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Cell Networks in Endocrine/Neuroendocrine Gland Function

Nathalie C. Guérineau, Pauline Campos, Paul R. Le Tissier, David J. Hodson, Patrice Mollard

10.1002/cphy.c210031

Source: Volume 12, Issue 2, April 2022

Published online: March 2022

Full Article on Wiley Online Library



Abstract

Reproduction, growth, stress, and metabolism are determined by endocrine/neuroendocrine systems that regulate circulating hormone concentrations. All these systems generate rhythms and changes in hormone pulsatility observed in a variety of pathophysiological states. Thus, the output of endocrine/neuroendocrine systems must be regulated within a narrow window of effective hormone concentrations but must also maintain a capacity for plasticity to respond to changing physiological demands. Remarkably most endocrinologists still have a “textbook” view of endocrine gland organization which has emanated from 20th century histological studies on thin 2D tissue sections. However, 21st‐century technological advances, including in‐depth 3D imaging of specific cell types have vastly changed our knowledge. We now know that various levels of multicellular organization can be found across different glands, that organizational motifs can vary between species and can be modified to enhance or decrease hormonal release. This article focuses on how the organization of cells regulates hormone output using three endocrine/neuroendocrine glands that present different levels of organization and complexity: the adrenal medulla, with a single neuroendocrine cell type; the anterior pituitary, with multiple intermingled cell types; and the pancreas with multiple intermingled cell types organized into distinct functional units. We give an overview of recent methodologies that allow the study of the different components within endocrine systems, particularly their temporal and spatial relationships. We believe the emerging findings about network organization, and its impact on hormone secretion, are crucial to understanding how homeostatic regulation of endocrine axes is carried out within endocrine organs themselves. © 2022 American Physiological Society. Compr Physiol 12:3371‐3415, 2022.

