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HSD2 neurons are a small group of
neurons A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
in the
brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is cont ...
which are uniquely sensitive to the mineralocorticosteroid hormone
aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...
, through expression of HSD11B2. They are located within the caudal
medulla oblongata The medulla oblongata or simply medulla is a long stem-like structure which makes up the lower part of the brainstem. It is anterior and partially inferior to the cerebellum. It is a cone-shaped neuronal mass responsible for autonomic (involun ...
, in the
nucleus of the solitary tract In the human brainstem, the solitary nucleus, also called nucleus of the solitary tract, nucleus solitarius, and nucleus tractus solitarii, (SN or NTS) is a series of purely sensory nuclei (clusters of nerve cell bodies) forming a vertical column ...
(NTS). HSD2 neurons are activated during a prolonged deficit in body sodium or fluid volume, as occurs after dietary sodium deprivation or during frank hypovolemia. They are also activated by supraphysiologic stimulation of the
mineralocorticoid receptor The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the ''NR3C2'' gene that is located on chromosome 4q31 ...
. They are inactivated when salt is ingested. To date, HSD2 neurons have been identified and studied only in rats and mice.


Basic characteristics

The term "HSD2 neurons" is used in the scientific literature to refer to a subpopulation of neurons in the NTS which express both the
mineralocorticoid receptor The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the ''NR3C2'' gene that is located on chromosome 4q31 ...
(MR) and 11-beta-hydroxysteroid dehydrogenase type 2 (HSD2). HSD2 is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that metabolizes
cortisol Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...
and other glucocorticosteroids, which typically prevent aldosterone from binding to the mineralocorticoid receptor. This pre-receptor mechanism for modifying
hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
binding is necessary for cellular sensitivity to aldosterone because, under physiologic conditions, cortisol circulates at 100-1000 times higher concentrations than aldosterone. As both cortisol and aldosterone bind the mineralocorticoid receptor with equal affinity, cortisol effectively crowds out aldosterone in cells without abundant HSD2. In cells with HSD2, however, aldosterone has increased access to the MR, such that increases and decreases in the circulating concentration of this hormone will produce a change in receptor activity. In HSD2 neurons (and all other cells that express both HSD2 and MR), aldosterone binds to MR and translocates it from the cytoplasm to the nucleus, causing transcriptional changes. Unlike aldosterone-sensitive cells in epithelial tissues (e.g. in the kidney), the physiologic effects of aldosterone-MR activation in HSD2 neurons are unknown. It has been suggested, but not proven, that aldosterone promotes the firing activity of these neurons. Aldosterone is not necessary for HSD2 neuron activation because this can be evoked by sodium deprivation even in rats without
adrenal glands The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which ...
, which are the exclusive source of circulating aldosterone. HSD2 neurons express the transcription factor
Phox2b PHOX was an American six-piece alternative folk / indie pop band from Baraboo, Wisconsin. Active from 2011 until 2017, they released their self-titled debut LP on June 24, 2014. History Prior to the formation of PHOX, many eventual members col ...
. This means that HSD2 neurons probably release the excitatory transmitter glutamate onto their synaptic target neurons, as all Phox2b-expressing neurons in the NTS express the vesicular glutamate transporter
VGlut2 Glutamate transporters are a family of neurotransmitter transporter proteins that move glutamate – the principal excitatory neurotransmitter – across a membrane. The family of glutamate transporters is composed of two primary subclasses: the ex ...
. HSD2 neurons do not produce a wide array of other proteins that typify most other subtypes of NTS neurons, including
tyrosine hydroxylase Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and t ...
, choline acetyltransferase,
nitric oxide synthase Nitric oxide synthases () (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and perista ...
,
cholecystokinin Cholecystokinin (CCK or CCK-PZ; from Greek ''chole'', "bile"; ''cysto'', "sac"; ''kinin'', "move"; hence, ''move the bile-sac (gallbladder)'') is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and ...
,
neurotensin Neurotensin is a 13 amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactin release and has significant interaction with the dopaminergic system. Neurotensin was first isolated from extracts of bovine h ...
,
neuropeptide FF NPFF Neuropeptide FF (FLFQPQRFa) is a mammalian amidated neuropeptide originally isolated from bovine brain and characterized as a pain-modulating peptide, with anti-opioid activity on morphine-induced analgesia. In humans, Neuropeptide FF pepti ...
,
substance P Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) and a member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its clos ...
,
somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-couple ...
, inhibin-β,
glucagon-like peptide-1 Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certa ...
,
corticotropin-releasing hormone Corticotropin-releasing hormone (CRH) (also known as corticotropin-releasing factor (CRF) or corticoliberin; corticotropin may also be spelled corticotrophin) is a peptide hormone involved in stress (biology), stress responses. It is a releasing ...
,
dynorphin Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, a ...
,
calretinin Calretinin, also known as calbindin 2 (formerly 29 kDa calbindin), is a calcium-binding protein involved in calcium signaling. In humans, the calretinin protein is encoded by the ''CALB2'' gene. Function This gene encodes an intracellular ca ...
, and
calbindin Calbindins are three different calcium-binding proteins: calbindin, calretinin and S100G. They were originally described as vitamin D-dependent calcium-binding proteins in the intestine and kidney in the chick and mammals. They are now classi ...
. A small number of HSD2 neurons (less than 2%) may express the neuropeptide
galanin Galanin is a neuropeptide encoded by the ''GAL'' gene, that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors. Much of galanin's function ...
. Their lack of expression of the aforementioned markers suggests that HSD2 neurons form a unique subpopulation within the NTS. To date, there is no information available about the electrophysiologic characteristics of these neurons.


