The baroreflex is a homeostatic feedback pathway responsible for maintaining stable blood flow to the brain. Baroreceptor signals are conveyed to the solitary nucleus and then to the caudal ventrolateral medulla (CVLM). The CVLM sends both excitatory and GABAergic inhibitory projections to the rostral ventrolateral medulla (RVLM), which in turn provides the key input to preganglionic sympathetic neurons in the spinal cord that control sympathetic nerve activity. The baroreflex pathway is polysynaptic, has a relatively long latency, and is solely reactive, modulating vasoconstriction and heart rate in response to a prior cardiovascular vicissitude such as a change in blood pressure (BP). In contrast, the vestibulo-sympathetic reflex (VSR) mediates proactive, direct and rapid BP modulation, initiating blood redistribution in the body at the onset of movement or a postural adjustment in order to assure consistent cerebral perfusion regardless of head position. The VSR is triggered by input from the vestibular end organs, which convey signals to neurons in the caudal vestibular nuclei (VNc) that project to CVLM and/or RVLM. Activation of this pathway through VNc causes changes in sympathetic nerve activity and BP. We have recently found that there are two limbs of the VSR, one that is GABAergic and putatively inhibitory, and another that is putatively excitatory and glutamatergic. The goal of the proposed research is to determine the specific connectivity of these two chemoanatomic facets of the VSR using a novel approach to activate individual end organs. testing the overall hypothesis that the direction of BP change resulting from stimulation reflects the differential activation, connectivity and synaptology of these two main limbs of the VSR. The project takes advantage of the spatial specificity of pulsed infrared laser stimulation of the vestibular end organs in order to discretely activate individual receptor regions. We will test the hypotheses that focal stimulation restricted to the utricle or saccule activates specific chemoanatomically-defined subtypes of VSR neurons that are topographically segregated within the VNC and project primarily to either RVLM or CVLM. In addition, we will investigate the effects of combined utricular, saccular and posterior semicircular canal activation on BP mediated by the VSR. Ultrastructural studies will be conducted to confirm the detailed anatomy of this pathway. Overall, this project addresses the anatomical bases for VSR responses, and is foundational for establishing the utility and efficacy of infrared laser stimulation as a next-generation treatment for vestibulo-autonomic disorders including neurogenic orthostatic hypotension and intolerance.

Public Health Relevance

? Public Health Relevance Neurogenic orthostatic hypotension and intolerance impact a large segment of the population, particularly the elderly. This project will generate fundamental information about the vestibular projections to central cardiovascular neurons that mediate changes in blood pressure in response to movement and postural adjustments. The results will suggest new minimally invasive and pharmacological therapies to ameliorate neurogenic orthostatic hypotension and intolerance that specifically target the dysfunctional pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC008846-10
Application #
9435108
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Poremba, Amy
Project Start
2008-03-01
Project End
2022-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Neurology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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
Cohen, Bernard; Martinelli, Giorgio P; Raphan, Theodore et al. (2013) The vasovagal response of the rat: its relation to the vestibulosympathetic reflex and to Mayer waves. FASEB J 27:2564-72
Highstein, Stephen M; Holstein, Gay R (2012) The anatomical and physiological framework for vestibular prostheses. Anat Rec (Hoboken) 295:2000-9
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
Rajguru, Suhrud M; Richter, Claus-Peter; Matic, Agnella I et al. (2011) Infrared photostimulation of the crista ampullaris. J Physiol 589:1283-94
Cohen, Bernard; Yakushin, Sergei B; Holstein, Gay R (2011) What does galvanic vestibular stimulation actually activate? Front Neurol 2:90
Bozdagi, O; Wang, X B; Martinelli, G P et al. (2011) Imidazoleacetic acid-ribotide induces depression of synaptic responses in hippocampus through activation of imidazoline receptors. J Neurophysiol 105:1266-75

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