Minocycline Activates the Nucleus of the Solitary Tract- Associated Network to Alleviate Lipopolysaccharide-Induced Neuroinflammation

Objective To examine the neuroanatomical substrates underlying the effects of minocycline in alleviating lipopolysaccharide(LPS)-induced neuroinflammation.Methods Forty C57BL/6 male mice were randomly and equally divided into eight groups.Over three conse-cutive days,saline was administered to four groups of mice and minocycline to the other four groups.Immediately after the administration of saline or minocycline on the third day,two groups of mice were additionally injected with saline and the other two groups were injected with LPS.Six or 24 hours after the last injection,mice were sacrificed and the brains were removed.Immunohistochemical staining across the whole brain was performed to detect microglia activation via Iba1 and neuronal activation via c-Fos.Morphology of microglia and the number of c-Fo-positive neurons were analyzed by Image-Pro Premier 3D.One-way ANOVA and Fisher’s least-significant differences were employed for statistical analyses.Results Minocycline alleviated LPS-induced neuroinflammation as evidenced by reduced activation of microglia in multiple brain regions,including the shell part of the nucleus accumbens(Acbs),paraventricular nucleus(PVN)of the hypothalamus,central nucleus of the amygdala(CeA),locus coeruleus(LC),and nucleus tractus solitarius(NTS).Minocycline significantly increased the number of c-Fo-positive neurons in NTS and area postrema(AP)after LPS treatment.Furthermore,in NTS-associated brain areas,including LC,lateral parabrachial nucleus(LPB),periaqueductal gray(PAG),dorsal raphe nucleus(DR),amygdala,PVN,and bed nucleus of the stria terminali(BNST),minocycline also significantly increased the number of c-Fo-positive neurons after LPS administration.Conclusion Minocycline alleviates LPS-induced neuroinflammation in multiple brain regions,possibly due to increased activation of neurons in the NTS-associated network.

Direct evidence of VEGF-mediated neuroregulation and afferent explanation of blood pressure dysregulation during angiogenic therapy

Objective:Oncocardiology is increasingly hot research field/topic in the clinical management of cancer with anti-angiogenic therapy of vascular endothelial growth factor(VEGF)that may cause cardiovascular toxicity,such as hypertension via vascular dysfunction and attenuation of eNOS/NO signaling in the baroreflex afferent pathway.The aim of the current study was to evaluate the potential roles of VEGF/VEGF receptors(VEGFRs)expressed in the baroreflex afferent pathway in autonomic control of blood pressure(BP)regulation.Methods:The distribution and expression of VEGF/VEGFRs were detected in the nodose ganglia(NG)and nucleus of tractus solitary(NTS)using immunostaining and molecular approaches.The direct role of VEGF was tested by NG microinjection under physiological and hypertensive conditions.Results:Immunostaining data showed that either VEGF or VEGFR2/VEGFR3 was clearly detected in the NG and NTS of adult male rats.Microinjection of VEGF directly into the NG reduced the mean blood pressure(MBP)dose-dependently,which was less dramatic in renovascular hypertension(RVH)rats,suggesting the VEGF-mediated depressor response by direct activation of the 1st-order baroreceptor neurons in the NG under both normal and disease conditions.Notably,this reduced depressor response in RVH rats was directly caused by the downregulation of VEGFR2,which compensated the up regulation of VEGF/VEGFR3 in the NG during the development of hypertension.Conclusion:It demonstrated for the first time that the BP-lowering property of VEGF/VEGFRs signaling via the activation of baroreflex afferent function may be a common target/pathway leading to BP dysregulation in anti-angiogenic therapy.

