The existence of a functional link between the vestibular system and blood pressure control has been known for nearly a century. It is currently thought that arterial baroreceptors participate in a regulatory circuit that maintains sympathetic tone through the baroreflex while signals from the vestibular end organs drive a faster mechanism that counteracts the effects of a change in posture. This latter circuit is often called the vestibulo-sympathetic reflex (VSR). Primary afferents of this pathway terminate on cells in the caudal vestibular nuclear complex (VNCc). These second order neurons, in turn, project to brainstem sites involved in cardiovascular regulation such as the rostral and caudal ventrolateral medullary regions (RVLM and CVLM, respectively). Cells in the RVLM are thought to integrate the vestibular input with baroreceptor and other sensory afferents and send excitatory projections to preganglionic sympathetic neurons in the intermediolateral cell column of the spinal cord. While the principal neurotransmitter of these presympathetic vasomotor RVLM cells is likely to be glutamate, numerous neuroactive molecules have been co-localized in these cells, including catecholamines of the C1 cell group. In addition, bulbospinal vasomotor RVLM cells receive monosynaptic GABAergic projections from the CVLM, which tonically inhibit the RVLM neurons. As a result, CVLM cells can be viewed as sympathoinhibitory interneurons in the vasomotor pathway. The long-term goal of our research program is to identify the neurotransmitters, receptors, and signaling pathways that participate in vestibulo- autonomic projections so they can be targeted specifically by pharmacotherapeutics to ameliorate vestibulo- autonomic disorders. The specific objective of this research project is to identify the structural and chemical anatomy of vestibular pathways that contribute to blood pressure regulation. The project has two aims that will be pursued using rats as the experimental model, bilateral sinusoidal galvanic vestibular stimulation to activate the vestibular nuclei, telemetric detection of blood pressure, anterograde and retrograde tract-tracing, and immunofluorescence detection of the immediate early gene protein product c-Fos together with pathway- specific neurotransmitters and modulators.
Aim 1 will identify the sensitivity, topography, cytology, neurotransmitter(s), and modulator(s) of vestibular neurons of the VSR.
This aim will test the overall hypothesis that VNCc cells of the VSR pathway have a morphological, hodological and/or chemoanatomical phenotype that is distinct from other VNCc neurons and the baroreflex pathway.
Aim 2 will identify the innervation pattern(s), synaptology and postsynaptic partners of vestibulo-sympathetic axons in RVLM and CVLM.
This aim will address our over-arching hypothesis by determining the neuronal and synaptic specificity of vestibular input to pre-sympathetic vasomotor circuitry. These hypotheses are fundamental to our long-term goal, since regions or cells where the VSR pathway is morphologically or chemoanatomically segregated from the baroreflex pathway are candidate sites for specific pharmacological intervention into the VSR.

Public Health Relevance

Orthostatic hypotension and vestibular side effects of drugs targeting the sympathetic nervous system (e.g. anti-hypertensive medications) impact large populations, especially the elderly. However, remarkably little is known about the neurochemical organization of vestibulo-sympathetic pathways. This project will provide fundamental information about the structural and chemical anatomy of vestibular projections to cardiovascular neurons in the ventrolateral medulla, may suggest new drug therapies to ameliorate orthostatic hypotension and intolerance, and may lead to the development of more specific anti-hypertensive medications that do not elicit disabling vestibular side effects such as dizziness and vertigo.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-B (05))
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Platt, Christopher
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Holstein, Gay R; Friedrich Jr, Victor L; Martinelli, Giorgio P (2016) Glutamate and GABA in Vestibulo-Sympathetic Pathway Neurons. Front Neuroanat 10:7
Holstein, Gay R; Friedrich Jr, Victor L; Martinelli, Giorgio P (2016) Imidazoleacetic acid-ribotide in vestibulo-sympathetic pathway neurons. Exp Brain Res 234:2747-60
Yakushin, Sergei B; Martinelli, Giorgio P; Raphan, Theodore et al. (2014) Vasovagal oscillations and vasovagal responses produced by the vestibulo-sympathetic reflex in the rat. Front Neurol 5:37
Holstein, Gay R; Friedrich Jr, Victor L; Martinelli, Giorgio P (2014) Projection neurons of the vestibulo-sympathetic reflex pathway. J Comp Neurol 522:2053-74
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Holstein, Gay R; Friedrich Jr, Victor L; Martinelli, Giorgio P et al. (2012) Fos expression in neurons of the rat vestibulo-autonomic pathway activated by sinusoidal galvanic vestibular stimulation. Front Neurol 3:4
Cohen, Bernard; Yakushin, Sergei B; Holstein, Gay R (2012) What does galvanic vestibular stimulation actually activate: response. Front Neurol 3:148
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Cohen, Bernard; Yakushin, Sergei B; Holstein, Gay R (2011) What does galvanic vestibular stimulation actually activate? Front Neurol 2:90

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