Blockage of the habenular nucleus can eliminate dyspnea induced by electrostimulation of the insular cortex

BACKGROUND： The insular cortex and habenular nucleus may be a regulatory center for obstructive sleep apnea syndrome, and dyspnea may be caused by insular cortex activity. The insular cortex is a cortical representation of obstructive sleep apnea syndrome. The habenular nucleus is a station for descending insular cortex activity. OBJECTIVE： Through actively stimulating the rat insular cortex, to observe rat respiratory movement, myoelectric activities of genioglossus, arterial partial pressure of oxygen, partial pressure of carbon dioxide and acidity-alkalinity, and to verify a hypothesis that the insular cortex is a superior-position regulation center, and the habenular nucleus is an inferior-position nervous nuclei of the insular cortex in patients with obstructive sleep apnea syndrome. DESIGN, TIME AND SETTING： The randomized, controlled animal study was performed at the Laboratory of Electrophysiology, Department of Physiology, Norman Bathune College of Medicine, Jilin University, China from September 2004 to June 2008. MATERIALS： We used L-glutamic acid （Dingguo Biological Product Research Center, Beijing, China）, lidocaine hydrochloride （Seventh Pharmacy Co., Ltd., Wuxi, China）, electric stimulator （Nihon Kohden, Japan）, and an AVL-OPTI blood gas analyzer （AVL Scientific Co., Roswell, GA, USA）. METHODS： The insular cortex of healthy adult Wistar rats underwent electrostimulation and L-glutamic acid stimulation to record changes in the myoelectric activity of genioglossus and respiratory movement. Some rats were injected with lidocaine to block the habenular nucleus before electrostimulation or L-glutamic acid stimulation. L-glutamic acid and lidocaine were injected by microelectrodes embedded in nuclear groups. MAIN OUTCOME MEASURES： Myoelectric activities of genioglossus, arterial partial pressure of oxygen, partial pressure of carbon dioxide and acidity-alkalinity were measured following apnea in rats undergoing electrostimulation in the insular cortex and following blockade of the habenular nucleus. RESULTS： Following electrostimulation and L-glutamic acid stimulation, rats developed apnea or respiratory rhythm disorders. Simultaneously, the amplitude of myoelectric activity of the genioglossus was reduced （P 〈 0.01 ）, and the electromyogram integral was decreased （P 〈 0.01）. Arterial blood gas analysis showed arterial blood acidosis, a decrease in pH （P 〈 0.05）, and an increase in the negative value of alkaline reserve （P 〈 0.01）. Lidocaine in the habenular nuclear blocked respiratory and other index changes after insular cortex stimulation. CONCLUSION： Dyspnea induced by stimulating the insular cortex may require the habenular nucleus. Paralysis of the habenular nucleus can completely eliminate insular cortex stimulation-induced dyspnea.

5-hydroxytryptamine-mediated apnea caused by the habenular nucleus

5-hydroxytryptamine contributes to the control of activities of the dilator muscle in the upper respiratory tract, and is derived from the raphe nuclei, in which the habenular nucleus exerts a sustaJned inhibitory effect. In the present study, respiratory motion curve of the genJoglossus muscle and peripheral 5-hydroxytryptamine changes were observed following L-glutamate stimulation of the habenular nucleus of adult Wistar rats. Results showed that the rats had apnea and decreased plasma 5-hydroxytryptamine content after the neurons in habenular nucleus were excited. Genioglossus muscle electromyogram amplitude and integral were significantly reduced. The genioglossus myoelectric activity and respiratory motion curve were similar to obstructive sleep apnea syndrome, thus confirming that the habenular nucleus is the key nucleus involved in the pathogenesis of obstructive sleep apnea syndrome, and is the primary regulated center in the raphe nuclei. Stimulation of the habenular nucleus may suppress 5-hydroxytryptamine release and result in apnea, which is similar to obstructive sleep apnea syndrome.

Melatonin changes in the pineal gland of sleep-deprived rats following habenular nucleus lesion

The habenular nucleus （Hb） is an important structure that regulates the function of the pineal gland which may affect melatonin content in the pineal gland after sleep deprivation （SD）. In the present study, high performance liquid chromatography showed that the melatonin content in the pineal gland was significantly reduced, and y-aminobutyric acid content in the Hb was significantly increased after SD. Furthermore, the melatonin content in the pineal gland was markedly reduced after Hb lesion under normal sleep and SD conditions. Immunohistochemistry showed that the number of Fos-positive neurons was significantly decreased in the lateral and medial Hb after SD. The findings demonstrate that the reduction of melatonin in the pineal gland after SD is related to decreased activity of Hb neurons, and that the Hb can regulate sleep-wake rhythm by influencing melatonin secretion in the pineal gland.