Figure 1. Figure 1. Compared anatomical organization of the endocrine/neuroendocrine cells within the secretory tissue. (A) Lobular organization of the chromaffin cell tissue within the rat adrenal medulla. Left picture, Bodian silver‐stained nerve fibers in acute slices. Dashed lines delineate lobules. Based on Kajiwara R, et al., 1997 205. Right picture, clusters of TH immunoreactive chromaffin cells. Kajiwara R, et al., 1997 205 with permission of John Wiley & Sons, Inc./CC BY 3.0. (B) Organization of the mammalian anterior pituitary. Schematic of a hemi‐anterior pituitary showing the preferential organization of the five hormone‐secreting cell types. (C) The endocrine pancreas is a multiunit structure, where upward of a million islets are diffusely scattered throughout the parenchyma. Each human islet of Langerhans is a self‐contained endocrine unit, comprising a number of cell types that secrete hormones involved in glucose homeostasis and other facets of metabolism. Images adapted from Servier Medical Art under a CC‐BY licence (https://creativecommons.org/licenses/by/3.0/).
Figure 2. Figure 2. Slice tissue preparations for studying endocrine/neuroendocrine function. (A) Acute pituitary slice and imaging methods to study pituitary cells in situ. (a) Acute slice preparation. The pituitary gland is immobilized within a droplet of ultra‐low temperature gelling agarose, before cutting at low temperature (1–4°C) with a vibrating microtome blade. (b) Imaging of pituitary cells in situ. Pituitary cells within an acute pituitary slice are imaged with two‐photon excitation microscopy (horizontal red lines). (c) Image deconvolution and 3D reconstruction of image stacks help to view the three‐dimension organization of fluorescent cells in the pituitary tissue. Fauquier T, et al., 2002 125 with permission of Elsevier. (B) Organotypic culture of a rat anterior pituitary gland, according to the roller tube technique described by Gahwiler 140. Measurement of prolactin secretion by radioimmunoassay in a 4 week‐old culture treated either with forskolin to increase hormone release or with the dopaminergic agonist bromocriptine (CB‐154) to inhibit PRL release. Guerineau NC, et al., 1997 161 with permission of Elsevier. (C) Organotypic co‐culture of mouse thoracic spinal cord and hemisectioned adrenal gland (roller tube technique, 42 days in vitro). Chromaffin cells still express the biosynthetic enzyme TH, exhibit spontaneous action potentials and spontaneous postsynaptic excitatory currents (patch‐clamp recordings). The thoracic spinal cord also exhibits spontaneous synaptic currents.
Figure 3. Figure 3. Ex vivo tissue and whole organ preparations for studying endocrine/neuroendocrine function. (A) Ex vivo preparation of the pancreas. (a) Procedure for mouse pancreas perfusion and removal. From Li DS, et al., 2009 238. (b) Islets (∼40–80) are perifused with buffer containing various glucose concentrations or generic depolarizing stimulus (KCl). Insulin secreted into the perfusate is assayed for insulin over a number of timepoints, revealing first and second‐phase responses. Adapted from Li DS, et al., 2009 238 and from Servier Medical Art under a CC‐BY licence (https://creativecommons.org/licenses/by/3.0/). (B) Ex vivo rat spinal cord‐splanchnic nerve‐adrenal gland preparation. (a) Ventral view of the thoracic section isolated from the animal. (b) Schematic representation helping to identify the various tissue components of the preparation. Wolf K, et al., 2016 455 with permission of John Wiley & Sons/Licensed under CC BY 4.0. (c) Experimental protocol to assess catecholamine secretion. The splanchnic nerve is electrically stimulated by a cuff electrode (CE). Catecholamine release is monitored by cyclic voltammetry with a carbon fiber electrode (FE) positioned at proximity of the medullary tissue (AM), which was unmasked after gland hemisection. Wolf K, et al., 2016 455 with permission of John Wiley & Sons, Inc./CC BY 4.0. (C) Ex vivo tissue preparations preserving the connections between the pituitary gland and the brain in the fish. (a) Use of a hypothalamus‐pituitary slice to monitor Lucifer yellow diffusion between pituitary cells in the teleost fish Oreochromis niloticus. Levavi‐Sivan B, et al., 2005 235 with permission of Oxford University Press. (b) Gonadotropin‐releasing hormone (GnRH)‐triggered cytosolic calcium rises imaged in fura‐2‐loaded gonadotrophs from a whole brain‐pituitary preparation of the teleost fish Oryzias latipes. From Karigo T, et al., 2014 208.
Figure 4. Figure 4. In vivo monitoring of the activity of endocrine/neuroendocrine cells. (A) Cellular in vivo imaging of the pituitary gland in fluorescent protein‐tagged transgenic mice with long‐range microscopy. (a) Schematics of the experimental arrangement. An air‐transmission 20x magnification objective with 2.8 cm working distance is fitted on a fluorescent microscope, equipped with a variable light beam excitation and an EM‐CDD camera acquisition setup. It allows real‐time in vivo imaging with adaptive final magnification (8–800x) of the ventral side of the pituitary gland is exposed in an anesthetized mouse after removal of the palate bone. (b) Fluorescent image (λex 488 nm) of the open palate bone of a GH‐eGFP mouse. Lafont C, et al., 2010 224 with permission of Proceedings of the National Academy of Science PNAS. (c) Schematic shows the arrangement of calcium imaging in head‐fixed animals injected with AAV5‐CAG‐GCAMP6s particles into the pituitary. (d) Field of GCAMP6s cells viewed from the dorsal pituitary side with the selection of cells as regions of interest (ROIs) shown in colored circles. Hoa O, et al., 2019 176 with permission of Oxford University Press. (e) Coordinated calcium spikes recorded in the cells shown in (d). (c,e) From Hoa O, et al., 2019 176. (B) In vivo extracellular recording of spontaneous chromaffin cell electrical activity in an anesthetized mouse, illustrated by the occurrence of both individual spikes (a, left inset) and bursting activities (a, right inset). (b) The electrical firing is reversibly abolished by a local application of the voltage‐gated Na+ channel blocker TTX on the splanchnic nerve. (c) Reversible decrease of the nerve stimulation‐evoked electrical activity in the presence of the nicotinic acetylcholine receptor antagonist hexamethonium. From Desarmenien MG, et al., 2013 101. (C) In vivo approach enabling simultaneous stimulation of the splanchnic nerve and adrenal venous blood collection in anesthetized mouse. After laparotomy, the left adrenal gland is uncovered and the renal vein and the conjonctive tissue containing the splanchnic nerve are isolated. The splanchnic nerve is placed on a bipolar stimulation electrode. The renal vein is ligated on both the kidney and vena cava sides to form a reservoir in which a heparinized catheter is implanted. Adrenal venous blood samples are collected before and during splanchnic nerve stimulation. Assay of catecholamine by ELISA shows that E and NE are secreted in a stimulus frequency‐dependent manner. From Desarmenien MG, et al., 2013 101.
Figure 5. Figure 5. Monitoring of hormone release in individual endocrine/neuroendocrine cells. (A) Amperometry‐based measurement of catecholamine secretion in rat acute adrenal slices. Catecholamine release is evoked by an iontophoretic application of the cholinergic agonist nicotine. (B) Use of the fluorescent probe FFN511 accumulated in secretory granules to track exocytosis in a mouse chromaffin cell. Individual granules are imaged by total internal reflection fluorescence microscopy. In response to high K+‐containing saline (dotted line), the fluorescence quickly decreases, reflecting granule exocytosis. Gubernator NG, et al., 2009 154 with permission of American Association for the Advancement of Science – AAAS.
Figure 6. Figure 6. Both extracellular and intracellular Ca2+ sources contribute to hormone exocytosis. Simultaneous measurement of membrane capacitance and cytosolic Ca2+ concentration [Ca2+]i in isolated endocrine/neuroendocrine cells. Representative examples of membrane capacitance increase in response to (A) a Ca2+ entry through voltage‐gated Ca2+ channels in a bovine chromaffin cell, From Augustine GJ and Neher E, 1992 21; (B) a Ca2+ entry through ligand (nicotine)‐gated ion channels in a bovine chromaffin cell, From Mollard P, et al., 1995 279; and (C) a Ca2+ release from internal stores in response to gonadotropin‐releasing hormone in an isolated rat gonadotroph, From Tse A, et al., 1993 422. Note that the source of Ca2+ engaged in exocytosis (extracellular, intracellular, or both) relies on the mode of action of each secretagogue. All mechanisms illustrated here can occur in all tissues, but unlikely to an equal extent.
Figure 7. Figure 7. Monitoring dye diffusion/transport in vivo. Schematics of the experimental arrangement. An air‐transmission 20x magnification objective with 2.8 cm working distance is fitted on a fluorescent microscope, equipped with a variable light beam excitation and an EM‐CDD camera acquisition setup. This allows real‐time in vivo imaging with adaptive final magnification (8x–800x) of the ventral side of the pituitary gland/pancreas surgically exposed in an anesthetized mouse. A jugular catheter is placed for i.v. injection and blood sampling and the pituitary/pancreas surfaces are continuously irrigated with saline through inlet and outlet tubes, respectively. Top panels: In vivo imaging of rhodamine dextran‐labeled vasculature in the pancreas (left) and pituitary gland (right).
Figure 8. Figure 8. Optogenetic control of hormonal secretion in endocrine cells. (A) Optogenetic stimulation of endocrine cells in the pituitary cells expressing optogenes after viral transfection. (a) Laser light illumination of the ventral pituitary side can be carried out in terminally anesthetized mice using a fiber optic acutely placed above the pituitary gland and connected to a laser source. Blood is sampled simultaneously using a jugular catheter or tail‐tip blood sampling. (b) Optogenetic stimulation of the pituitary cells can be carried out in awake mice in which a fiber optic has previously been chronically implanted directly above the target cells. Mice are subjected to simultaneous tail‐tip blood sampling. (c) GH pulses triggered by a train of laser blue light pulses (300‐ms pulses at 1 Hz) in vivo in GH‐Cre mice expressing ChR2 specifically in GH cells. From Hoa O, et al., 2019 176. (B) Photopharmacological modulation of insulin secretion in vivo. (a) Photopharmacology relies on endogenously expressed receptors and ion channels to optically control cell function. The fourth‐generation light‐activated sulfonylurea, JB253, converts ATP‐sensitive K+ (KATP) channels into molecular photoswitches, allowing reversible stimulation of beta‐cell function. The light‐activated sulfonylurea JB253 thus allows optical control of KATP channel activity, voltage‐dependent Ca2+ channel activity, and insulin release. (b) Schematic showing the experimental protocol for optical control of glucose homeostasis using JB253. (c) JB253 (50 mg/kg, administered per os) significantly lowers glycemia in animals exposed to blue light. Mehta ZB, et al., 2017 263 with permission of Springer Nature/Licensed under CC BY 4.0. (C) Optical modulation of stimulus‐secretion coupling in adrenal chromaffin cells. (a) Modulation of stimulus‐secretion coupling using a synthetic chemistry approach based on ruthenium diimine complexes in a RubpyC17‐loaded mouse chromaffin cells (right picture). Rohan JG, et al., 2013 340 with permission of American Chemical Society. (b) Light illumination electronically excites RubpyC17 and generates a photoexcited complex that is either an electron donor or an electron acceptor. The presence of a reductant substrate in the extracellular medium allows electron transfer from the donor to RubpyC17, generating a negative surface potential at the cell membrane, which is detected by the cell as a depolarization. Optically driven changes in the electrical activity (c) and catecholamine secretion (d) in a RubpyC17‐loaded mouse chromaffin cell. (b‐d) From Rohan JG, et al., 2013 340.
