Upregulation of brain-derived neurotrophic factor expression in nodose ganglia and the lower brainstem of hypertensive rats.

J Neurosci Res. 2013 Feb;91(2):220-9.

Vermehren-Schmaedick A, Jenkins VK, Hsieh HY, Brown AL, Page MP, Brooks VL, Balkowiec A.

Department of Integrative Biosciences, Oregon Health & Science University, Portland, Oregon 97239, USA.

Abstract

Hypertension leads to structural and functional changes at baroreceptor synapses in the medial nucleus tractus solitarius (NTS), but the underlying molecular mechanisms remain unknown. Our previous studies show that brain-derived neurotrophic factor (BDNF) is abundantly expressed by rat nodose ganglion (NG) neurons, including baroreceptor afferents and their central terminals in the medial NTS. We hypothesized that hypertension leads to upregulation of BDNF expression in NG neurons. To test this hypothesis, we used two mechanistically distinct models of hypertension, the spontaneously hypertensive rat (SHR) and the deoxycorticosterone acetate (DOCA)-salt rat. Young adult SHRs, whose blood pressure was significantly elevated compared with age-matched Wistar-Kyoto (WKY) control rats, exhibited dramatic upregulation of BDNF mRNA and protein in the NG. BDNF transcripts from exon 4, known to be regulated by activity, and exon 9 (protein-coding region) showed the largest increases. Electrical stimulation of dispersed NG neurons with patterns that mimic baroreceptor activity during blood pressure elevations led to increases in BDNF mRNA that were also mediated through promoter 4. The increase in BDNF content of the NG in vivo was associated with a significant increase in the percentage of BDNF-immunoreactive NG neurons. Moreover, upregulation of BDNF in cell bodies of NG neurons was accompanied by a significant increase in BDNF in the NTS region, the primary central target of NG afferents. A dramatic increase in BDNF in the NG was also detected in DOCA-salt hypertensive rats. Together, our study identifies BDNF as a candidate molecular mediator of activity-dependent changes at baroafferent synapses during hypertension.

Copyright © 2012 Wiley Periodicals, Inc.

PMID: 23172808

Agnieszka Balkowiec-1

Changes in arterial blood pressure are signaled to the brain by nerve cells called baroreceptors. In our earlier study (Journal of Neurochemistry 108: 450-464, 2009), we found that baroreceptors synthesize a molecule called brain-derived neurotrophic factor (BDNF), known to be critically important for the development and plasticity of the nervous system. The study revealed that BDNF is also present at the central end of baroreceptors in the brainstem nucleus tractus solitarius (NTS), where they connect to second-order neurons in the cardio-respiratory control pathway. Moreover, we found that stimulation of nerve cells, with patterns that mimic the baroreceptor activity during an increase in blood pressure, leads to release of BDNF.

In the current study, we used two distinct rat models of hypertension to examine BDNF levels in baroreceptors and other nerve cells involved in the cardio-respiratory regulation. Consistent with our previous study, we found that production of BDNF in cardio-respiratory nerve cells increases dramatically during hypertension, both in neuronal cell bodies and their central terminals in the brainstem NTS. To our knowledge, this is the first study to link BDNF and high blood pressure.

We are now able to knock down BDNF in the blood pressure control system and can move toward answering the next critical question: Does BDNF contribute to development of hypertension, or does it provide a compensatory mechanism counteracting those that lead to hypertension?

We believe that our findings have potential implications for the prevention and treatment of high blood pressure, which affects about one in three adults in the United States.

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