The research proposed here will provide new information regarding the CNS autonomic circuits that regulate cardiovascular functions. The grant is focused on the nucleus tractus solitarius (NTS) of the rat, in particular, and we will analyze the anatomical connections and functional responses of a newly discovered group of aldosterone- and sodium-sensitive neurons. There neurons co-express both mineralocorticoid receptors and 11 2-hydroxysteroid dehydrogenase type 2 (HSD2) - the critical enzyme that permits aldosterone to bind selectively to mineralocorticoid receptors. The proposed studies are designed to evaluate the central sites that project to these neurons, and establish the putative neurotransmitter systems that regulate them. These include the analysis of inputs from the hypothalamus and selected forebrain sites. In addition, the organization of vagal inputs to the HSD2 neurons will be studied in order to determine the peripheral origin of this innervation. The HSD2 neurons have been hypothesized to be the key neural elements driving salt appetite, and another one of the objectives is to map the efferent connections of one of its major relay sites in the dorsolateral pons called the pre-locus coeruleus nucleus. Another study is designed to generate transgenic rats for conditional cell ablation experiments in which the HSD2-containing of the NTS neurons will be selectively destroyed with diphtheria toxin, and then, these rats will be tested for salt and water intake. The long-term goal of this research is to establish a better understanding of the central sites involved in blood pressure regulation, including gaining new insights into the central pathways which function in sodium homeostasis.

Public Health Relevance

The brain regulates vital functions, including control of blood pressure and heart functions - which depend upon a wide range of feedback signals. One of the important internal bodily messages provides information about the sodium homeostasis, and since salt-induced hypertension is a significant health risk in some humans, research in this area is important. The studies presented here deal with the brain circuits controlling salt intake, and will provide new insights into the brain pathways which control sodium balance and ultimately, central regulation of the cardiovascular system.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
Program Officer
Thrasher, Terry N
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Washington University
Schools of Medicine
Saint Louis
United States
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Miller, Rebecca L; Denny, George O; Knuepfer, Mark M et al. (2015) Blockade of ENaCs by amiloride induces c-Fos activation of the area postrema. Brain Res 1601:40-51
Miller, Rebecca L; Loewy, Arthur D (2014) 5-HT neurons of the area postrema become c-Fos-activated after increases in plasma sodium levels and transmit interoceptive information to the nucleus accumbens. Am J Physiol Regul Integr Comp Physiol 306:R663-73
Miller, Rebecca L; Wang, Michelle H; Gray, Paul A et al. (2013) ENaC-expressing neurons in the sensory circumventricular organs become c-Fos activated following systemic sodium changes. Am J Physiol Regul Integr Comp Physiol 305:R1141-52
Miller, Rebecca L; Loewy, Arthur D (2013) ENaC ýý-expressing astrocytes in the circumventricular organs, white matter, and ventral medullary surface: sites for Na+ regulation by glial cells. J Chem Neuroanat 53:72-80
Miller, R L; Knuepfer, M M; Wang, M H et al. (2012) Fos-activation of FoxP2 and Lmx1b neurons in the parabrachial nucleus evoked by hypotension and hypertension in conscious rats. Neuroscience 218:110-25
Miller, R L; Stein, M K; Loewy, A D (2011) Serotonergic inputs to FoxP2 neurons of the pre-locus coeruleus and parabrachial nuclei that project to the ventral tegmental area. Neuroscience 193:229-40
Shin, Jung-Won; Geerling, Joel C; Stein, Matthew K et al. (2011) FoxP2 brainstem neurons project to sodium appetite regulatory sites. J Chem Neuroanat 42:1-23
Geerling, Joel C; Stein, Matthew K; Miller, Rebecca L et al. (2011) FoxP2 expression defines dorsolateral pontine neurons activated by sodium deprivation. Brain Res 1375:19-27
Geerling, Joel C; Shin, Jung-Won; Chimenti, Peter C et al. (2010) Paraventricular hypothalamic nucleus: axonal projections to the brainstem. J Comp Neurol 518:1460-99
Stein, Matthew K; Loewy, Arthur D (2010) Area postrema projects to FoxP2 neurons of the pre-locus coeruleus and parabrachial nuclei: brainstem sites implicated in sodium appetite regulation. Brain Res 1359:116-27

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