Acute hypernatremia promotes anxiolysis and attenuates stress-induced activation of the hypothalamic-pituitary-adrenal axis in male mice.
Previous investigation by our laboratory found that acute hypernatremia potentiates an oxytocinergic tone that inhibits parvocellular neurosecretory neurons in the paraventricular nucleus of the hypothalamus (PVN), attenuates restraint-induced surges in corticosterone (CORT), and reduces anxiety-like behavior in male rats. To investigate the neural mechanisms mediating these effects and extend our findings to a more versatile species, we repeated our studies using laboratory mice. In response to 2.0M NaCl injections, mice had increased plasma sodium concentrations which were associated with a blunted rise in CORT subsequent to restraint challenge relative to 0.15M NaCl injected controls. Immunofluorescent identification of the immediate early gene product Fos found that 2.0M NaCl treatment increased the number of activated neurons producing oxytocin in the PVN. To evaluate the effect of acute hypernatremia on PVN neurons producing corticotropin-releasing hormone (CRH), we used the Cre-lox system to generate mice that produced the red fluorescent protein, tdTomato, in cells that had Cre-recombinase activity driven by CRH gene expression. Analysis of brain tissue from these CRH-reporter mice revealed that 2.0M NaCl treatment caused a dramatic reduction in Fos-positive nuclei specifically in CRH-producing PVN neurons. This altered pattern of activity was predictive of alleviated anxiety-like behavior as mice administered 2.0M NaCl spent more time exploring the open arms of an elevated-plus maze than 0.15M NaCl treated controls. Taken together, these results further implicate an oxytocin-dependent inhibition of CRH neurons in the PVN and demonstrate the impact that slight elevations in plasma sodium have on hypothalamic-pituitary-adrenocortical axis output and anxiety-like behavior.
Department of Pharmacodynamics, College of Pharmacy, University of Florida, PO Box 100487, Gainesville, FL 32611, United States. Electronic address: smith6jt@ufl.edu.
Justin A
JA
Smith
Department of Pharmacodynamics, College of Pharmacy, University of Florida, PO Box 100487, Gainesville, FL 32611, United States. Electronic address: stone0338@ufl.edu.
Lei
L
Wang
Department of Pharmacodynamics, College of Pharmacy, University of Florida, PO Box 100487, Gainesville, FL 32611, United States. Electronic address: hhiller@cop.ufl.edu.
Helmut
H
Hiller
Department of Pharmacodynamics, College of Pharmacy, University of Florida, PO Box 100487, Gainesville, FL 32611, United States. Electronic address: gator.ctaylor@gmail.com.
Christopher T
CT
Taylor
Department of Physiology and Functional Genomics, College of Medicine University of Florida, PO Box 100274, Gainesville, FL 32610, United States. Electronic address: adekloet@ufl.edu.
Annette D
AD
de Kloet
Department of Pharmacodynamics, College of Pharmacy, University of Florida, PO Box 100487, Gainesville, FL 32611, United States. Electronic address: ekrause@cop.ufl.edu.
Eric G
EG
Krause
D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006955:Hypernatremia; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D011863:Radioimmunoassay; D012149:Restraint, Physical / Q000009:adverse effects; D012964:Sodium / Q000097:blood; D012965:Sodium Chloride / Q000008:administration & dosage; D013315:Stress, Psychological / Q000097:blood / Q000209:etiology / Q000473:pathology* / Q000628:therapy*; D000097573:Red Fluorescent Protein
D003346:Corticotropin-Releasing Hormone; D008164:Luminescent Proteins; D009479:Neuropeptides; D012964:Sodium; D012965:Sodium Chloride; D000097573:Red Fluorescent Protein; C105172:CORT protein, human
Anxiety; Corticotropin-releasing-hormone; Depression; Hypernatremia; Hypertension; Oxytocin