Blockade of Neuropeptide Y Y1 Receptors in the Dorsomedial Hypothalamus Increases Sympathetic Nerve Activity via Projections to the Hypothalamic Paraventricular Nucleus

Abstract

Arcuate Neuropeptide Y (NPY) neurons tonically suppress basal sympathetic nerve activity (SNA) via binding of NPY to NPY Y1 receptors (NPY1R) in the hypothalamic paraventricular nucleus (PVN) and the dorsomedial hypothalamus (DMH). Projection targets of PVN pre‐sympathetic neurons that are inhibited by NPY include the rostral ventrolateral medulla. However, the downstream targets of DMH NPY‐receptive neurons are unknown. Because DMH neurons send a major projection to the PVN, we hypothesized that the PVN is one target. To test this hypothesis, male Npy1r‐cre mice (n=2) received unilateral DMH injections of an adeno‐associated virus, which allows for the cre‐dependent expression of a fluorescent protein (mCherry) in the cell bodies and axon fibers of NPY1R‐containing neurons. After about two weeks, the animals were sacrificed, and their brains were immunohistochemically processed to enhance the mCherry signal. In support of our hypothesis, we identified an abundance of mCherry‐labeled fibers in the PVN. A second prominent projection target was the nucleus raphe pallidus, an important medullary region involved in the regulation of brown adipose tissue thermogenesis. Next, to test the physiological significance of the DMH projection to the PVN, in α‐chloralose anesthetized WT male mice (n=5), we first bilaterally injected the selective NPY1R antagonist, BIBO3304 (30 nl of 10 mM/L), into the DMH, which increased (all P<0.05) splanchnic SNA (SSNA) by 40±12% control, mean arterial pressure (MAP) from 82±5 to 97±6 mmHg, and heart rate (HR) from 449±35 to 554±29 bpm. After 15 min, the inhibitory GABAA agonist, muscimol (30 nL of 1 mM/L), was injected bilaterally into the PVN and reversed the effects of DMH BIBO3304: SSNA decreased to 112±7 % control, MAP to 83±7 mmHg, and HR to 471±25 bpm. In conclusion, NPY tonically inhibits DMH pre‐sympathetic neurons that express NPY1R and project to the PVN.Support or Funding InformationHL128181; APS/Hearst UGSRFThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.