Structural and functional connectivity from the dorsomedial hypothalamus to the ventral medulla as a chronological amplifier of sympathetic outflow

Yosuke Kono,Shigefumi Yokota,Shuntaro Okazaki,Kanji Sugita,Hiroshi Onimaru,Yohei Hasebe,Masashi Yoshizawa,Yasumasa Okada,Kotaro Takeda,Isato Fukushi,Yosuke Arima,Itaru Yazawa,Takako Toda,Keiichi Koizumi,Mieczyslaw Pokorski

doi:10.1038/s41598-020-70234-4

Abstract

Psychological stress activates the hypothalamus, augments the sympathetic nervous output, and elevates blood pressure via excitation of the ventral medullary cardiovascular regions. However, anatomical and functional connectivity from the hypothalamus to the ventral medullary cardiovascular regions has not been fully elucidated. We investigated this issue by tract-tracing and functional imaging in rats. Retrograde tracing revealed the rostral ventrolateral medulla was innervated by neurons in the ipsilateral dorsomedial hypothalamus (DMH). Anterograde tracing showed DMH neurons projected to the ventral medullary cardiovascular regions with axon terminals in contiguity with tyrosine hydroxylase-immunoreactive neurons. By voltage-sensitive dye imaging, dynamics of ventral medullary activation evoked by electrical stimulation of the DMH were analyzed in the diencephalon-lower brainstem-spinal cord preparation of rats. Although the activation of the ventral medulla induced by single pulse stimulation of the DMH was brief, tetanic stimulation caused activation of the DMH sustained into the post-stimulus phase, resulting in delayed recovery. We suggest that prolonged excitation of the DMH, which is triggered by tetanic electrical stimulation and could also be triggered by psychological stress in a real life, induces further prolonged excitation of the medullary cardiovascular networks, and could contribute to the pathological elevation of blood pressure. The connectivity from the DMH to the medullary cardiovascular networks serves as a chronological amplifier of stress-induced sympathetic excitation. This notion will be the anatomical and pathophysiological basis to understand the mechanisms of stress-induced sustained augmentation of sympathetic activity.

Highlights

Psychological stress activates the hypothalamus, augments the sympathetic nervous output, and elevates blood pressure via excitation of the ventral medullary cardiovascular regions
In two rats that were most optimally injected with biotinylated dextran amine (BDA) into the dorsomedial hypothalamus (DMH), in which the BDA deposit was confined to the DMH (Fig. 3A, Supplementary Fig. 3), anterogradely BDA-labeled fibers and axon terminals were distributed bilaterally, with a clear-cut ipsilateral dominance, in the reticular formation of the medulla oblongata
We found bouton-like varicosities labeled with BDA were in close apposition to the dendrites of tyrosine hydroxylase (TH)-immunoreactive neurons (Fig. 3F–I, Supplementary Fig. 4)

Summary

Introduction

Psychological stress activates the hypothalamus, augments the sympathetic nervous output, and elevates blood pressure via excitation of the ventral medullary cardiovascular regions. The connectivity from the DMH to the medullary cardiovascular networks serves as a chronological amplifier of stress-induced sympathetic excitation This notion will be the anatomical and pathophysiological basis to understand the mechanisms of stress-induced sustained augmentation of sympathetic activity. It has been known that hypothalamic excitation activates the rostral ventrolateral medulla (RVLM), medullary raphe regions, and intermediate lateral cell column of the spinal cord, augmenting sympathetic activity, heart rate, and blood p ressure[6,7,8]. This study seeks to define the anatomical and functional connectivity from the DMH to the medulla to clarify the neural substrate mediating the propagation of stress-induced sympathetic activity and to gain insight into the pathophysiology of hypertension

Methods

Results

Conclusion