Figure 9. Figure 9. Macroscopic anatomy and innervation of rat the adrenal gland. (A) Double immunofluorescent staining of laminin (in green) which labels both the cortex and the medulla and tyrosine hydroxylase (in red) which stains the neurosecretory chromaffin cell tissue. Note the chromaffin cell organization in clusters. (B) Schematic representation of the spinal‐adrenal innervation. The preganglionic innervation synapsing onto chromaffin cells extensively occurs through a direct pathway without relaying the sympathetic chain or the suprarenal ganglion. (C) Immunofluorescent detection of nerve fibers invading the medulla with an anti‐neurofilament antibody.
Figure 10. Figure 10. Scheme of the adrenal medulla stimulus‐secretion coupling. Two interconnected pathways underlie adrenal catecholamine secretion from chromaffin cells. The master stimulus comes from ACh release by splanchnic nerve terminals synapsing onto chromaffin cells. In addition, and reinforcing or even supplanting the cholinergic synaptic neurotransmission, chromaffin cell intercellular communication mediated by gap junctions contributes to hormone release. Based on, with permission, Colomer C, et al. 2009 80; Colomer C, et al. 2012 82; Desarmenien MG, et al. 2013 101; Guerineau NC, 2018 156; Hodson DJ, et al., 2015 177; Martin AO, et al., 2001 257.
Figure 11. Figure 11. Gap junctions in the rodent chromaffin cell tissue. (A) Immunohistofluorescent detection of Cx36 in the mouse medulla. Note the punctiform labeling, representative of gap junctional plaques. (B) Lucifer yellow diffusion between gap junction‐coupled rat chromaffin cells in acute adrenal slices. The fluorescent dye was introduced into a single chromaffin cell through a patch pipette and diffused into coupled cells within a couple of minutes.
Figure 12. Figure 12. Monitoring functional gap junction‐mediated intercellular coupling by electrophysiological recordings of cell pairs. (A) Schematic representation of the dual patch‐clamp technique, used to monitor junctional currents in a chromaffin cell pair. Two adjacent cells (cell 1 and cell 2) are patch‐clamped and recorded in the current‐clamp mode. A depolarizing current step is applied to cell 1 (cell 1*) and the subsequent membrane potential changes are simultaneously monitored in both cell 1 and cell 2. (B) Cell 1 depolarization does not evoke potential changes in cell 2, indicating that the two cells are not functionally coupled by gap junctions. (C,D) Propagation of the depolarization evoked in cell 1, resulting either in a small depolarization in cell 2 (= weak electrical coupling) or in the triggering of action potentials (= robust electrical coupling). Regarding subsequent hormone secretion, the latter case is particularly relevant, because of the [Ca2+]i transients ensuing each action potentials.
Figure 13. Figure 13. Functional gap junctional coupling between chromaffin cells. Rat acute adrenal slices were loaded with a calcium‐sensitive fluorescent probe and [Ca2+]i were simultaneously imaged in neighboring chromaffin cells. (A) A single cell was electrically stimulated, leading to a burst of action potentials. A [Ca2+]i increase is recorded in the stimulated cell, as expected, but also in an adjacent chromaffin cell. Martin AO, et al., 2001 257 with permission of Society for Neuroscience. (B) Similar simultaneous [Ca2+]i increases in several adjacent cells in response to an iontophoretic application of nicotine.
Figure 14. Figure 14. Catecholamine exocytosis in gap junctions‐coupled chromaffin cells. Secretory events from individual chromaffin cells were detected by amperometry in acute slices. (A) A single chromaffin cell is stimulated by iontophoretically applied nicotine and the ensuing rise in [Ca2+]i is imaged in the stimulated cell (cell 1*) and in two adjacent cells (cell 2 and cell 3). Cell 2 responded to cell 1 stimulation by an increase in [Ca2+]i, while no [Ca2+]i change occurred in cell 3. Martin AO, et al., 2001 257 with permission of Society for Neuroscience. (B) Catecholamine exocytosis recorded in either cell 2 (a) or cell (b), in response to the nicotinic stimulation of cell 1. Secretory events, observed as outward current deflections, were detected in cell 2, which exhibited [Ca2+]i rise upon cell 1 stimulation, but not in cell 3. From Martin AO, et al., 2001 257.
Figure 15. Figure 15. Adrenal medullary gap junctions contribute to catecholamine secretion in vivo. (A) Up‐regulation of Cx36 immunoreactivity in the adrenal medullary tissue of stressed rats (cold exposure at 4°C, 5 days). Desarmenien MG, et al., 2013 101 with permission of Springer Nature. (B) Involvement of gap junctions in hormone secretion was assessed by intraperitoneal injection of the uncoupling agent carbenoxolone (CBX), an uncoupling agent, or its inactive structural analog glycyrrhizic acid (GZA) in anesthetized control or cold stressed mice. In control animals, CBX significantly reduces NE but not E secretion evoked by a high frequency (4 Hz) splanchnic nerve stimulation. In stressed mice in which Cx36 gap junction expression is enhanced, both splanchnic nerve stimulation‐triggered NE and E release are dampened by CBX. From Desarmenien MG, et al., 2013 101.
Figure 16. Figure 16. Summary of the adaptive mechanisms of chromaffin tissue to cope with physiological stressful situations (birth, acute stress). The data were collected from experiments carried out on both males and females, as specified. ND, not determined.
Figure 17. Figure 17. Somatotroph cell network development and organization. GH cells develop to form a cell continuum across the mouse's lifespan. Surface rendering of GH‐GFP cell contours from two‐photon image stacks of GH‐GFP pituitaries. Animal ages are indicated on the right of 3D representations of GH cell positioning (E, embryos; P, postnatal). From Bonnefont X, et al., 2005 42.
Figure 18. Figure 18. Relationships between endocrine cell networks and the pituitary vasculature. (A) Typical cell network motifs imaged in 3D using 2‐photon microscopy. Top panel: interconnected clusters of somatotrophs in 2‐month‐old male GH‐GFP (green) mice. Bottom panel: Honeycomb units of the PRL cell network in female PRL‐DsRed (red) mice. Le Tissier PR, et al., 2012 230 with permission of Elsevier. (B) Hemi‐pituitary‐scale 2‐photon imaging in a double transgenic GH‐GFP (green)/PRL‐DsRed (red) female mouse. The pituitary is orientated with the top and bottom of the image representing the dorsal and ventral sides of the pituitary, respectively. Le Tissier PR, et al., 2012 230 with permission of Elsevier. (C) and (D) Schematic representation of the anatomical relationship of pituitary fenestrated capillaries (grey) with the GH cell (C, cells in green), PRL cell (D, cells in red) networks. Le Tissier PR, et al., 2012 230 with permission of Elsevier/Licensed under CC BY 3.0.
Figure 19. Figure 19. Connectivity and calcium activity of somatotrophs cells. GHRH triggers recurrent motifs of GH cell connectivity in the lateral zones. (A) Field of GH cells labeled with EGFP in the lateral zone. Only cells circled with a dashed line were also loaded with the fluorescent calcium dye fura‐2. The yellow and green lines illustrate the potent cell pairs for two recorded GH cells. Bonnefont X, et al., 2005 42 with permission of Proceedings of the National Academy of Science PNAS. (B) Representative traces of calcium spikes due to electrical activity before and after GHRH (10 nM) application. (C) Linear correlation (Pearson R) between calcium recordings among all cell pairs (C1‐C2, C1‐C3, … CN‐1‐CN) taken every 5 min. Although some cell pairs displayed high R values, no large‐scale cell connectivity (P < 0.001) was observed during spontaneous calcium spiking but recurrent motifs of connectivity among large cell ensembles were observed in lateral regions (P < 0.001) after GHRH application. (D) Distribution of numbers of connected cell pairs versus time of calcium recording. GHRH triggered a delayed, cycling increase in connected cell pairs. From Bonnefont X, et al., 2005 42.
Figure 20. Figure 20. Lactotroph organization and plasticity. (A) Lactotrophs are organized into a three‐dimensional network. Structural connectivity is low in nulliparas (left panel) but increases in primiparas (middle panel). Following weaning, connectivity is maintained despite cessation of stimulus (right panel). Insets are typical cell profiles in PRL‐DsRed transgenic mice. Hodson DJ, et al., 2012 180 with permission of Springer Nature. (B) Top panels show representative cytosolic Ca2+ traces in nullipara lactotrophs (AU, arbitrary units) (left panel), primiparas (middle panel), and following weaning (right panel). Bottom panel shows a functional connectivity map depicting the location of significantly correlated cell pairs. From Hodson DJ, et al., 2012 180.
Figure 21. Figure 21. Pituitary microcirculation and molecule diffusion. In vivo imaging of incoming molecules through the microvasculature, fate of products released into the extracellular space, and in situ oxygen response to GHRH. (A) Time‐lapse imaging of 4‐kDa rhodamine dextran in pituitary vessels at high magnification. Values indicate the time delay after i.v. dye injection. Lafont C, et al., 2010 224 with permission of Proceedings of the National Academy of Science PNAS. (B) Decay times for fluorescence clearance in blood vessels following iontophoretic injections of 4‐ and 20‐kDa fluorescent dyes, respectively. The red line represents a simulation of the 4‐kDa dye clearance from the vessel as its measured blood flow. (C) In vivo measurements of heart rate (top trace), pituitary O2 levels (middle traces), and red blood cell velocity (bottom traces) in anesthetized GH‐eGFP mice before (left) and after (right) i.v. GHRH injection. From Lafont C, et al., 2010 224.


