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

【作者】 于雷； 张潇洋； 陈张朋； 朱景宁； 王建军；

【机构】 南京大学鼓楼校区；

【摘要】 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 regulation of muscle tone and postural control,and the denervation of orexinergic system on IVN may also contribute to motor deficits in cataplexy.更多还原

【Abstract】 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 OX2 receptors.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 regulation of muscle tone and postural control,and the denervation of orexinergic system on IVN may also contribute to motor deficits in cataplexy.更多还原