Study on Action of Acupuncture on Ventromedial Nucleus of Hypothalamus in Obese Rats

Effects of acupuncture on the spontaneous discharge of nerve cells and levels of monoamine neurotransmitters in ventromedial nucleus of hypothalamus (VMH) of the obese rats were investigated. Results indicated that the levels of tyrosine (Tyr) and dopamine (DA) were lowered, the levels of 5-hydroxytryptamine (5-HT) and 5-hydoxyindole acetic acid (5-HIAA) increased, and the frequency of the spontaneous discharge of nerve cells in VMH lowered in the obese rat group as compared with the normal group. When acupuncture obtained the effect of weight reduction, the frequency of spontaneous discharges of nerve cells in VMH were markedly increased, and the levels of Tyr, DA and tryptamine (Typ) and 5-HT/5-HIAA ratio elevated, and the 5-HT level lowered. It is suggested that the virtuous regulative action of acupuncture on VMH might be one of the key factors in acupuncture for weight reduction.

Expression of gastrointestinal nesfatin-1 and gastric emptying in ventromedial hypothalamic nucleus- and ventrolateral hypothalamic nucleus-lesioned rats

AIM: To determine the expression levels of gastrointestinal nesfatin-1 in ventromedial hypothalamic nucleus (VMH)-lesioned (obese) and ventrolateral hypothalamic nucleus (VLH)-lesioned (lean) rats that exhibit an imbalance in their energy metabolism and gastric mobility.

Melanocortin-4 Receptor Expression in the Rostral Ventromedial Medulla Involved in Modulation of Nociception in Transgenic Mice

The rostral ventromedial medulla （RVM） is a prominent component of the descending modulatory system involved in the control of spinal nociceptive transmission. In the current study, we investigated melanocortin-4 receptor （MC4R） expression in the RVM, where the neurons involved in modulation of nociception reside. Using a line of mice expressing green fluorescent protein （GFP） under the control of the MC4R promoter, we found a large number of GFP-positive neurons in the RVM [nucleus raphe magnus （NRM） and nucleus gigantocellularis pars a （NGCa）]. Fluorescence immunohisto- chemistry revealed that approximately 10% of MC4R-GFP-positive neurons coexpressed tyrosine hydroxylase, indicating that they were catecholaminergic, whereas 50%-75% of those coexpressed tryp- tophan hydroxylase, indicating that they were serotonergic. Our findings support the hypothesis that MC4R signaling in RVM may modulate the activity of serotonergic sympathetic outflow sensitive to nociceptive signals, and that MC4R signaling in RVM may contribute to the descending modulation of nociceptive transmission.

Inhibition of Glial Activation in Rostral Ventromedial Medulla Attenuates Mechanical Allodynia in a Rat Model of Cancer-induced Bone Pain

Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP). Rostral ventromedial medulla (RVM) is a critical component of descending nociceptive facilitation circuitry, but so far the mechanisms are poorly known. In this study, we investigated the role of RVM glial activation in the descending nociceptive facilitation circuitry in a CIBP rat model. CIBP rats showed significant activation of microglia and astrocytes, and also up-regulation of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and pro-inflammatory mediators released by glial cells (IL-1β, IL-6, TNF-α and brain-derived neurotrophic factor) in the RVM. Stereotaxic microinjection of the glial inhibitors (minocycline and fluorocitrate) into CIBP rats’ RVM could reverse the glial activation and significantly attenuate mechanical allodynia in a time-dependent manner. RVM microinjection of p38 MAPK inhibitor (SB203580) abolished the activation of microglia, reversed the associated up-regulation of proinflammatory mediators and significantly attenuated mechanical allodynia. Taken together, these results suggest that RVM glial activation is involved in the pathogenesis of CIBP. RVM microglial p38 MAPK signaling pathway is activated and leads to the release of downstream pro-inflammatory mediators, which contribute to the descending facilitation of CIBP.

Effects of ventromedial hypothalamic somatostatin on gastric somatostatin and acid secretion in rats

The effects of somatostatin and cysteamine injected into theventromedial nucleus of hypothalamus(VMH)on somatostatin-likeimmunoreactivity(SLI)concentration in the gastric antral mucosa and portal veinplasma,as well as the gastric acid secretion were studied in anesthetized rats.TheSLI concentration in the gastric antral mucosa and portal vein plasma and thegastric acid output were significantly increased one hour after the injection ofsomatostatin(0.5μg/0.5μ1)into the VMH.Four hours later,the SLI concentrationin the mucosa was still higher than the control level,while the SLI level in theplasma and the acid secretion were close to those of controls.On the contrary,the SLI concentration in the mucosa and plasma and the acid output weremarkedly decreased at four hours after the injection of cysteamine(15μg/0.5μ1)into the VMH.The present results suggest that both exogenous and endogenoussomatostatin in the VMH have a facilitatory action on the gastric somatostatinconcentration and its release as well as on the gastric acid secretion,thus provid-ing evidence for hypothalamic control of gastric somatostatin and acid secretion.