Ginkgo Leaf Extract and Armillariella Mellea Powders Oral(银杏蜜环口服溶液) attenuates inflammation of microglia in habenular nucleus through CX3CL1-CX3CR1 axis in post stroke depression

OBJECTIVE The Ginkgo Leaf Extract and Armillariella Mellea Powders Oral(Yinxingmihuan Koufu Rongye,YXMH),a representative drug for"Treating both Brain and Heart",showed considerable clinical effects in isch⁃emic cardiovascular and cerebral vascular diseases.Recently,it is reported that YXMH has the potential for treating myocardial and cerebral ischemia related mental disorders,such as post stroke depression(PSD)and chronic heart disease(CHD)associated anxiety disorder.However,its mechanism has not been clearly elucidated.Meanwhile,increasing evidence revealed that there are close functional links between depression and habenular nucleus.The present study investigates the underlying mechanism of YXMH on attenuating the inflammation of microglia in habenular nucleus through CX3CL1-CX3CR1 axis in in a rat model of PSD.METHODS Rats were randomly devided into sham group,model group,Ginaton group(18 mg·kg^-1),Armillariella Mellea group(600 mg·kg-1),Fluoxetine group(10 mg·kg^-1),YXMH high-dose group(618 mg·kg^-1)and YXMH low-dose group(309 mg·kg^-1).The PSD model was induced by transarterial microembolization combined with sleep deprivation(2-Chloro-D-phenylalanine,PCPA,IH,200 mg·kg^-1,for 3 times,before the behavior test)in SD male rats.Then rats were treated with corresponding medicaments through gavage once a day until 3 weeks later,followed by body mass measurement,neurological deficit score evaluation,gripping strength and thermal withdrawl latency measurement,as well as depression related behavioral indicators,the open field test(OFT)and sucrose preference test.The pathological morphological changes of habenular nucleus was observed by HE staining,the expression of IBA-1 was measured and analyzed by immunohistochemistry staining,and alterations of proteins and genes related to the CX3CL1-CX3CR1 axis were analyzed using Western blotting(CX3CL1,CX3CR1)and real-time polymerase chain reaction(PCR)(CX3CL1,CX3CR1).RESULTS Compared with the sham group,rats in the model group manifested as decreased body mass,deficient neurological behavior and gripping strength,reduced loco⁃motor activity and sugar water consumption,as well as elevated thermal withdrawl latency(P<0.05,P<0.01).Mean⁃while,the pathological morphology of the habenular nucleus on the ischemic hemisphere showed significant neuronal degeneration,microglial proliferation,inflammatory cells and glia cells infiltration,together with up-regualted expression of IBA-1,CX3CL1,CX3CR1 protein and CX3CL1,CX3CR1 mRNA.YXMH attenuated inflammation of microglia in habenular nucleus through improving pathological morphology,inhibiting IBA-1 activation,down-regulating the expres⁃sion of CX3CL1 and CX3CR1 proteins and genes,and thus improved the behavior performance of ischemic injury and depression.CONCLUSION YXMH ameliorates neurological deficit and depressive behavior in rat model of PSD induced by transarterial microembolization combined with sleep deprivation,and the mechanism is probably related to attenu⁃ating inflammation of microglia in habenular nucleus through CX3CL1-CX3CR1 axis.

刺激兔缰核引起的缺血性心电变化

本研究观察了电刺激兔缰核（ＨＢ）、终纹床核（ＢＮＳＴ）引起的血压、缺血性心电变化及其与下丘脑背内侧核（ＤＭＨ）的关系。实验在氯醛糖－脲酯麻醉、迷走神经切断的兔中进行。结果显示：１．电刺激ＨＢ引起以ＥＣＧ－ＳＴ压低为主的缺血性心电变化及血压升高、心率加快。损毁以ＤＭＨ为中心的下丘脑内侧区，可明显减弱刺激ＨＢ引起的缺血性心电变化，但不能减弱刺激ＨＢ的升压作用。２．电刺激ＢＮＳＴ引起血压升高，未有明显缺血性心电变化。损毁以ＤＭＨ为中心的下丘脑内侧区，不能减弱刺激ＢＮＳＴ的升压作用。

Effects of 5-hydroxytryptamine ascending pathways of dorsal raphe nuclei and habenular nucleus on the respiration and blood pressure of rats

Obstructive sleep apnea syndrome （OSAS） was a disease of breath obstacle happened in the process of sleep. The central mechanism of OSAS has not yet been fully elucidated. Most of studies focused on raphe nuclei and 5-hydroxytryptamine （5-HT）, and showed that brain serotonergic activity might be decreased in OSAS. It is well known that the dorsal and medial raphe nuclei provide almost all the serotonergic innervation to the forebrain. A previous study evaluated the stimulation of the dorsal raphe nuclei （DRN） in the rat inducing mainly pressor and sympathoexcitatory responses.

Role of 5-hydroxytryptamine expression in cerebellar Purkinje cells in obstructive sleep apnea syndrome

In the present study, electrical stimulation to the rat insular cortex induced apnea or respiratory disturbance, reduced amplitude of genioglossal electromyogram, and decreased electromyogram integrals. In addition, arterial blood gas analysis showed arterial blood acidosis, reduced pH values, increased alkali reserve negative values, decreased peripheral blood 5-hydroxytryptamine content, and increased 5-hydroxytryptamine expression in cerebellar Purkinje cells. Following lidocaine injection to block the habenular nucleus, abnormalities in breath, genioglossal electromyogram, and blood gas values disappeared, and peripheral blood 5-hydroxytryptamine content returned to levels prior to electric stimulation. However, 5-hydroxytryptamine expression in cerebellar Purkinje cells remained high. The results suggested that 5-hydroxytryptamine expression in Purkinje cells did not correlate with ventilation function involving insular cortex and habenular nucleus.