Cervical vagus nerve stimulation augments spontaneous discharge in second- and higher-order sensory neurons in the rat nucleus of the solitary tract

Abstract

Vagus nerve stimulation (VNS) currently treats patients with drug-resistant epilepsy, depression, and heart failure. The mild intensities used in chronic VNS suggest that primary visceral afferents and central nervous system activation are involved. Here, we measured the activity of neurons in the nucleus of the solitary tract (NTS) in anesthetized rats using clinically styled VNS. Our chief findings indicate that VNS at threshold bradycardic intensity activated NTS neuron discharge in one-third of NTS neurons. This VNS directly activated only myelinated vagal afferents projecting to second-order NTS neurons. Most VNS-induced activity in NTS, however, was unsynchronized to vagal stimuli. Thus, VNS activated unsynchronized activity in NTS neurons that were second order to vagal afferent C-fibers as well as higher-order NTS neurons only polysynaptically activated by the vagus. Overall, cardiovascular-sensitive and -insensitive NTS neurons were similarly activated by VNS: 3/4 neurons with monosynaptic vagal A-fiber afferents, 6/42 neurons with monosynaptic vagal C-fiber afferents, and 16/21 polysynaptic NTS neurons. Provocatively, vagal A-fibers indirectly activated C-fiber neurons during VNS. Elevated spontaneous spiking was quantitatively much higher than synchronized activity and extended well into the periods of nonstimulation. Surprisingly, many polysynaptic NTS neurons responded to half the bradycardic intensity used in clinical studies, indicating that a subset of myelinated vagal afferents is sufficient to evoke VNS indirect activation. Our study uncovered a myelinated vagal afferent drive that indirectly activates NTS neurons and thus central pathways beyond NTS and support reconsideration of brain contributions of vagal afferents underpinning of therapeutic impacts. Acute vagus nerve stimulation elevated activity in neurons located in the medial nucleus of the solitary tract. Such stimuli directly activated only myelinated vagal afferents but indirectly activated a subpopulation of second- and higher-order neurons, suggesting that afferent mechanisms and central neuron activation may be responsible for vagus nerve stimulation efficacy.

Capsaicin Enhances Glutamatergic Synaptic Transmission to Neonatal Rat Hypoglossal Motor Neurons via a TRPV1-Independent Mechanism

“…HMNs receive strong glutamatergic inputs from several regions, including respiratory central drive from Dbx1 positive interneurons in the reticular formation (Koizumi et al, 2008 ; Revill et al, 2015 ). It is likely that these last order premotor interneurons also integrate inputs from vagal afferent-driven NTS neurons (Bailey et al, 2002 ; Bailey and Fregosi, 2006 ; Beaumont et al, 2017 ), as well as TRPV1 positive trigeminal somatosensory neurons (Cavanaugh et al, 2011 ), as in vivo studies show that respiratory rhythm drives and modulates both whisking and sniffing behaviors (Moore et al, 2013 , 2014 ). Recently, capsaicin, acting via TRPV1 receptors, has been shown to cause potent inhibition of the respiratory central pattern generator in the rhythmically active brainstem-spinal cord in vitro preparation and in plethysmographic in vivo recordings, but had no effect in a rhythmically active brainstem slice (Ren et al, 2017 ).…”

“…The coordination of HMN activity with other upper airway muscles during oral behaviors suggests that visceral and nociceptive afferent feedback are likely to modulate HMNs or their inputs (Fregosi and Ludlow, 2014 ). Pulmonary and airway vagal afferents terminate extensively on, and activate, neurons in the nucleus tractus solitarius (NTS) and area postrema (Beaumont et al, 2017 ); these central neurons then project directly or indirectly to HMNs (Travers and Norgren, 1983 ; Bailey and Fregosi, 2006 ) (Figure 1A ). One distinguishing property of many vagal afferents is expression of the transient receptor potential vanilloid type 1 (TRPV1) receptor (Doyle et al, 2002 ; Hermes et al, 2016 ), a calcium permeable non-selective cation channel that is activated by the vanilloid capsaicin (Caterina et al, 1997 ; Messeguer et al, 2006 ), acidic pH (<6) (Tominaga et al, 1998 ), heat (Caterina et al, 1997 ) or membrane depolarization (Voets et al, 2004 ).…”

“…Moreover, capsaicin has also been reported to modulate synaptic transmission to an adjacent brainstem structure, the dorsal motor nucleus of the vagus (DMVs) (Xu and Smith, 2015 ) via a pre-synaptic mechanism. Most recently, capsaicin has been shown to modulate central respiratory rhythmic activity in medullary brain slices (Beaumont et al, 2017 ). However, the direct effects of capsaicin on synaptic inputs to HMNs have not been reported.…”

Improving the quality of neurosteroid induced anaesthesia in rodents

“…HMNs receive strong glutamatergic inputs from several regions, including respiratory central drive from Dbx1 positive interneurons in the reticular formation (Koizumi et al, 2008;Revill et al, 2015). It is likely that these last order premotor interneurons also integrate inputs from vagal afferent-driven NTS neurons (Bailey et al, 2002;Bailey & Fregosi, 2006;Beaumont et al, 2017), as well as TRPV1…”

“…Interestingly, NTS and area posterma receive pulmonary and airway vagal afferents (Beaumont et al, 2017), which show expression of the TRPV1 receptors (Doyle et al, 2002;Hermes et al, 2016). Although, TRPV1 expression is reported in several brain structures, including cortex, dentate gyrus, hypothalamus, thalamus, trigeminal somatosensory neurons and spinal cord (Mezey et al, 2000;Roberts et al, 2004;Cavanaugh et al, 2011), no TRPV1 expression has been reported in the hypoglossal motor nucleus.…”