Figure 1. Compared anatomical organization of the endocrine/neuroendocrine cells within the secretory tissue. (A) Lobular organization of the chromaffin cell tissue within the rat adrenal medulla. Left picture, Bodian silver‐stained nerve fibers in acute slices. Dashed lines delineate lobules. Based on Kajiwara R, et al., 1997 205. Right picture, clusters of TH immunoreactive chromaffin cells. Kajiwara R, et al., 1997 205 with permission of John Wiley & Sons, Inc./CC BY 3.0. (B) Organization of the mammalian anterior pituitary. Schematic of a hemi‐anterior pituitary showing the preferential organization of the five hormone‐secreting cell types. (C) The endocrine pancreas is a multiunit structure, where upward of a million islets are diffusely scattered throughout the parenchyma. Each human islet of Langerhans is a self‐contained endocrine unit, comprising a number of cell types that secrete hormones involved in glucose homeostasis and other facets of metabolism. Images adapted from Servier Medical Art under a CC‐BY licence (https://creativecommons.org/licenses/by/3.0/).


Figure 2. Slice tissue preparations for studying endocrine/neuroendocrine function. (A) Acute pituitary slice and imaging methods to study pituitary cells in situ. (a) Acute slice preparation. The pituitary gland is immobilized within a droplet of ultra‐low temperature gelling agarose, before cutting at low temperature (1–4°C) with a vibrating microtome blade. (b) Imaging of pituitary cells in situ. Pituitary cells within an acute pituitary slice are imaged with two‐photon excitation microscopy (horizontal red lines). (c) Image deconvolution and 3D reconstruction of image stacks help to view the three‐dimension organization of fluorescent cells in the pituitary tissue. Fauquier T, et al., 2002 125 with permission of Elsevier. (B) Organotypic culture of a rat anterior pituitary gland, according to the roller tube technique described by Gahwiler 140. Measurement of prolactin secretion by radioimmunoassay in a 4 week‐old culture treated either with forskolin to increase hormone release or with the dopaminergic agonist bromocriptine (CB‐154) to inhibit PRL release. Guerineau NC, et al., 1997 161 with permission of Elsevier. (C) Organotypic co‐culture of mouse thoracic spinal cord and hemisectioned adrenal gland (roller tube technique, 42 days in vitro). Chromaffin cells still express the biosynthetic enzyme TH, exhibit spontaneous action potentials and spontaneous postsynaptic excitatory currents (patch‐clamp recordings). The thoracic spinal cord also exhibits spontaneous synaptic currents.


