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Hypothalamic histaminergic and orexinergic modulation on the medial vestibular nucleus

Hypothalamic histaminergic and orexinergic modulation on the...

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中国生理学会第24届全国会员代表大会暨生理学学术大会

作者：朱景宁 Jian-Jun Wang 南京大学 Department of Biological Science and Technology and state Key Laboratory of Pharmaceutical Biotechnology School of Life SciencesNanjing University

Central histaminergic system and central orexinergic system both restrictedly originate in the hypothalamus but innervate almost the whole brain,including various subcortical motor structures.In brainstem,the medial vestibular nucleus（MVN）,a key motor center for stabilization,coordination and compensation of head and eye movements,receives direct hypothalamic histaminergic and orexinergic projections.Here,we report that both histamine and orexin postsynaptically excite type-A and type-Bneurons in the MVN in a concentration dependent manner.Na+-Ca2+exchangers（NCXs）coupled to histamine H1 receptors and hyperpolarization-activated cyclic nucleotide-gated（HCN）channels linked to histamine H2 receptors co-mediate the strong postsynaptic excitatory effect of histamine on the MVN neurons.On the other hand,orexin 1 receptors（OX1Rs）and orexin 2 receptors（OX2Rs）,together with their downstream coupling NCXs and nonselective cation channels（NSCCs）,underlie the excitation of orexin on the MVN neurons.Furthermore,orexin increased the sensitivity of MVN neurons to the rectangle and ramp current stimulations without altering neuronal dynamic properties.And orexin also caused a frequency-dependent gain enhancement and phase-lead shift of MVN neurons to sinusoid-like current stimulations.Interestingly,endogenous orexinergic modulation on MVN neurons was critical when animals traversing a rotating balance beam as opposed to a static one.All these results demonstrate that histamine and orexin modulates not only excitability but also sensitivity of the MVN neurons and suggest that hypothalamic histaminergic and orexinergic innervation on MVN may play a crucial role in somatic motor control.The findings also suggest novel potential targets for clinical treatment of vestibular disorders,such as vertigo,motion sickness,nausea and nystagmus.

关键词： Histamine Orexin Medial vestibular nucleus motor control

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Orexin A excites neurons of the inferior vestibular nucleus in rats by co-activation of OX1 and OX2 receptors

Orexin A excites neurons of the inferior vestibular nucleus ...

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中国生理学会第24届全国会员代表大会暨生理学学术大会

作者：于雷张潇洋陈张朋朱景宁王建军南京大学鼓楼校区

Central orexinergic system deficiency in humans,canines,and rodents results in cataplexy,a motor deficit characterized by sudden loss of muscle,strongly indicating an active role of orexin in motor control.Interestingly,our previous studies have already found that orexin excites neurons in the cerebellar nuclei and lateral vestibular nucleus.However,the effect of orexin on neurons in the inferior vestibular nucleus（IVN）,the largest nucleus among the vestibular nuclear complex and holding an important integrative position in integration of vestibular,multisensory,and cerebellar signals in the control of body posture,is still largely unknown.In the present study,by using whole-cell patch clamp recording and q PCR,action of orexin A on neurons in the IVN and the underlying receptor mechanisms are investigated.Of 31 IVN neurons,28（90.3%）responded to the orexin A stimulation.In current clamp experiments,bath application of orexin A significantly depolarized the membrane potential and increased the firing rate of the IVN neurons.Correspondingly,orexin A induced an inward current with a concentration-dependent manner on IVN neurons and the EC50 was 94.41 n M.Furthermore,TTX did not block orexin A-induced excitation on the IVN neurons,suggesting a marked postsynaptic excitatory effect induced by orexin A.Finally,[Ala11,D-Leu15]-orexin B,a specific OX2 receptor agonist,mimicked the orexin A-induced excitatory effect on IVN neurons,and the effect of orexin A was partly blocked by SB-334867,a selective OX1 receptor antagonist,indicating that orexin A excites the IVN neurons by co-activation of both OX1 and OX2receptors.The result is consistent with q PCR data that both OX1 and OX2 receptor m RNAs wereexpressed in the rat IVN.In conclusion,the results demonstrate a direct excitatory action of orexin A on the IVN neurons,which is mediated by both postsynaptic OX1 and OX2 receptors.The findings suggest that the direct modulation of central orexinergic system on the IVN may actively participate in the vestibular-mediated regula

关键词： Cataplexy Inferior vestibular nucleus orexin OX1 receptors OX2 receptors

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Cerebellar fastigial nuclear inputs impinge on feeding-related neurons in ventromedial hypothalamic nucleus in rats

Cerebellar fastigial nuclear inputs impinge on feeding-relat...

