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Selective activation of agouti‐related protein neurons rapidly decreases arterial pressure and sympathetic nerve activity in mice (682.4)
Author(s) -
Shi Zhigang,
Brooks Virginia
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.682.4
Subject(s) - medicine , endocrinology , neuropeptide y receptor , chemistry , population , rostral ventrolateral medulla , receptor , neuropeptide , biology , heart rate , blood pressure , environmental health
In addition to stimulating food intake, Neuropeptide Y (NPY) acts in the hypothalamic paraventricular nucleus (PVN) to decrease sympathetic nerve activity (SNA) and arterial pressure (AP). PVN NPY inputs arise from the brainstem and the arcuate nucleus (ArcN), with the latter population co‐expressing agouti‐related protein (AgRP). However, whether ArcN AgRP/NPY neurons are sympathoinhibitory is unknown. To test this hypothesis, we employed designer receptors exclusively activated by designer drugs (DREADD) technology to specifically activate ArcN NPY/AgRP neurons in mice. In this approach, mutated stimulatory muscarinic receptors (hM3Dq) are insensitive to endogenous ligands, but following binding of the otherwise inert ligand, Clozapine‐N‐oxide (CNO), depolarize neurons. Cre‐recombinase‐dependent adeno‐associated virus (AAV)‐hM3Dq‐mCherry was nanoinjected bilaterally into the ArcN of AgRP‐Ires‐cre mice (AgRP‐Cre mice). After ~2 weeks, to functionally confirm AgRP neuronal hM3Dq expression, AgRP‐Cre mice (n=5) received ip injections of CNO (0.3 mg/kg), to activate AgRP neurons, or on another day, ip saline. After 4 hr, compared to ip saline, ip CNO increased food intake (0.95±0.07 g, CNO; 0.59±0.07 g, saline; P<0.05) and body weight (change in body weight: 0.23±0.1 g, CNO; ‐0.38±0.07 g, saline; P<0.05). Next, in AgRP‐Cre α‐chloralose‐anesthetized mice (n=3), ip CNO rapidly decreased mean AP (MAP; ‐14.1±0.3 mmHg; P<0.05), heart rate (HR; ‐42±4 bpm; P<0.05) and splanchnic SNA (SSNA; ‐41±2% control; P<0.05), and these effects were sustained for at least 1 hr; ip saline had no effects. In WT mice, neither saline nor CNO significantly altered MAP, HR or SSNA. In conclusion, direct activation of ArcN AgRP/NPY neurons is sufficient to decrease SNA, HR and MAP. Grant Funding Source : Supported by HL088552 and AHA.