Figure 3. Ex vivo tissue and whole organ preparations for studying endocrine/neuroendocrine function. (A) Ex vivo preparation of the pancreas. (a) Procedure for mouse pancreas perfusion and removal. From Li DS, et al., 2009 238. (b) Islets (∼40–80) are perifused with buffer containing various glucose concentrations or generic depolarizing stimulus (KCl). Insulin secreted into the perfusate is assayed for insulin over a number of timepoints, revealing first and second‐phase responses. Adapted from Li DS, et al., 2009 238 and from Servier Medical Art under a CC‐BY licence (https://creativecommons.org/licenses/by/3.0/). (B) Ex vivo rat spinal cord‐splanchnic nerve‐adrenal gland preparation. (a) Ventral view of the thoracic section isolated from the animal. (b) Schematic representation helping to identify the various tissue components of the preparation. Wolf K, et al., 2016 455 with permission of John Wiley & Sons/Licensed under CC BY 4.0. (c) Experimental protocol to assess catecholamine secretion. The splanchnic nerve is electrically stimulated by a cuff electrode (CE). Catecholamine release is monitored by cyclic voltammetry with a carbon fiber electrode (FE) positioned at proximity of the medullary tissue (AM), which was unmasked after gland hemisection. Wolf K, et al., 2016 455 with permission of John Wiley & Sons, Inc./CC BY 4.0. (C) Ex vivo tissue preparations preserving the connections between the pituitary gland and the brain in the fish. (a) Use of a hypothalamus‐pituitary slice to monitor Lucifer yellow diffusion between pituitary cells in the teleost fish Oreochromis niloticus. Levavi‐Sivan B, et al., 2005 235 with permission of Oxford University Press. (b) Gonadotropin‐releasing hormone (GnRH)‐triggered cytosolic calcium rises imaged in fura‐2‐loaded gonadotrophs from a whole brain‐pituitary preparation of the teleost fish Oryzias latipes. From Karigo T, et al., 2014 208.