Input and output connections

The efferent projections (axonal output) of HSD2 neurons have been investigated to a significant degree using conventional neuroanatomical tracers. Their primary output targets are the pre-locus coeruleus (pre-LC), the innermost portion of the external lateral parabrachial subnucleus (PBel), and the anterior, ventrolateral
bed nucleus of the stria terminalis The stria terminalis (or terminal stria) is a structure in the brain consisting of a band of fibers running along the lateral margin of the ventricular surface of the thalamus. Serving as a major output pathway of the amygdala, the stria termina ...
(BSTvl). The next-order input and output connections of these target regions have been investigated in detail as well. Additional information about the efferent projections of HSD2 neurons can be found in ref. Regarding the afferent (input) connections to HSD2 neurons, available information is less complete. Experiments with conventional tracers and
immunofluorescence Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on microbiological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specif ...
staining have demonstrated peripheral viscerosensory input from the
vagus nerve The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and right ...
, input from nearby neurons in the NTS and area postrema, and descending input from the medial
central nucleus of the amygdala The central nucleus of the amygdala (CeA or aCeN) is a nucleus within the amygdala. It "serves as the major output nucleus of the amygdala and participates in receiving and processing pain information." CeA "connects with brainstem areas that con ...
(CeA) and
paraventricular hypothalamic nucleus The paraventricular nucleus (PVN, PVA, or PVH) is a nucleus in the hypothalamus. Anatomically, it is adjacent to the third ventricle and many of its neurons project to the posterior pituitary. These projecting neurons secrete oxytocin and a smaller ...
(PVN). It is likely that other sources of input exist, but a comprehensive study of HSD2 neuron afferent connections has not been conducted.


HSD2 neuron activity

An immediate-early gene,
c-fos Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the ''FOS'' gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Jinkin ...
, has been used to study the activation and inactivation of HSD2 neurons extensively
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
. The presence of nuclear c-Fos implies recent, elevated neuronal activity, and c-Fos disappears after neurons become quiescent. Very few HSD2 neurons exhibit any c-Fos in a normal animal. If, however, sodium is removed from the diet for several days to a week, most HSD2 neurons become c-Fos-positive. Then, if salty food is eaten or a concentrated saline solution is imbibed, their c-Fos disappears. Several other experimental conditions that reduce extracellular fluid volume—including PEG-hypovolemia,
diuresis Diuresis () is increased urination (polyuria) or, in the related word senses more often intended, the physiological process that produces such an increase or the administration of medications to encourage that process. It involves extra urine pro ...
, and
adrenalectomy Adrenalectomy (Latin root Ad "near/at" + renal "related to the kidneys" + Greek '' ‑ectomy'' “out-cutting”; sometimes written as ADX for the procedure or resulting state) is the surgical removal of one (unilateral) or both (bilateral) adren ...
—also activate HSD2 neurons, although none do so to as great an extent as simply removing sodium from the diet. All of these conditions, with the exception of adrenalectomy, cause a large elevation of circulating aldosterone. Correspondingly, repeated administration of the mineralocorticosteroid hormone deoxycorticosterone acetate (DOCA) produces a moderate increase in HSD2 neuron activity (c-Fos) without any sodium or volume deficit. However, even after adrenalectomy, HSD2 neurons become activated by sodium deprivation, proving that MR activation is not necessary for their activity. Thus, aldosterone may be sufficient, but is not necessary for their activation, meaning that these neurons integrate additional neural or hormonal input signals. All of the aforementioned manipulations which activate HSD2 neurons also produce sodium appetite in rats. If sodium-deprived rats are allowed access to salt, they imbibe a large quantity of it, and soon afterwards their HSD2 neurons are inactivated (they exhibit little or no c-Fos within 1–2 hours). This phenomenon of salt-intake-induced inactivation also occurs after sodium appetite and HSD2 neuron activation are produced by DOCA, which does not produce any sodium or volume deficit. Thus, HSD2 neuron inactivation by salt intake does not reflect simply the repletion of a physiologic deficit, and may instead reflect active inhibition triggered by salt ingestion. The exact mechanism for this inhibition remains unknown. An interesting and unique feature of HSD2 neuron activity is that they are not activated by several stimuli that produce pronounced c-Fos activation in most other neurons in the NTS. These stimuli include severe dehydration induced by hypertonic saline administration, salt ingestion (above), and changes in blood pressure. Thus, HSD2 neurons ''are'' selectively activated by conditions which do not significantly affect surrounding NTS neurons, and they are ''not'' stimulated (or are actively inhibited) by conditions that do prominently activate most other NTS neurons.


HSD2 neuron functions

The close association between sodium deprivation and HSD2 neuron activation—and between salt ingestion and HSD2 neuron ''in''activation—led to the suggestion that these neurons are important for driving sodium appetite. Other functional roles have been hypothesized. For discussion, see reviews in and. At present, however, no data exist to show whether these neurons are necessary or sufficient for any particular neurologic or physiologic function.


References

{{Nervous tissue Neurons Brainstem