Modulation Of Central Histaminergic And Noradrenergic Systems On Neuronal Activity Of Inferior Vestibular Nucleus

The central histaminergic system originating from tuberomammillary nucleus(TMN)of the hypothalamus and the central noradrenergic system originating from locus ceruleus(LC)in brainstem widely innervate to almost all regions of the brain including spinal cord.Belonging to monoaminergic system,the two systems are very similar in some aspects blow:(i)their neurotransmitters,histamine and noradrenaline,both contain one amino group that is connected to an aromatic ring by a two-carbon chain(-CH2-CH2-);(ii)their fiber endings all form varicosities instead of typical synaptic specializations;and(iii)their receptors are all metabotropic.Intriguingly,there are some evidences suggesting both of the systems may participate in somatic motor control.The deficiency of central histaminergic or noradrenergic systems may elicit abnormal behaviors and diseases,including motor dysfunctions.However,the actions and the underlying mechanisms of the central histaminergic and noradrenergic systems on neurons in central motor structures have still not been entirely investigated.Among the central motor structures,the central vestibular nuclei,including the lateral vestibular nucleus(LVN),medial vestibular nucleus(MVN),superior vestibular nucleus(SVN)and inferior vestibular nucleus(IVN),in brainstem constitute a sensorimotor complex that integrates vestibular,visual and motor signals to make compensatory eye and head movements as well as postural adjustments.The IVN,also called the descending or spinal vestibular nucleus,is the largest nucleus in the central vestibular nuclear complex in brainstem.Among them,the IVN receives predominantly otolith inputs and afferents from the semicircular canals and vermis of the cerebellum,and projects to the contralateral vestibular nuclei,cerebellum,reticular formation,as well as to the spinal cord.Therefore,unlike the other three vestibular nuclei,the IVN is generally considered as a key structure integrating vestibular,multisensory,and cerebellar signals in the vestibular nuclear complex.Studies from our and other laboratories have revealed that the vestibular nuclei are innervated by both histaminergic and noradrenergic fibers.Besides,the vestibular nuclei are also endowed with both histamine and adrenergic receptors.These results suggest that central histaminergic and central noradrenergic system may participate in motor control through their direct innervations on these subcortical motor structures.Thus,by using quantitative RT-PCR,immunostaining and extracellular recordings on brain slices,the present study was designed to investigate the effect of the histamine/central histaminergic system and/or noradrenaline/central noradrenergic system on neuronal activities of the IVN and the underlying receptor mechanisms.1.Histamine/central histaminergic system on neuronal activities of IVNAnti-histaminergic drugs have traditionally been used for clinical treatment of balance disorders and symptoms,such as vertigo,motion sickness,nausea and nystagmus.Besides the peripheral vestibular apparatus in the inner ear,the central vestibular nuclear complex in brainstem is also a critical target for those anti-histaminergic drugs.Thus,by using extracellular recordings and immunostaining on brain slices,the present study was designed to investigate whether the histamine/histaminergic system may modulate neuronal activities of the IVN.The results show that:(?)histamine excited most of the IVN neurons in a concentration dependent manner;(?)the excitatory effect of histamine on IVN neurons was a direct postsynaptic action;(?)the histamine-induced excitations on IVN neurons were mediated by the activation of both postsynaptic H1(coupling Na1-Ca2+ exchangers and H2 receptors(coupling HCN channel);and(?)immunofluorescence double labeling results showed that H1 receptor and H2 receptor co-expressed in IVN neurons.These results demonstrate that histamine/central histaminergic projections modulate neuronal activities of the IVN,and subsequently influence its somatic motor functions,including vestibular spinal reflexes and integration of vestibular,cerebellar and multisensory signals.2.Noradrenaline/central noradrenergic system on neuronal activities of IVNThe central noradrenergic system is well documented in controlling and regulating several non-somatic functions such as arousal and attention,affective disorders,learning and memory,sleep,anxiety and nociception.But our knowledge about the function of noradrenaline in somatic motor control,especially in vestibular system which plays an important role in vestibular signals integration and balance control,is still deficient.Hence,we use quantitative RT-PCR and extracellular recordings on brain slices to investigate the effect of noradrenaline on IVN neurons.The results show that:(?)the mRNAs of adrenergic ?1,?2 and ? receptors were all expressed in IVN neurons;(?)noradrenaline excited most of the IVN neurons in a concentration-dependent manner;(?)the noradrenaline-induced effects were co-mediated by adrenergic ?1,?2 and ?2 receptors,in which ?1 and ?2 receptors mediated an excitatory effect whereas ?2 receptors mediated an inhibitory effect,but the overall effects induced by noradrenaline were excitation;and(?)althrough adrenergic ?1 and ?3 receptor were also expressed in IVN neuron in a relatively small amount,but they did not mediate any direct effect of noradrenaline on IVN neuronal activity.These results indicate that noradrenaline/central noradrenergic projections may play an important role in IVN-mediated vestibular reflexes and motor control via a direct modulation on neuronal activities of the IVN.In conclusion,histamine/central histaminergic system and noradrenaline/central noradrenergic system directly modulate the neuronal activity of IVN,indicating that monoaminergic afferent system in IVN may exert an important physiological role in vestibular reflexes and motor control through the IVN circuitry.Unlike central noradrenaline system which originates from the lower brainstem,the central histaminergic system origins from the hypothalamus,a higher center for autonomic/visceral regulation.Therefore,we speculate that the hypothalamic histaminergic system bridging the nonsomatic center to somatic motor structures may actively modulate the vestibular nuclear neurons and subsequently participate in motor control and somatic-visceral integration.In fact,vestibular-related diseases are always accompanied with various visceral dysfunctions,such as vomiting.Thus,understanding of the monoaminergic afferent system in the vestibular nuclei,especially the histaminergic afferent system,may help us to dig the deep functions of vestibular nuclei and the mechanisms underlying the somatic-visceral integration.The findings may also provide new guidance for clinical treatment of vestibular-related diseases and help to improve the vestibular compensation of patients.