Figure 4. In vivo monitoring of the activity of endocrine/neuroendocrine cells. (A) Cellular in vivo imaging of the pituitary gland in fluorescent protein‐tagged transgenic mice with long‐range microscopy. (a) Schematics of the experimental arrangement. An air‐transmission 20x magnification objective with 2.8 cm working distance is fitted on a fluorescent microscope, equipped with a variable light beam excitation and an EM‐CDD camera acquisition setup. It allows real‐time in vivo imaging with adaptive final magnification (8–800x) of the ventral side of the pituitary gland is exposed in an anesthetized mouse after removal of the palate bone. (b) Fluorescent image (λex 488 nm) of the open palate bone of a GH‐eGFP mouse. Lafont C, et al., 2010 224 with permission of Proceedings of the National Academy of Science PNAS. (c) Schematic shows the arrangement of calcium imaging in head‐fixed animals injected with AAV5‐CAG‐GCAMP6s particles into the pituitary. (d) Field of GCAMP6s cells viewed from the dorsal pituitary side with the selection of cells as regions of interest (ROIs) shown in colored circles. Hoa O, et al., 2019 176 with permission of Oxford University Press. (e) Coordinated calcium spikes recorded in the cells shown in (d). (c,e) From Hoa O, et al., 2019 176. (B) In vivo extracellular recording of spontaneous chromaffin cell electrical activity in an anesthetized mouse, illustrated by the occurrence of both individual spikes (a, left inset) and bursting activities (a, right inset). (b) The electrical firing is reversibly abolished by a local application of the voltage‐gated Na+ channel blocker TTX on the splanchnic nerve. (c) Reversible decrease of the nerve stimulation‐evoked electrical activity in the presence of the nicotinic acetylcholine receptor antagonist hexamethonium. From Desarmenien MG, et al., 2013 101. (C) In vivo approach enabling simultaneous stimulation of the splanchnic nerve and adrenal venous blood collection in anesthetized mouse. After laparotomy, the left adrenal gland is uncovered and the renal vein and the conjonctive tissue containing the splanchnic nerve are isolated. The splanchnic nerve is placed on a bipolar stimulation electrode. The renal vein is ligated on both the kidney and vena cava sides to form a reservoir in which a heparinized catheter is implanted. Adrenal venous blood samples are collected before and during splanchnic nerve stimulation. Assay of catecholamine by ELISA shows that E and NE are secreted in a stimulus frequency‐dependent manner. From Desarmenien MG, et al., 2013 101.


Figure 5. Monitoring of hormone release in individual endocrine/neuroendocrine cells. (A) Amperometry‐based measurement of catecholamine secretion in rat acute adrenal slices. Catecholamine release is evoked by an iontophoretic application of the cholinergic agonist nicotine. (B) Use of the fluorescent probe FFN511 accumulated in secretory granules to track exocytosis in a mouse chromaffin cell. Individual granules are imaged by total internal reflection fluorescence microscopy. In response to high K+‐containing saline (dotted line), the fluorescence quickly decreases, reflecting granule exocytosis. Gubernator NG, et al., 2009 154 with permission of American Association for the Advancement of Science – AAAS.


Figure 6. Both extracellular and intracellular Ca2+ sources contribute to hormone exocytosis. Simultaneous measurement of membrane capacitance and cytosolic Ca2+ concentration [Ca2+]i in isolated endocrine/neuroendocrine cells. Representative examples of membrane capacitance increase in response to (A) a Ca2+ entry through voltage‐gated Ca2+ channels in a bovine chromaffin cell, From Augustine GJ and Neher E, 1992 21; (B) a Ca2+ entry through ligand (nicotine)‐gated ion channels in a bovine chromaffin cell, From Mollard P, et al., 1995 279; and (C) a Ca2+ release from internal stores in response to gonadotropin‐releasing hormone in an isolated rat gonadotroph, From Tse A, et al., 1993 422. Note that the source of Ca2+ engaged in exocytosis (extracellular, intracellular, or both) relies on the mode of action of each secretagogue. All mechanisms illustrated here can occur in all tissues, but unlikely to an equal extent.


Figure 7. Monitoring dye diffusion/transport in vivo. Schematics of the experimental arrangement. An air‐transmission 20x magnification objective with 2.8 cm working distance is fitted on a fluorescent microscope, equipped with a variable light beam excitation and an EM‐CDD camera acquisition setup. This allows real‐time in vivo imaging with adaptive final magnification (8x–800x) of the ventral side of the pituitary gland/pancreas surgically exposed in an anesthetized mouse. A jugular catheter is placed for i.v. injection and blood sampling and the pituitary/pancreas surfaces are continuously irrigated with saline through inlet and outlet tubes, respectively. Top panels: In vivo imaging of rhodamine dextran‐labeled vasculature in the pancreas (left) and pituitary gland (right).


