Selective optogenetic stimulation of efferent fi bers in the vagus nerve of a large mammal

Background: Electrical stimulation applied to individual organs, peripheral nerves, or specific brain regions has been used to treat a range of medical conditions. In cardiovascular disease, autonomic dysfunction contributes to the disease progression and electrical stimulation of the vagus nerve has been pursued as a treatment for the purpose of restoring the autonomic balance. However, this approach lacks selectivity in activating function- and organ-specific vagal fibers and, despite promising results of many preclinical studies, has so far failed to translate into a clinical treatment of cardiovascular disease. Objective: Here we report a successful application of optogenetics for selective stimulation of vagal efferent activity in a large animal model (sheep). Methods and results: Twelve weeks after viral transduction of a subset of vagal motoneurons, strong axonal membrane expression of the excitatory light-sensitive ion channel ChIEF was achieved in the efferent projections innervating thoracic organs and reaching beyond the level of the diaphragm. Blue laser or LED light (>10 mW mm 2 ; 1 ms pulses) applied to the cervical vagus triggered precisely timed, strong bursts of efferent activity with evoked action potentials propagating at speeds of ~6 m s 1 . Conclusions: These findings demonstrate that in species with a large, multi-fascicled vagus nerve, it is possible to stimulate a specific sub-population of efferent fibers using light at a site remote from the vector delivery, marking an important step towards eventual clinical use of optogenetic technology for autonomic neuromodulation. © 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/

Selective optogenetic stimulation of efferent fibers in the vagus nerve of a large mammal

BACKGROUND: Electrical stimulation applied to individual organs, peripheral nerves, or specific brain regions has been used to treat a range of medical conditions. In cardiovascular disease, autonomic dysfunction contributes to the disease progression and electrical stimulation of the vagus nerve has been pursued as a treatment for the purpose of restoring the autonomic balance. However, this approach lacks selectivity in activating function- and organ-specific vagal fibers and, despite promising results of many preclinical studies, has so far failed to translate into a clinical treatment of cardiovascular disease. OBJECTIVE: Here we report a successful application of optogenetics for selective stimulation of vagal efferent activity in a large animal model (sheep). METHODS AND RESULTS: Twelve weeks after viral transduction of a subset of vagal motoneurons, strong axonal membrane expression of the excitatory light-sensitive ion channel ChIEF was achieved in the efferent projections innervating thoracic organs and reaching beyond the level of the diaphragm. Blue laser or LED light (>10 mW mm-2; 1 ms pulses) applied to the cervical vagus triggered precisely timed, strong bursts of efferent activity with evoked action potentials propagating at speeds of ∼6 m s-1. CONCLUSIONS: These findings demonstrate that in species with a large, multi-fascicled vagus nerve, it is possible to stimulate a specific sub-population of efferent fibers using light at a site remote from the vector delivery, marking an important step towards eventual clinical use of the optogenetic technology for autonomic neuromodulation

Widespread horse-based mobility arose around 2,200 BCE in Eurasia

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordData availability:All collapsed and paired-end sequence data for samples sequenced in this study are available in compressed FASTQ format through the European Nucleotide Archive under accession number PRJEB71445, together with rescaled and trimmed bam sequence alignments against the nuclear horse reference genomes. Previously published ancient data used in this study are available under accession numbers PRJEB7537, PRJEB10098, PRJEB10854, PRJEB22390, PRJEB31613, and PRJEB44430, and detailed in Supplementary Table 1. The genomes of 78 modern horses, publicly available, were also accessed as indicated in their corresponding original publications, and in Supplementary Table 1.Code availability: The software to calculate generation time changes based on the recombination clock is available without restriction on Bitbucket (https://bitbucket.org/plibradosanz/generationtime/src/master/) and Zenodo (10.5281/zenodo.10842666; https://zenodo.org/records/10842666)Horses revolutionized human history with fast mobility. However, the timeline between their domestication and widespread integration as a means of transportation remains contentious. Here we assemble a large collection of 475 ancient horse genomes to assess the period when these animals were first reshaped by human agency in Eurasia. We find that reproductive control of the modern domestic lineage emerged ~2,200 BCE (Before Common Era), through close kin mating and shortened generation times. Reproductive control emerged following a severe domestication bottleneck starting no earlier than ~2,700 BCE, and coincided with a sudden expansion across Eurasia that ultimately resulted in the replacement of nearly every local horse lineage. This expansion marked the rise of widespread horse-based mobility in human history, which refutes the commonly-held narrative of large horse herds accompanying the massive migration of steppe peoples across Europe ~3,000 BCE and earlier. Finally, we detect significantly shortened generation times at Botai ~3,500 BCE, a settlement from Central Asia associated with corrals and a subsistence economy centered on horses. This supports local horse husbandry before the rise of modern domestic bloodlines.Arts and Humanities Research Council (AHRC