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中国生理学会第十届全国青年生理学工作者学术会议

作者：李斌 Qian-Xing ZHUANG He-Ren GAO Jing-Ning ZHU Jian-Jun WANG 南京大学 Department of Biological Science and Technology and state Key Laboratory of Pharmaceutical Biotechnology School of Life SciencesMailbox 426Nanjing University

＜正＞The cerebellum participates in regulating nonsomatic visceral activities including food intake via the direct cerebellohypothalamic projections.The ventromedial hypothalamic nucleus（VMN）has traditionally been implicated in feeding behavior,energy balance,and body weight regulation.Previous studies have indicated that neurons in the VMN receive feeding-related signals from the gastric vagal nerves and blood glucose.And ghrelin,a peptide primarily produced in the stomach,stimulates both feeding and

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5-HT2A receptor-mediated excitation on cerebellar fastigial nucleus neurons and promotion of motor behaviors in rats

5-HT2A receptor-mediated excitation on cerebellar fastigial ...

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中国神经科学学会第十届全国学术会议

作者： Chang-Zheng ZHANG Qian-Xing ZHUANG Guang-Ying LI Jing-Ning ZHU Jian-Jun WANG Department of Biological Science and Technology and state Key Laboratory of Pharmaceutical Biotechnology School of Life SciencesNanjing University

It has long been known that serotonergic afferent inputs are the third largest afferent population in the cerebellum after mossy fibers and climbing fibers.However,the role of serotonergic inputs in cerebellar mediated motor behaviors is still largely unknown.Here,we show that only 5-HT receptor among the 5-HT receptor subfamily are expressed and localized in the rat cerebellar fastigial nucleus(FN),one of the ultimate outputs of the spinocerebellum precisely regulating trunk and limb movements.Remarkably,selective activation of 5-HT receptors(n = 42) evokes a postsynaptic excitatory effect on FN neurons in a concentration dependent manner,which is in accord with the 5-HT-elicited excitation on the same neurons,whereas separate activation of 5-HT and 5-HT receptors(n =39 and 35,respectively) has no effect on FN neurons.Moreover,selective 5-H receptor antagonist M100907(n = 32)rather than 5-HT and 5-HT receptor antagonists(n = 27 and 23,respectively) considerably blocks the excitatory effect of 5-HT on FN neurons,and M100907 also concentration-dependently antagonizes excitations induced by 5-HT and 5-HT receptor agonist TCB-2(n = 12 and 10,respectively).Consequently,selective activation of 5-Hreceptors in bilateral FNs significantly promotes rat motor performances on accelerating rota-rod and balance beam(n =12),narrows stride width rather than stride length in locomotion gait(n = 13),but does not influence forelimb grip strength(n = 13) and overground movements in an open field(n = 13).Notably,all these motor behavioral effects of activation of 5-HT receptors are highly consistent with those of microinjection of 5-HT in FNs,and blockage of the endogenous serotonergic inputs mediated by 5-HT receptors in FNs markedly attenuates these motor performances.Therefore,all these results demonstrate that postsynaptic S-HT receptors hold a position in 5-HT-mediated enhancement of cerebellar FN related motor behaviors,suggesting that serotonergic afferent inputs may actively participates in cerebellar motor control through

关键词： 5-HT 5-HT2A receptors cerebellar fastigial nucleus motor control

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Hypothalamic histaminergic and orexinergic modulation on cerebellar and vestibular motor control

Hypothalamic histaminergic and orexinergic modulation on cer...

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中国神经科学学会第十届全国学术会议

作者： Jing-Ning ZHU Jian-Jun WANG Department of Biological Science and Technology School of Life SciencesNanjing University