Figure 8. Optogenetic control of hormonal secretion in endocrine cells. (A) Optogenetic stimulation of endocrine cells in the pituitary cells expressing optogenes after viral transfection. (a) Laser light illumination of the ventral pituitary side can be carried out in terminally anesthetized mice using a fiber optic acutely placed above the pituitary gland and connected to a laser source. Blood is sampled simultaneously using a jugular catheter or tail‐tip blood sampling. (b) Optogenetic stimulation of the pituitary cells can be carried out in awake mice in which a fiber optic has previously been chronically implanted directly above the target cells. Mice are subjected to simultaneous tail‐tip blood sampling. (c) GH pulses triggered by a train of laser blue light pulses (300‐ms pulses at 1 Hz) in vivo in GH‐Cre mice expressing ChR2 specifically in GH cells. From Hoa O, et al., 2019 176. (B) Photopharmacological modulation of insulin secretion in vivo. (a) Photopharmacology relies on endogenously expressed receptors and ion channels to optically control cell function. The fourth‐generation light‐activated sulfonylurea, JB253, converts ATP‐sensitive K+ (KATP) channels into molecular photoswitches, allowing reversible stimulation of beta‐cell function. The light‐activated sulfonylurea JB253 thus allows optical control of KATP channel activity, voltage‐dependent Ca2+ channel activity, and insulin release. (b) Schematic showing the experimental protocol for optical control of glucose homeostasis using JB253. (c) JB253 (50 mg/kg, administered per os) significantly lowers glycemia in animals exposed to blue light. Mehta ZB, et al., 2017 263 with permission of Springer Nature/Licensed under CC BY 4.0. (C) Optical modulation of stimulus‐secretion coupling in adrenal chromaffin cells. (a) Modulation of stimulus‐secretion coupling using a synthetic chemistry approach based on ruthenium diimine complexes in a RubpyC17‐loaded mouse chromaffin cells (right picture). Rohan JG, et al., 2013 340 with permission of American Chemical Society. (b) Light illumination electronically excites RubpyC17 and generates a photoexcited complex that is either an electron donor or an electron acceptor. The presence of a reductant substrate in the extracellular medium allows electron transfer from the donor to RubpyC17, generating a negative surface potential at the cell membrane, which is detected by the cell as a depolarization. Optically driven changes in the electrical activity (c) and catecholamine secretion (d) in a RubpyC17‐loaded mouse chromaffin cell. (b‐d) From Rohan JG, et al., 2013 340.


Figure 9. Macroscopic anatomy and innervation of rat the adrenal gland. (A) Double immunofluorescent staining of laminin (in green) which labels both the cortex and the medulla and tyrosine hydroxylase (in red) which stains the neurosecretory chromaffin cell tissue. Note the chromaffin cell organization in clusters. (B) Schematic representation of the spinal‐adrenal innervation. The preganglionic innervation synapsing onto chromaffin cells extensively occurs through a direct pathway without relaying the sympathetic chain or the suprarenal ganglion. (C) Immunofluorescent detection of nerve fibers invading the medulla with an anti‐neurofilament antibody.


Figure 10. Scheme of the adrenal medulla stimulus‐secretion coupling. Two interconnected pathways underlie adrenal catecholamine secretion from chromaffin cells. The master stimulus comes from ACh release by splanchnic nerve terminals synapsing onto chromaffin cells. In addition, and reinforcing or even supplanting the cholinergic synaptic neurotransmission, chromaffin cell intercellular communication mediated by gap junctions contributes to hormone release. Based on, with permission, Colomer C, et al. 2009 80; Colomer C, et al. 2012 82; Desarmenien MG, et al. 2013 101; Guerineau NC, 2018 156; Hodson DJ, et al., 2015 177; Martin AO, et al., 2001 257.


Figure 11. Gap junctions in the rodent chromaffin cell tissue. (A) Immunohistofluorescent detection of Cx36 in the mouse medulla. Note the punctiform labeling, representative of gap junctional plaques. (B) Lucifer yellow diffusion between gap junction‐coupled rat chromaffin cells in acute adrenal slices. The fluorescent dye was introduced into a single chromaffin cell through a patch pipette and diffused into coupled cells within a couple of minutes.


Figure 12. Monitoring functional gap junction‐mediated intercellular coupling by electrophysiological recordings of cell pairs. (A) Schematic representation of the dual patch‐clamp technique, used to monitor junctional currents in a chromaffin cell pair. Two adjacent cells (cell 1 and cell 2) are patch‐clamped and recorded in the current‐clamp mode. A depolarizing current step is applied to cell 1 (cell 1*) and the subsequent membrane potential changes are simultaneously monitored in both cell 1 and cell 2. (B) Cell 1 depolarization does not evoke potential changes in cell 2, indicating that the two cells are not functionally coupled by gap junctions. (C,D) Propagation of the depolarization evoked in cell 1, resulting either in a small depolarization in cell 2 (= weak electrical coupling) or in the triggering of action potentials (= robust electrical coupling). Regarding subsequent hormone secretion, the latter case is particularly relevant, because of the [Ca2+]i transients ensuing each action potentials.


Figure 13. Functional gap junctional coupling between chromaffin cells. Rat acute adrenal slices were loaded with a calcium‐sensitive fluorescent probe and [Ca2+]i were simultaneously imaged in neighboring chromaffin cells. (A) A single cell was electrically stimulated, leading to a burst of action potentials. A [Ca2+]i increase is recorded in the stimulated cell, as expected, but also in an adjacent chromaffin cell. Martin AO, et al., 2001 257 with permission of Society for Neuroscience. (B) Similar simultaneous [Ca2+]i increases in several adjacent cells in response to an iontophoretic application of nicotine.


Figure 14. Catecholamine exocytosis in gap junctions‐coupled chromaffin cells. Secretory events from individual chromaffin cells were detected by amperometry in acute slices. (A) A single chromaffin cell is stimulated by iontophoretically applied nicotine and the ensuing rise in [Ca2+]i is imaged in the stimulated cell (cell 1*) and in two adjacent cells (cell 2 and cell 3). Cell 2 responded to cell 1 stimulation by an increase in [Ca2+]i, while no [Ca2+]i change occurred in cell 3. Martin AO, et al., 2001 257 with permission of Society for Neuroscience. (B) Catecholamine exocytosis recorded in either cell 2 (a) or cell (b), in response to the nicotinic stimulation of cell 1. Secretory events, observed as outward current deflections, were detected in cell 2, which exhibited [Ca2+]i rise upon cell 1 stimulation, but not in cell 3. From Martin AO, et al., 2001 257.


