Circuit-Specific Control of Blood Pressure by PNMT‑Expressing Nucleus Tractus Solitarii Neurons

The nucleus tractus solitarii(NTS)is one of the morphologically and functionally defined centers that engage in the autonomic regulation of cardiovascular activity.Phenotypically-characterized NTS neurons have been implicated in the differential regulation of blood pressure(BP).Here,we investigated whether phenylethanolamine N-methyltransferase(PNMT)-expressing NTS(NTS^(PNMT))neurons contribute to the control of BP.We demonstrate that photostimulation of NTS^(PNMT)neurons has variable effects on BP.A depressor response was produced during optogenetic stimulation of NTS^(PNMT)neurons projecting to the paraventricular nucleus of the hypothalamus,lateral parabrachial nucleus,and caudal ventrolateral medulla.Conversely,photostimulation of NTS^(PNMT)neurons projecting to the rostral ventrolateral medulla produced a robust pressor response and bradycardia.In addition,genetic ablation of both NTS^(PNMT)neurons and those projecting to the rostral ventrolateral medulla impaired the arterial baroreflex.Overall,we revealed the neuronal phenotype-and circuit-specific mechanisms underlying the contribution of NTS^(PNMT)neurons to the regulation of BP.

A Neural Circuit Mechanism Controlling Breathing by Leptin in the Nucleus Tractus Solitarii

Leptin,an adipocyte-derived peptide hormone,has been shown to facilitate breathing.However,the central sites and circuit mechanisms underlying the respiratory effects of leptin remain incompletely understood.The present study aimed to address whether neurons expressing leptin receptor b(LepRb)in the nucleus tractus solitarii(NTS)contribute to respiratory control.Both chemogenetic and optogenetic stimulation of LepRb-ex-pressing NTS(NTS^(LepRb))neurons notably activated breathing.Moreover,stimulation of NTS^(LepRb) neurons projecting to the lateral parabrachial nucleus(LPBN)not only remarkably increased basal ventilation to a level similar to that of the stimulation of all NTS^(LepRb) neurons,but also activated LPBN neurons projecting to the preBotzinger complex(preBotC).By contrast,ablation of NTS^pRb neurons projecting to the LPBN notably eliminated the enhanced respiratory effect induced by NTSLepRb neuron stimulation.In brainstem slices,bath application of leptin rapidly depolarized the membrane potential,increased the spontaneous firing rate,and accelerated the Ca2+transients in most NTSLepRb neurons.Therefore,leptin potentiates breathing in the NTS most likely via an NTS-LPBN-preBdtC circuit.

Light-activated nitric-oxide overproduction theranostic nanoplatform based on long-circulating biomimetic nanoerythrocyte for enhanced cancer gas therapy

The limited intratumoral perfusion of nitric oxide(NO)-carrying nanoparticles into solid tumors caused by the inherent biological barriers in vivo greatly attenuates their generated efficacy. Herein, through entrapping heat-sensitive NO donors(BNN6)on mesoporous polydopamine nanoparticles(M-PDA) and subsequently enveloping with red blood cells membranes, a heatresponsive biomimetic theranostic nanoerythrocyte(M/B@R) is developed to boost NO-based cancer therapy. The reserved intact structure of red blood cells membranes(RBCm) endows M/B@R with superior biosafety and stealth properties for prolonged circulation time and subsequent enhanced tumor accumulation. Once internalized in tumors and excited by nearinfrared light(NIR, 808 nm) irradiation, M/B@R can not only yield plenty of heat for photothermal therapy(PTT) but also achieve the overproduction of NO for highly-efficient NO gas therapy due to its high loading capacity and NIR-absorbing property of M-PDA. The generated NO further ensures the formation of ONOO^(-) which possesses remarkable toxicity to tumor as well as alleviating tumor hypoxia. It is found that M/B@R with NIR as the excitation source can significantly induce synthetic lethality to tumors via the hyperthermia, DNA damage and the ease of tumor hypoxia. Simultaneously, M/B@R also exhibits the potential for bimodal fluorescence and photothermal imaging. The RBCm-camouflaged NO delivery nanoplatform with bimodal imaging capability in this work may provide a new combinatorial paradigm to induce PTT/NO for cancer theranostic applications.