Fos expression in neurons of the rat vestibulo-autonomic pathway activated by sinusoidal galvanic vestibular stimulation.

Gay R Holstein,Bernard Cohen,Dmitri Ogorodnikov,Giorgio P Martinelli,Sergei B Yakushin,Victor L Friedrich

doi:10.3389/fneur.2012.00004

Abstract

The vestibular system sends projections to brainstem autonomic nuclei that modulate heart rate and blood pressure in response to changes in head and body position with regard to gravity. Consistent with this, binaural sinusoidally modulated galvanic vestibular stimulation (sGVS) in humans causes vasoconstriction in the legs, while low frequency (0.02–0.04 Hz) sGVS causes a rapid drop in heart rate and blood pressure in anesthetized rats. We have hypothesized that these responses occur through activation of vestibulo-sympathetic pathways. In the present study, c-Fos protein expression was examined in neurons of the vestibular nuclei and rostral ventrolateral medullary region (RVLM) that were activated by low frequency sGVS. We found c-Fos-labeled neurons in the spinal, medial, and superior vestibular nuclei (SpVN, MVN, and SVN, respectively) and the parasolitary nucleus. The highest density of c-Fos-positive vestibular nuclear neurons was observed in MVN, where immunolabeled cells were present throughout the rostro-caudal extent of the nucleus. c-Fos expression was concentrated in the parvocellular region and largely absent from magnocellular MVN. c-Fos-labeled cells were scattered throughout caudal SpVN, and the immunostained neurons in SVN were restricted to a discrete wedge-shaped area immediately lateral to the IVth ventricle. Immunofluorescence localization of c-Fos and glutamate revealed that approximately one third of the c-Fos-labeled vestibular neurons showed intense glutamate-like immunofluorescence, far in excess of the stain reflecting the metabolic pool of cytoplasmic glutamate. In the RVLM, which receives a direct projection from the vestibular nuclei and sends efferents to preganglionic sympathetic neurons in the spinal cord, we observed an approximately threefold increase in c-Fos labeling in the sGVS-activated rats. We conclude that localization of c-Fos protein following sGVS is a reliable marker for sGVS-activated neurons of the vestibulo-sympathetic pathway.

Highlights

The family of immediate early genes has over 40 members, including c-fos, c-jun, and c-myc
SINUSOIDAL galvanic vestibular stimulation (GVS) We recently reported that binaural sinusoidally modulated galvanic vestibular stimulation (sGVS) can cause a sudden reduction in blood pressure and heart rate in anesthetized rats (Cohen et al, 2011)
These induced vasovagal-like responses have two components, a transient drop in blood pressure that spontaneously recovers over several minutes and oscillations in blood pressure and heart rate that occur at twice the frequency of stimulation

Summary

Introduction

The family of immediate early genes has over 40 members, including c-fos, c-jun, and c-myc. The protein product of c-fos activation, c-Fos, is transported to the cell nucleus, where it dimerizes with members of the Jun protein family to form activator protein (AP)-1 transcriptional complexes. Such complexes, in turn, participate in the subsequent regulation of target (late) gene expression (for reviews, see Morgan and Curran, 1991; Hughes and Dragunow, 1995; Durchdewald et al, 2009). Since induction of c-fos mRNA and accumulation of c-Fos protein can occur trans-synaptically, it is possible to identify functionally related neurons at multiple stages along neural pathways of interest (Dragunow and Faull, 1989). While the extended period of c-Fos protein accumulation precludes the possibility of identifying sequential synaptic connections based on temporal dissection, as is done with viral vector www.frontiersin.org

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