Ventromedial Thalamus-Projecting DCN Neurons Modulate Associative Sensorimotor Responses in Mice

The deep cerebellar nuclei(DCN)integrate various inputs to the cerebellum and form the final cerebellar outputs critical for associative sensorimotor learning.However,the functional relevance of distinct neuronal subpopulations within the DCN remains poorly understood.Here,we examined a subpopulation of mouse DCN neurons whose axons specifically project to the ventromedial(Vm)thalamus(DCNVm neurons),and found that these neurons represent a specific subset of DCN units whose activity varies with trace eyeblink conditioning(tEBC),a classical associative sensorimotor learning task.Upon conditioning,the activity of DCNVm neurons signaled the performance of conditioned eyeblink responses(CRs).Optogenetic activation and inhibition of the DCNVm neurons in well-trained mice amplified and diminished the CRs,respectively.Chemogenetic manipulation of the DCNVm neurons had no effects on non-associative motor coordination.Furthermore,optogenetic activation of the DCNVm neurons caused rapid elevated firing activity in the cingulate cortex,a brain area critical for bridging the time gap between sensory stimuli and motor execution during tEBC.Together,our data highlights DCNVm neurons’function and delineates their kinematic parameters that modulate the strength of associative sensorimotor responses.

COMPARISON OF THE EFFECTS OF MEDIAL PRE OPTIC AREA AND VENTROMEDIAL NUCLEUS OF HYPOTHALAMUS ON THE DISCHARGES OF NORADRENERGIC NEURONS IN LOCUS COERULEUS IN FEMALE RATS AT DIFFERENT STAGES OF ESTROUS CYCLE

In the structure of brain the medial preoptic area (MPO) and ventromedial nucleus of hypothalamus (VMN)are the two parts where the estrogen receptors concentrate but have opposite effects on sexual behavior. Recently estrogen receptors have been known to be located in the locus coeruleus(LC), where noradrenergic(NE) fibres terminate in the hypothalamus arising from cell bodies. The discharge rate of NE-ergic neurons in LC can be increased by electrical stimulation of MPO in a female rat at estrus stage, and decreased at diestrus stage. These studies help us to infer that VMN might have some modulation influence on NE-ergic neurons in LC. In order to study the pattern activities

Role of prefrontal cortex-nucleus accumbens glutamatergic projection in heroin reward and motivation

OBJECTIVE Glutamatergic projections from prefrontal cortex(PFc) to nucleus accumbens(NAc) regulate the dopamine(DA) release in NAc.However,it is not clear whether this circuit is effective for the reward and motivation of heroin addiction.Our study investigates the effects of metabotropic glutamate receptor 2/3(mGluR2/3) and the projections from ventromedial prefrontal cortex(vmPFc) to the NAc shell on the reward and motivation of heroin-addicted rats.METHODS First,rats were trained to selfadministration for 14 d.On the 15 thday,parts of rats were injected with mGluR 2/3 agonist LY379268(0.1,0.3 and 1.0 mg·kg-1,ip) systematically and another parts of rats were bilaterally microinjected with LY379268(0.3 and 1.0 g·L^(-1))at the volume of 0.5 μL into the ventral tegmental area(VTA),NAc core or NAc shell,respectively.All rats were followed by heroin self-administration testing under fixed ratio 1(FR1) schedule or progressed ratio(PR) schedule to observe the effect of LY379268 on the heroin reward or motivation.Second,rats were injected chemogenetic glutamatergic virus(pAAV-CaMKIIa-hM3 D(Gq)-mCherry or pAOV-CaMKIIa-hM4 D(Gi)-mCherry-3 Flag) or negative control virus in vmPFc,and trained to heroin self-administration for 14 d.On the 15 thday,rats were bilateral y microinjected with clozapine-N-oxide(CNO,1 mmol·L^(-1),0.5 μL) into NAc shell and tested the effect on the heroin reward or motivation.Finally,rats were injected optogenetical glutamatergic virus(AAV2/9-CaM KⅡ-hChR2-EYFP) or negative control virus in vmPFc,implanted 16 channel photoelectrode in ipsilateral NAc shell,and trained to heroin selfadministration for 14 d.On the 15 thday,rats were tested heroin reward under FR1 procedure with blue light stimulation in the wavelength of470 nm,frequency of 25 HZ and power of 5 mW.Each stimulation lasting for 1 h and interval for1 h.The spike changes before and after stimulation in NAc Shel neural nerve was recorded.RESULTS LY379268 cloud dose-dependent attenuated the heroin reward or motivation and the local effective site was mainly in the NAc shell.Chemogenetic results showed activation or inactivation the projection from vmPFc to NAc shell enhanced or attenuated the heroin reward and motivation,respectively.Optogenetical stimulation the same projection also enhanced the heroin reward,and a tonic neuronal firing at the nerve of NAc shell was observed during the light stimulation session.CONCLUSION mGluR2/3 activation in the NAc shell is involved in the inhibition of heroin reward and motivation.Activation the projection from PFc to NAc shell can enhance the effects on heroin reward and motivation.

