User:Joel.geerling/Sandbox

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HSD2 neurons

Disambiguation: Aldosterone-sensitive neurons (in the nucleus of the solitary tract), Aldo-sensitive neurons, Central effects of aldosterone, Aldosterone in the brain

Basic description -located in the brainstem, specifically, near the caudal (far back) end of the dorsomedial (top-middle) medulla oblongata(link), in a specific and well-studied region called the nucleus of the solitary tract (NTS, link). -thought to be directly sensitive to the hormone(linke) aldosterone(link) -This is based on their mRNA expression and protein production of HSD11B2(link) and the mineralocorticoid receptor(link) (refs).

Discovery -Funder 1995 mRNA for 11hsd2 -Arriza/Swanson/Evans 1988 mRNA for mr -Geerling/Loewy 2006 protein-Ab labeling co-localizing HSD2 and MR -Geerling/Loewy several papers 2006-2009 identifications of some of the unique properties of HSD2 neurons, including their unusual pattern of activation with sodium/volume depletion and inactivation with salt ingestion, their afferent (input) and efferent (output) synaptic connections, and downstream activity patterns in their output circuitry. -Possible role in driving sodium appetite

Location, specifically -(brainstem --> caudal dorsomedial medulla oblongata --> NTS --> just ventral to(beneath) the area postrema(link) and the thin subpostremal subnucleus of the NTS(link--probably no article yet), spanning the interdigitated borders of NTS subnuclei referred to variously as "medial", "gelatinosa", "subpostrema", "intermediate"...) -relationship to other known subpopulations of neurons in the NTS (incl esp A2), DMV, etc.

Mechanism of action and functional effects of aldosterone in HSD2 neurons -The mineralocorticoid receptor (MR) is -The exact epigenetic(link) effects of aldosterone-MR activation on the gene expression patterns in these neurons (and in other cells) are not completely understood; for further discussion of this topic, see (links). -Furthermore, the specific effects of aldosterone on the cellular input-output functions of HSD2 neurons are not known at this time; for further discussions on the general topic of mineralocorticoid receptor activation in neurons, see (links -- incl NatNeurosci gluR trafficing, Marian Joels' work re. Ca/excitability, etc.) -Given that physiological manipulations, such as dietary sodium deprivation(link) that produce large elevations in aldosterone production also cause the neuronal acitvation of HSD2 neurons in the NTS, one hypothesis is that aldosterone acts in these neurons to somehow promote their excitability by afferent signals. There is, as yet, no direct cellular/molecular evidence to support or refute this hypothesis. Note that, whether or not aldosterone-MR trancriptional changes modulate the excitability of these neurons, aldosterone by itself does not appear to be necessary for their activation by other (as-yet unidentified) physiological stimuli because the HSD2 neurons are still activated by severe sodium/volume depletion after adrenalectomy, which eliminates aldosterone production. 

Possible role(s) of HSD2 neurons in brain function -Just discovered as a distinct group of neurons in the early 2000s -We only have preliminary details about their organization and function, most of it neuroanatomical; only crude, initial physiologic evidence is available -Even if we had great -Possibilities include (give refs) -- stimulation of sodium appetite, suppression of other appetites

Ontogeny (Growth and Development) -Phox2b-expression --> developmental implications (refs, incl Gray) and glutamatertic phenotype (ref, Stornetta Phox2b-to-VGLUT1 identity pattern) -lack of available evidence -lack of information about presence/absence/characteristics/connections in species other than rat, and to some extent, mice.

Input connections -Incomplete anatomic information (+/-vagus(Shin/Loewy), +/-PVH(Geerling/Shin/Loewy), +/-AP(Sequiera/Geerling/Loewy, ?local-NTS-circuit connections(no ev), ++CeA(Geerling/Loewy06, ?BST, other -- NOT comprehensive)

Output connections -More complete (summarize findings from 2006 JCN efferents study) -emphasis = pre-LC, PBel-i, LHA-BSTvl continuum... -link to articles on pre-LC, PBel-i (FoxP2+ neurons) and BSTvl output connections, hypothesized input-output/circuit functions, phsyiologic/pathophysiologic roles in mammals in general, humans/patients in particular...

Currently unresolved issues -necessity/sufficiency experiments -input connections, ephys -output ephys, circuit functions -?other species -?pathophysiologic roles (affording any ?therapeutic opportunities for the care of human patients)