of the pupil (mydriasis) induced by a haptic task, suggesting a change in LC activation. Results show that chewing significantly increased both the velocity of number retrieval (without affecting the number of errors) and the mydriasis associated with the haptic task, whereas simple task repetition did not modify either retrieval or mydriasis. Handgrip exercise, instead, significantly decreased both parameters. Effects were significantly stronger and longer lasting when subjects chewed hard pellets. Finally, chewing-induced improvements in performance and changes in mydriasis were positively correlated, which suggests that trigeminal signals enhanced by chewing may boost the cognitive performance by increasing LC activity.

Short-Term Effects of Chewing on Task Performance and Task-Induced Mydriasis: Trigeminal Influence on the Arousal Systems.

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.

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

Article	Year
Neuronal responses to tilt within the rat cerebellar vermis. Brain research bulletin\| PubMed ID: 18992305	2009
Noradrenergic modulation of neuronal responses to n-methyl-d-aspartate in the vestibular nuclei: an electrophysiological and immunohistochemical study. Neuroscience\| PubMed ID: 24508745	2014
Effects of bicuculline application on the somatosensory responses of secondary vestibular neurons. Neuroscience\| PubMed ID: 27579770	2016
Short-Term Effects of Chewing on Task Performance and Task-Induced Mydriasis: Trigeminal Influence on the Arousal Systems. Frontiers in neuroanatomy\| PubMed ID: 28848404	2017
Trigeminal, Visceral and Vestibular Inputs May Improve Cognitive Functions by Acting through the Locus Coeruleus and the Ascending Reticular Activating System: A New Hypothesis. Frontiers in neuroanatomy\| PubMed ID: 29358907	2017

Massimo Barresi

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