Figure 15. Adrenal medullary gap junctions contribute to catecholamine secretion in vivo. (A) Up‐regulation of Cx36 immunoreactivity in the adrenal medullary tissue of stressed rats (cold exposure at 4°C, 5 days). Desarmenien MG, et al., 2013 101 with permission of Springer Nature. (B) Involvement of gap junctions in hormone secretion was assessed by intraperitoneal injection of the uncoupling agent carbenoxolone (CBX), an uncoupling agent, or its inactive structural analog glycyrrhizic acid (GZA) in anesthetized control or cold stressed mice. In control animals, CBX significantly reduces NE but not E secretion evoked by a high frequency (4 Hz) splanchnic nerve stimulation. In stressed mice in which Cx36 gap junction expression is enhanced, both splanchnic nerve stimulation‐triggered NE and E release are dampened by CBX. From Desarmenien MG, et al., 2013 101.


Figure 16. Summary of the adaptive mechanisms of chromaffin tissue to cope with physiological stressful situations (birth, acute stress). The data were collected from experiments carried out on both males and females, as specified. ND, not determined.


Figure 17. Somatotroph cell network development and organization. GH cells develop to form a cell continuum across the mouse's lifespan. Surface rendering of GH‐GFP cell contours from two‐photon image stacks of GH‐GFP pituitaries. Animal ages are indicated on the right of 3D representations of GH cell positioning (E, embryos; P, postnatal). From Bonnefont X, et al., 2005 42.


Figure 18. Relationships between endocrine cell networks and the pituitary vasculature. (A) Typical cell network motifs imaged in 3D using 2‐photon microscopy. Top panel: interconnected clusters of somatotrophs in 2‐month‐old male GH‐GFP (green) mice. Bottom panel: Honeycomb units of the PRL cell network in female PRL‐DsRed (red) mice. Le Tissier PR, et al., 2012 230 with permission of Elsevier. (B) Hemi‐pituitary‐scale 2‐photon imaging in a double transgenic GH‐GFP (green)/PRL‐DsRed (red) female mouse. The pituitary is orientated with the top and bottom of the image representing the dorsal and ventral sides of the pituitary, respectively. Le Tissier PR, et al., 2012 230 with permission of Elsevier. (C) and (D) Schematic representation of the anatomical relationship of pituitary fenestrated capillaries (grey) with the GH cell (C, cells in green), PRL cell (D, cells in red) networks. Le Tissier PR, et al., 2012 230 with permission of Elsevier/Licensed under CC BY 3.0.


Figure 19. Connectivity and calcium activity of somatotrophs cells. GHRH triggers recurrent motifs of GH cell connectivity in the lateral zones. (A) Field of GH cells labeled with EGFP in the lateral zone. Only cells circled with a dashed line were also loaded with the fluorescent calcium dye fura‐2. The yellow and green lines illustrate the potent cell pairs for two recorded GH cells. Bonnefont X, et al., 2005 42 with permission of Proceedings of the National Academy of Science PNAS. (B) Representative traces of calcium spikes due to electrical activity before and after GHRH (10 nM) application. (C) Linear correlation (Pearson R) between calcium recordings among all cell pairs (C1‐C2, C1‐C3, … CN‐1‐CN) taken every 5 min. Although some cell pairs displayed high R values, no large‐scale cell connectivity (P < 0.001) was observed during spontaneous calcium spiking but recurrent motifs of connectivity among large cell ensembles were observed in lateral regions (P < 0.001) after GHRH application. (D) Distribution of numbers of connected cell pairs versus time of calcium recording. GHRH triggered a delayed, cycling increase in connected cell pairs. From Bonnefont X, et al., 2005 42.


Figure 20. Lactotroph organization and plasticity. (A) Lactotrophs are organized into a three‐dimensional network. Structural connectivity is low in nulliparas (left panel) but increases in primiparas (middle panel). Following weaning, connectivity is maintained despite cessation of stimulus (right panel). Insets are typical cell profiles in PRL‐DsRed transgenic mice. Hodson DJ, et al., 2012 180 with permission of Springer Nature. (B) Top panels show representative cytosolic Ca2+ traces in nullipara lactotrophs (AU, arbitrary units) (left panel), primiparas (middle panel), and following weaning (right panel). Bottom panel shows a functional connectivity map depicting the location of significantly correlated cell pairs. From Hodson DJ, et al., 2012 180.


Figure 21. Pituitary microcirculation and molecule diffusion. In vivo imaging of incoming molecules through the microvasculature, fate of products released into the extracellular space, and in situ oxygen response to GHRH. (A) Time‐lapse imaging of 4‐kDa rhodamine dextran in pituitary vessels at high magnification. Values indicate the time delay after i.v. dye injection. Lafont C, et al., 2010 224 with permission of Proceedings of the National Academy of Science PNAS. (B) Decay times for fluorescence clearance in blood vessels following iontophoretic injections of 4‐ and 20‐kDa fluorescent dyes, respectively. The red line represents a simulation of the 4‐kDa dye clearance from the vessel as its measured blood flow. (C) In vivo measurements of heart rate (top trace), pituitary O2 levels (middle traces), and red blood cell velocity (bottom traces) in anesthetized GH‐eGFP mice before (left) and after (right) i.v. GHRH injection. From Lafont C, et al., 2010 224.
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Article Title: Cell Networks in Endocrine/Neuroendocrine Gland Function
 

How to Cite

Nathalie C. Guérineau, Pauline Campos, Paul R. Le Tissier, David J. Hodson, Patrice Mollard. Cell Networks in Endocrine/Neuroendocrine Gland Function. Compr Physiol 2022, 12: 3371-3415. doi: 10.1002/cphy.c210031