Diversity of sympathetic vasoconstrictor pathways and their plasticity after spinal cord injury

Sympathetic vasoconstrictor pathways pass through paravertebral ganglia carrying ongoing and reflex activity arising within the central nervous system to their vascular targets. The pattern of reflex activity is selective for particular vascular beds and appropriate for the physiological outcome (vasoconstriction or vasodilation). The preganglionic signals are distributed to most postganglionic neurones in ganglia via synapses that are always suprathreshold for action potential initiation (like skeletal neuromuscular junctions). Most postganglionic neurones receive only one of these “strong” inputs, other preganglionic connections being ineffective. Pre- and postganglionic neurones discharge normally at frequencies of 0.5–1 Hz and maximally in short bursts at <10 Hz. Animal experiments have revealed unexpected changes in these pathways following spinal cord injury. (1) After destruction of preganglionic neurones or axons, surviving terminals in ganglia sprout and rapidly re-establish strong connections, probably even to inappropriate postganglionic neurones. This could explain aberrant reflexes after spinal cord injury. (2) Cutaneous (tail) and splanchnic (mesenteric) arteries taken from below a spinal transection show dramatically enhanced responses in vitro to norepinephrine released from perivascular nerves. However the mechanisms that are modified differ between the two vessels, being mostly postjunctional in the tail artery and mostly prejunctional in the mesenteric artery. The changes are mimicked when postganglionic neurones are silenced by removal of their preganglionic input. Whether or not other arteries are also hyperresponsive to reflex activation, these observations suggest that the greatest contribution to raised peripheral resistance in autonomic dysreflexia follows the modifications of neurovascular transmission

Genetic determinants of daytime napping and effects on cardiometabolic health

This is the final version. Available from Nature Research via the DOI in this record. Summary GWAS statistics are publicly available at The Sleep Disorder Knowledge Portal webpage: http://sleepdisordergenetics.org/.Daytime napping is a common, heritable behavior, but its genetic basis and causal relationship with cardiometabolic health remain unclear. Here, we perform a genome-wide association study of self-reported daytime napping in the UK Biobank (n = 452,633) and identify 123 loci of which 61 replicate in the 23andMe research cohort (n = 541,333). Findings include missense variants in established drug targets for sleep disorders (HCRTR1, HCRTR2), genes with roles in arousal (TRPC6, PNOC), and genes suggesting an obesity-hypersomnolence pathway (PNOC, PATJ). Association signals are concordant with accelerometer-measured daytime inactivity duration and 33 loci colocalize with loci for other sleep phenotypes. Cluster analysis identifies three distinct clusters of nap-promoting mechanisms with heterogeneous associations with cardiometabolic outcomes. Mendelian randomization shows potential causal links between more frequent daytime napping and higher blood pressure and waist circumference.National Institute of HealthNational Institute of HealthNational Institute of HealthNational Institute of HealthNational Institute of HealthMGH Research Scholar Fund, Academy of FinlandMedical Research CouncilSpanish Government of Investigation, Development and InnovationSeneca FoundationNIDDKInstrumentarium Science FoundationYrjö Jahnsson Foundatio

News Interviews: Clayman and Heritage’s The News Interview

News interviews: Clayman and Heritage’s ‘The News Interview

Slow and incomplete sympathetic reinnervation of rat tail artery restores the amplitude of nerve-evoked contractions provided a perivascular plexus is present

We have investigated the recovery of sympathetic control following reinnervation of denervated rat tail arteries by relating the reappearance of noradrenergic terminals to the amplitude of nerve-evoked contractions of isometrically mounted artery segments in vitro. We have also assessed reactivity to vasoconstrictor agonists. Freezing the collector nerves near the base of the tail in adult rats denervated the artery from ∼40 mm along the tail. Restoration of the perivascular plexus declined along the length of the tail, remaining incomplete for >6 mo. After 4 mo, nerve-evoked contractions were prolonged but of comparable amplitude to control at ∼60 mm along the tail; they were smaller at ∼110 mm. At ∼60 mm, facilitation of contractions to short trains of stimuli by the norepinephrine transporter blocker, desmethylimipramine, and by the α-adrenoceptor antagonist, idazoxan, was reduced in reinnervated arteries. Blockade of nerve-evoked contractions by the α-adrenoceptor antagonist, prazosin, was less and by idazoxan greater than control after 8 wk but similar to control after 16 wk. Sensitivity of reinnervated arteries to the α- adrenoceptor agonist, phenylephrine, was raised in the absence but not in the presence of desmethylimipramine. Sensitivity to the α- adrenoceptor agonist, clonidine, was maintained in 16-wk reinnervated arteries when it had declined in controls. Thus regenerating sympathetic axons have a limited capacity to reinnervate the rat tail artery, but nerve-evoked contractions match control once a relatively sparse perivascular plexus is reestablished. Functional recovery involves prolongation of contractions and deficits in both clearance of released norepinephrine and autoinhibition of norepinephrine release