An intact behavior comprises not only somatic（motor） but also nonsomatic components,including visceral,emotional,cognitive and other high functions.Therefore,a somatic-nonsomatic integration is critical for generation of an appropriate and coordinated behavioral response to changes in the internal and external environment.However,the underlying neural substrates and mechanisms are still enigmatic.Intriguingly,the central histaminergic and orexinergic systems originating from the hypothalamus,a high center for autonomic（nonsomatic） regulation,innervate almost the whole brain,including various subcortical motor structures.The cerebellum and vestibular nuclei in the brainstem hold a key position in modulation of muscle tone,posture and ongoing movements.Here,we show that histamine and orexin not only selectively excite projection neurons rather than interneurons in the cerebellar nuclei,but also depolarize projection neurons in the lateral vestibular nucleus and type-A and type-B neurons in the medial vestibular nucleus.Moreover,the receptor and ionic mechanisms underlying the histamine- and orexin-induced excitations on different neurons in the cerebellum and vestibular nuclei are various.Via increasing the activity and sensitivity of cerebellar and vestibular nuclear neurons,both hypothalamic histaminergic and orexinergic afferent inputs promote motor behaviors,especially motor balance and coordination,through the cerebellar and vestibular circuits.In particular,hypothalamic orexinergic innervation on motor structures is critical when an animal is facing a major motor challenge as opposed to during rest and general movements.These results suggest that the central histaminergic and orexinergic system bridging the nonsomatic center to somatic motor structures may actively participate in motor control and play a crucial role in somatic-nonsomatic integration.

关键词： histamine orexin hypothalamus cerebellum vestibular nuclei

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Postsynaptic mechanisms underlying the excitatory action of histamine on medial vestibular nucleus neurons in rats

Postsynaptic mechanisms underlying the excitatory action of ...

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中国神经科学学会第十届全国学术会议

作者： Xiao-Yang ZHANG Lei YU Qian-Xing ZHUANG Shi-Yu PENG Jing-Ning ZHU Jian-Jun WANG Department of Biological Science and Technology School of Life SciencesNanjing University

Anti-histaminergic drugs have been widely used in clinical treatment of vestibular disorders and their presynaptic actions on central vestibular nuclei are concentrated on.However,the postsynaptic actions of histamine on the vestibular nuclei,particularly,the detailed underlying mechanisms,remain largely unknown.In the present study,by using whole-cell patch-clamp recordings,quantitative real-time RT-PCR and immunostainings,the postsynaptic receptor and ionic mechanisms of histamine are investigated on neurons in the medial vestibular nucleus(MVN),holding a key position in stabilization,coordination and compensation of head and eye movements.Histamine excited both type-A(26/26,100%) and type-B(50/50,100%) MVN neurons,which were identified according to the shapes of their afterhyperpolarization action potentials.In the presence of TTX,histamine still evoked a concentration-dependent excitatory response on type-A and type-B MVN neurons with half-maximal activation(EC50) of 7.1 and 5.7 μM,respectively,suggesting a postsynaptic excitatory action of the amine.Electrophysiological,quantitative real-time RT-PCR,and together with immunostaimng results demonstrate that histamine H and H receptors co-mediated the histamine-induced postsynaptic excitation on MVN neurons.Furthermore,both application of KB-R7943,a selective inhibitor for Na-Ca exchangers(NCXs),or replacement of external Na with Tris totally blocked the 2-PyEA(agonist for histamine H eceptor)-induced inward current,indicating a contribution of NCXs to excitation induced by activation of H receptors.In addition,quantitative real-time RT-PCR data revealed that NCX1 and NCX3 rather than NCX2 may contribute to the histamine H-receptor-induced excitatory effect on MVN neurons.On the other hand,the dimaprit(agonist for histamine H receptor)-induced current was totally blocked by ZD7288,a selective blocker of HCN channels,indicating HCN channels mediated the effect of activation of H receptors.Additionally,quantitative real-time RT-PCR data revealed that the histamin

关键词： histamine medial vestibular nuclei histamine receptors Na+-Ca2+ exchangers HCN channels

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Postsynaptic mechanisms underlying the excitatory action of histamine on medial vestibular nucleus neurons in rats

Postsynaptic mechanisms underlying the excitatory action of ...

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中国生理学会第十届全国青年生理学工作者学术会议

作者： Xiao-Yang Zhang 于雷 Qian-Xing Zhuang Shi-Yu Peng Jing-Ning Zhu Jian-Jun Wang Department of Biological Science and Technology and state Key Laboratory of Pharmaceutical Biotechnology School of Life SciencesMailbox 426Nanjing University 南京大学

＜正＞Anti-histaminergic drugs have been widely used in clinical treatment of vestibular disorders.The medial vestibular nucleus（MVN）,the most concerned subnucleus in the vestibular nuclear complex in brainstem and holding a key position in stabilization,coordination and compensation of head and eye movements,is considered to be the most critical central target for anti-histaminergic drugs.

关键词： Histamine medial vestibular nucleus H1 receptors H2 receptors Na+-Ca2+ exchangers（NCXs） hyperpolarization-activated cyclic nucleotide-gated（HCN）channels

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