Central Nervous System Control of Glucose Homeostasis

Hypothalamus and brain stem play important roles in Glucose Homeostasis. There are two types of cells in the hypothalamus: Glucose excited (GE) and Glucose inhibited (GI). GE increases glucose concentration and GI decreases glucose concentration. They are located in ventromedial (VMH), arcuate, lateral, dorsomedial and paraventricular areas of hypothalamus. Nucleus of solitary tract, area postrema, dorsomedial nucleus of vagus and basolateral medulla are also related to glucose homeostasis. VMH contains sympathetic nucleus and upregulates plasma glucose and decreases hepatic glycogen, while lateral hypothalamus contains parasympathetic and down regulates plasma glucose. Through Glut-1, dependent transport glucose enters neurons and astrocytes. Glucose is metabolized and provides energy for GE and GI neurons. Their activity is guided by blood sugar level. Blood sugar level sends numerous signals through vagal pathway from periphery. Neuron astrocyte establishes via autonomic system connections with liver, pancreas, adrenal gland and maintains glucose homeostasis. Post prandial glucose levels are regulated by CNS.

The Time-Effect Relationship of Central Action in Acupuncture Treatment for Weight Reduction

Purpose: To study the time-effect relationship of action of acupuncture on the satiety center of ventromedial nucleus of hypothalamus (VMH) in rats with experimental obesity. Methods: Microelectrode recording method of nerve cells and stereotaxic technique for brain were adopted with discharge frequency (Hz/s) of nerve impulse in VMH as the index, and the time-effect of acupuncture action in different periods between groups were observed. Results: Electric activity in acupuncture group was higher than that in the obesity model group (P<0.001) and the normal group (P<0.01) respectively, and the curve of acupuncture action within 2 hours showed irregular fluctuation. Conclusion: Acupuncture can increase excitability of the satiety center, with a better long-term effect.

Chemokine signaling involving chemokine (C-C motif) ligand 2 plays a role in descending pain facilitation

Objective Despite accumulating evidence on a role of immune cells and their associated chemicals in mecha- nisms of pain, few studies have addressed the potential role of chemokines in the descending facilitation of persistent pain. The present study was undertaken to test the hypothesis that the chemokine （C-C motif） ligand 2 （CCL2） （commonly known as monocyte chemoattractant protein-1） signaling in the rostral ventromedial medulla （RVM）, a pivotal structure in brainstem pain modulatory circuitry, is involved in descending pain facilitation in rats. Methods An L5 spinal nerve ligation （SNL） was produced in rats under pentobarbital anesthesia. Western blot and immunohistochemistry were used to detect the expression levels of CCL2 and CCL2 receptor （CCR2）, and examine their distributions compared with the neuronal marker NeuN as well as glial markers glial fibrillary acidic protein （GFAP, astroglial） and CD 11 b （microglial）, respectively. Results SNL induced an increase in CCL2 expression in the RVM, and this returned to the control level at 4 weeks after injury. The induced CCL2 colocalized with NeuN, but not with GFAP and CD1 lb. CCR2 was also upregu- lated by SNL in the RVM, and this increase lasted for at least 4 weeks. CCR2 was colocalized with CD1 lb but not GFAP. Few RVM neurons also exhibited CCR2 staining. Neutralizing CCL2 with an anti-CCL2 antibody （0.2-20 ng） or injecting RS-102895 （0.1-10 pmol）, a CCR2b chemokine receptor antagonist, into the RVM on day 1 after SNL, significantly at- tenuated the established thermal and mechanical hypersensitivity. In addition, injection of recombinant rat CCL2 （0.03-3 pmol） into the RVM induced dose-dependent hyperalgesia, which was prevented by pretreatment with RS-102895 （10 pmol）. Interleukin-β （IL-1]3）, a potent inducer of neuronal CCL2, was also selectively upregulated in RVM reactive as- trocytes. Injection of IL-1 ]3 （120 fmol） into the RVM induced behavioral hyperalgesia, which was blocked by RS-102895 （10 pmol）. However, an IL-1 receptor antagonist （3 pmol） did not prevent CCL2 （3 pmol）-induced hyperalgesia. These results suggest that the effect of CCL2 is downstream to IL-113 signaling. Conclusion The IL-1 β and CCL2-CCR2 signaling cascades play a role in neuron-glia-cytokine interactions and the descending facilitation of neuropathic pain.