Anterior Cingulate Cortex Mediates Hyperalgesia and Anxiety Induced by Chronic Pancreatitis in Rats

Central sensitization is essential in maintaining chronic pain induced by chronic pancreatitis(CP),but cortical modulation of painful CP remains elusive.Here,we examined the role of the anterior cingulate cortex(ACC)in the pathogenesis of abdominal hyperalgesia in a rat model of CP induced by intraductal administration of trinitrobenzene sulfonic acid(TNBS).TNBS treatment resulted in long-term abdominal hyperalgesia and anxiety in rats.Morphological data indicated that painful CP induced a significant increase in FOS-expressing neurons in the nucleus tractus solitarii(NTS)and ACC,and some FOS-expressing neurons in the NTS projected to the ACC.In addition,a larger portion of ascending fibers from the NTS innervated pyramidal neurons,the neural subpopulation primarily expressing FOS under the condition of painful CP,rather than GABAergic neurons within the ACC.CP rats showed increased expression of vesicular glutamate transporter 1,and increased membrane trafficking and phosphorylation of the N-methyl-D-aspartate receptor(NMDAR)subunit NR2B and theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR)subunit GluR1 within the ACC.Microinjection of NMDAR and AMPAR antagonists into the ACC to block excitatory synaptic transmission significantly attenuated abdominal hyperalgesia in CP rats,which was similar to the analgesic effect of endomorphins injected into the ACC.Specifically inhibiting the excitability of ACC pyramidal cells via chemogenetics reduced both hyperalgesia and comorbid anxiety,whereas activating these neurons via optogenetics failed to aggravate hyperalgesia and anxiety in CP rats.Taken together,these findings provide neurocircuit,biochemical,and behavioral evidence for involvement of the ACC in hyperalgesia and anxiety in CP rats,as well as novel insights into the cortical modulation of painful CP,and highlights the ACC as a potential target for neuromodulatory interventions in the treatment of painful CP.

Evolution of gustatory reflex systems in the brainstems of fishes

The great number of species of teleosts permits highly specialized forms to evolve to occupy particular niches.This diversity allows for extreme variations in brain structure according to particular sensory or motor adaptations.In the case of the taste system,goldfish(Carassius auratus L.,1758)and some carps have evolved a specialized in-traoral food-sorting apparatus along with corresponding specializations of gustatory centers in the brainstem.A comparison of circuitry within the complex vagal lobe of goldfish,and of the simpler gustatory lobes in catfish(Ictalurus punctatus Rafinesque,1818)shows numerous similarities in organization and neurotransmitters.Double labeling studies using horseradish peroxidase and biotinylated dextran amine in catfish shows a direct projection from the vagal lobe to the motoneurons of nucleus ambiguus which innervate oropharyngeal musculature.Therefore,a three neuron reflex arc connects gustatory input to motor output.In the vagal lobe of goldfish,a similar three neuron arc can be identified:from primary gustatory afferent,to vagal lobe interneuron,thence to dendrites of the vagal motoneurons that innervate the pharyngeal muscles.Therefore,despite large differences in the gross appearance of the vagal gustatory systems in the brains of catfish and goldfish,the essential connectivity and circuitry is similar.This suggests that evolutionary change in the central nervous system largely proceeds by rearrangement and elaboration of existing systems,rather than by addition of new structures or circuits.

c-Fos expression in rat brainstem following intake of sucrose or saccharin

To examine whether the activation of brainstem neurons during intake of a sweet tastant is due to orosensory signals or post-ingestive factors,we compared the distribution of c-Fos-like immunoreactivity(c-FLI)in the nucleus of the solitary tract(NST)and parabrachial nucleus(PBN)of brainstem following ingestion of 0.25 M sucrose or 0.005 M saccharin solutions.Immunopositive neurons were localized mainly in the middle zone of the PBN and four rostral-caudal subregions of the NST.Intake of sucrose increased the number of FLI neurons in almost every subnucleus of the PBN(F_((2,13))=7.610,P=0.023),in addition to the caudal NST at the level of the area postrema(F_((2,13))=10.777,P=0.003)and the NST intermediate zone(F_((2,13))=7.193,P=0.014).No significant increase in the number of c-Fos positive neurons was detected in response to saccharin ingestion,although there was a trend towards a modest increase in a few select NST and PBN nuclei.These results suggest that the PBN and NST may be involved in sweet taste perception and modulation of sweet tastant intake,but the significantly enhanced intensity of Fos expression induced by sucrose indicates that PBN/NST neuronal activity is driven by the integrated effects of sweet taste sensation and post-ingestive signals.