Mechanisms Underlying Brainstem Regulation On Cardiovascular And Motor Functions

The brainstem is composed of the midbrain,pons and medulla oblongata,which plays an important role in regulating basic physiological functions such as respiration,sleep,cardiovascular and motor control.The rostral ventromedial medulla(RVMM)and medial vestibular nuclear(MVN)located in the medulla are involved in modulating cardiovascular and vestibular function in the central nervous system.Dysfunction of the RVMM and MVN may cause hypertension and vestibular dysfunction like head tilt and postural asymmetry.Therefore,a deeper understanding of the neural mechanisms of RVMM and MVN could boost the development of new therapeutic strategies for hypertension and vestibular diseases.Based on the potential therapeutic targets such as receptors and ion channels,this study aims to investigate the roles and mechanisms of H4 receptors—the newest found histamine receptor,which is a star drug development target—in tuning cardiovascular function through RVMM as well as the ion channels in MVN involved in neuronal sensitivity regulation of vestibular compensation.1.Expression and cardiovascular regulation of histamine H₄receptor in rostral ventromedial medullaHypertension is the leading cause of cardiovascular disease and premature death.Most studies have focused on developing antihypertensive strategies by targeting peripheral cardiovascular system.Notably,cardiovascular activities are highly regulated by the central nervous system.However,mechanisms underlying central cardiovascular control as well as potential brain targets for antihypertensive treatment remain unknown.Here,we report that the most recently discovered histamine H₄receptor activation produces depressor and bradycardia effects by exciting rostral ventromedial medulla(RVMM)neurons in rats.1)We found that histaminergic neurons originated from hypothalamic tuberomammillary nucleus(TMN)can directly projected to the histamine H₄ receptor expressed RVMM,a vital cardiovascular regulatory center.2)Bath application of histamine or selective H₄ receptor agonist VUF 8430 excited RVMM neurons in brain slice containing RVMM via the activation of postsynaptic histamine H₄ receptors.3)Intra-RVMM microinjection of histamine or VUF 8430induced significant depressor and bradycardia response in rats.4)Moreover,pretreatment with selective H₄ receptor antagonist JNJ 10191584 in RVMM totally blocked the depressor and bradycardia effects induced by optogenetic selective activation of the TMN-RVMM histaminergic projections.Furthermore,we determined the antihypertensive effect of RVMM H₄ receptor activation in spontaneous hypertensive rats(SHR).5)SHR exhibited higher c-Fos expression in the hypothalamic histaminergic neurons compared with the normotensive Wistar-Kyoto rats.6)Microinjection of VUF 8430 into RVMM remarkably ameliorated hypertension of SHR via the activation of H₄ receptors.These results reveal a novel cardiovascular effect of histamine H₄ receptors in RVMM,which may pave ways for the development of brain therapeutic targets for hypertension.2.Changes in sensitivity of bilateral medial vestibular nuclear neurons responding to input stimuli during vestibular compensation and the underlying ionic mechanismVestibular compensation is an important model for developing the prevention and intervention strategies of vestibular disorders,and investigating the plasticity of the adult central nervous system induced by peripheral injury.Medial vestibular nucleus(MVN)in brainstem is critical center for vestibular compensation.Its neuronal excitability and sensitivity has been implicated in normal function of vestibular system.Previous studies mainly focused on the changes in neuronal excitability of the MVN in lesional side of the rat model of vestibular compensation following the unilateral labyrinthectomy(UL).However,the plasticity of sensitivity of bilateral MVN neurons dynamically responding to input stimuli is still largely unknown.In the present study,by using q PCR,whole-cell patch clamp recording in acute brain slices and behavioral techniques,1)we observed that 6 h after UL,rats showed a significant deficit in spontaneous locomotion,and a decrease in excitability of type B neurons in the ipsilesional rather than contralesional MVN.By contrast,type B neurons in the contralesional rather than ipsilesional MVN exhibited an increase in response sensitivity to the ramp and step input current stimuli.2)One week after UL,both the neuronal excitability of the ipsilesional MVN and the neuronal sensitivity of the contralesional MVN recovered to the baseline,accompanied by a compensation of spontaneous locomotion.3)The data showed that the small conductance Ca²⁺-activated K⁺(SK)channel involved in the regulation of type B MVN neuronal sensitivity,showed a selective decrease in expression in the contralesional MVN 6 h after UL,and returned to normal level 1 w later.4)Pharmacological blockage of SK channel in contralateral MVN to inhibit the UL-induced functional plasticity of SK channel significantly delayed the compensation of vestibular motor dysfunction.These results suggest that the changes in plasticity of the ipsilesional MVN neuronal excitability,together with the contralesional MVN neuronal sensitivity,may both contribute to the development of vestibular symptoms as well as vestibular compensation,and SK channel may be an essential ionic mechanism responsible for the dynamic changes of MVN neuronal sensitivity during vestibular compensation.To sum up,this study not only deepens the understanding of the cardiovascular regulatory function of H₄ receptors in RVMM and the mechanism of the intrinsic plasticity of MVN neurons after vestibular disease,but also promotes the clinical development of new therapeutic strategies for cardiovascular and vestibular diseases targeting central H₄ receptors and ion channels mediating vestibular compensatory.