Potentiation of the lateral habenula-ventral tegmental area pathway underlines the susceptibility to depression in mice with chronic pain

Chronic pain often develops severe mood changes such as depression.However,how chronic pain leads to depression remains elusive and the mechanisms determining individuals’responses to depression are largely unexplored.Here we found that depression-like behaviors could only be observed in 67.9%of mice with chronic neuropathic pain,leaving 32.1%of mice with depression resilience.We determined that the spike discharges of the ventral tegmental area(VTA)-projecting lateral habenula(LHb)glutamatergic(Glu)neurons were sequentially increased in sham,resilient and susceptible mice,which consequently inhibited VTA dopaminergic(DA)neurons through a LHbGlu-VTAGABA-VTADA circuit.Furthermore,the LHbGlu-VTADA excitatory inputs were dampened via GABAB receptors in a pre-synaptic manner.Regulation of LHb-VTA pathway largely affected the development of depressive symptoms caused by chronic pain.Our study thus identifies a pivotal role of the LHb-VTA pathway in coupling chronic pain with depression and highlights the activity-dependent contribution of LHbGlu-to-VTADA inhibition in depressive behavioral regulation.

Comparison of two vasopressor protocols for preventing hypotension post-spinal anesthesia during cesarean section: a randomized controlled trial

Background:Norepinephrine infusion decreases hypotension after spinal anesthesia during cesarean section.This study aimed to compare the efficacy of norepinephrine infusion and ephedrine bolus against post-spinal hypotension in parturients.Methods:In this double-blinded,randomized controlled clinical trial,parturients scheduled for elective cesarean section were randomly allocated to receive norepinephrine infusion(0.05μg·kg^(-1)·min^(-1))just before spinal anesthesia continuing for 30 min or ephedrine bolus(0.15 mg/kg)just before spinal anesthesia.A rescue bolus(5μg norepinephrine for the norepinephrine group,and 5 mg ephedrine for the ephedrine group)was administered whenever hypotension occurred.Our primary outcome was the incidence of hypotension within 30 min of spinal anesthesia administration.Secondary outcomes included maternal and neonatal outcomes 30 min after spinal block,and neonatal cerebral oxygenation 10 min after birth.Results:In total,190 patients were enrolled;of these patients,177 were included in the final analysis.Fewer patients suffered hypotension in the norepinephrine group than in the ephedrine group(29.5%vs.44.9%,odds ratio[OR]:0.51,95%confidence interval[CI]:0.28-0.95,P=0.034).Moreover,the tachycardia frequency was lower in the norepinephrine group than in the ephedrine group(OR:0.22,95%CI:0.11-0.44,P<0.001),and patients suffered less nausea and vomiting(OR:0.28,95%CI:0.11-0.70,P=0.004).There was no difference in Apgar scores and umbilical arterial blood gas analysis between the two groups.However,neonatal cerebral regional saturations were significantly higher after birth in the norepinephrine group than in the ephedrine group(mean difference:2.0%,95%CI:0.55%-3.45%,P=0.008).Conclusion:In patients undergoing elective cesarean section with spinal anesthesia,norepinephrine infusion compared to ephedrine bolus resulted in less hypotension and tachycardia,and exhibited potential neonatal benefits.

Understanding sequence effect in DNA bending elasticity by molecular dynamic simulations

Structural elasticity of double-strand DNAs is very important for their biological functions such as DNA-ligand binding and DNA-protein recognition.By all-atom molecular dynamics simulations,we investigated the bending elasticity of DNA with three typical sequences including poly(A)-poly(T)(AA-TT),poly(AT)-poly(TA)(AT-TA),and a generic sequence(GENE).Our calculations indicate that,AA-TT has an apparently larger bending persistence length(P~63 nm)than GENE(P~49 nm)and AT-TA(P~48 nm)while the persistence length of AT-TA is only very slightly smaller than that of GENE,which agrees well with those from existing works.Moreover,through extensive electrostatic calculations,we found that the sequence-dependent bending elasticity is attributed to the sequence-dependent electrostatic bending energy for AA-TT,AT-TA and GENE,which is coupled to their backbone structures.Particularly,the apparently stronger bending stiffness of AA-TT is attributed to its narrower minor groove.Interestingly,for the three DNAs,we predicted the non-electrostatic persistence length of~17 nm,thus electrostatic interaction makes the major contribution to DNA bending elasticity.The mechanism of electrostatic energy dominating sequence effect in DNA bending elasticity is furtherly illustrated through the electrostatic calculations for a grooved coarse-grained DNA model where minor groove width and other microscopic structural parameters can be artificially adjusted.