A novel GABA-mediated corticotropin-releasing hormone secretory mechanism in the median eminence

Kakizawa, Keisuke; Watanabe, Miho; Mutoh, Hiroki; Okawa, Yuta; Yamashita, Miho; Yanagawa, Yuchio; Itoi, Keiichi; Suda, Takafumi; Osuga, Yutaka; Fukuda, Atsuo

doi:10.1126/sciadv.1501723

Cited by 44 publications

(32 citation statements)

References 71 publications

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“…6h ) in the ventral layer of the ME. This is in accordance with reports showing TRH- and CRH-positive fibers in close proximity to the fenestrated capillaries of the portal venous system 12 , 30 . However, CNO administration only elevated TSH (Fig.…”

Section: Resultssupporting

confidence: 93%

Tanycytes control the hormonal output of the hypothalamic-pituitary-thyroid axis

et al. 2017

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The hypothalamic–pituitary–thyroid (HPT) axis maintains circulating thyroid hormone levels in a narrow physiological range. As axons containing thyrotropin-releasing hormone (TRH) terminate on hypothalamic tanycytes, these specialized glial cells have been suggested to influence the activity of the HPT axis, but their exact role remained enigmatic. Here, we demonstrate that stimulation of the TRH receptor 1 increases intracellular calcium in tanycytes of the median eminence via Gαq/11 proteins. Activation of Gαq/11 pathways increases the size of tanycyte endfeet that shield pituitary vessels and induces the activity of the TRH-degrading ectoenzyme. Both mechanisms may limit the TRH release to the pituitary. Indeed, blocking TRH signaling in tanycytes by deleting Gαq/11 proteins in vivo enhances the response of the HPT axis to the chemogenetic activation of TRH neurons. In conclusion, we identify new TRH- and Gαq/11-dependent mechanisms in the median eminence by which tanycytes control the activity of the HPT axis.

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Section: Resultssupporting

confidence: 93%

Tanycytes control the hormonal output of the hypothalamic-pituitary-thyroid axis

et al. 2017

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“…The regulatory mechanisms of [Cl − ] i are involved in a wide range of acute neuronal insults, such as ischemia or traumatic injury, as well as in chronic disorders, including epilepsy, autism, and Down syndrome. Regulation of [Cl − ] i is also a major player in the control of neuroendocrine responses (54)(55)(56), and a very recent study puts KCC2 in key position in synaptic plasticity mechanisms that are likely to underlie cognitive impairment during senescence (57). These wide-ranging observations extend the scope and impact of technical advances in in vivo Cl − imaging.…”

Section: Discussionmentioning

confidence: 84%

Simultaneous two-photon imaging of intracellular chloride concentration and pH in mouse pyramidal neurons in vivo

Sato

Artoni

Landi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

132

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Intracellular chloride ([Cl−] i ) and pH (pH i ) are fundamental regulators of neuronal excitability. They exert wide-ranging effects on synaptic signaling and plasticity and on development and disorders of the brain. The ideal technique to elucidate the underlying ionic mechanisms is quantitative and combined two-photon imaging of [Cl − ] i and pH i , but this has never been performed at the cellular level in vivo. Here, by using a genetically encoded fluorescent sensor that includes a spectroscopic reference (an element insensitive to Cl − and pH), we show that ratiometric imaging is strongly affected by the optical properties of the brain. We have designed a method that fully corrects for this source of error. Parallel measurements of [Cl − ] i and pH i at the single-cell level in the mouse cortex showed the in vivo presence of the widely discussed developmental fall in [Cl − ] i and the role of the K-Cl cotransporter KCC2 in this process. Then, we introduce a dynamic twophoton excitation protocol to simultaneously determine the changes of pH i and [Cl − ] i in response to hypercapnia and seizure activity.I ntracellular ion concentrations are controlled by plasmalemmal transporters and channels, which generate and dissipate ionic electrochemical gradients, respectively (1). In recent years, regulation of the intracellular Cl − concentration ([Cl − ] i ) in neurons has attracted lots of attention, because it is the main ion that carries current across GABA A (and also, glycine) receptors. Changes in [Cl − ] i exert an immediate effect on the reversal potential of GABAergic currents (E GABA ) and, thereby, on the properties of GABA A receptor-mediated transmission (2-4). The "ionic plasticity" of GABAergic signaling involves not only the passive flux of Cl − ions through membrane channels but also, a number of ion transporters that regulate [Cl − ] i . Furthermore, this mechanism is under the control of intracellular signaling cascades that regulate the expression patterns as well as functional properties of ion transporters and channels (5, 6). With regard to long-term ionic modulation of GABAergic transmission, a case in point is the decrease in [Cl − ] i that is generally thought to take place during maturation of most central neurons. According to this widely accepted scenario, the Na-K-2Cl cotransporter NKCC1 accumulates Cl − in immature neurons, thereby promoting depolarizing GABA responses (3, 7-9), which is followed by developmental upregulation of the neuron-specific K-Cl cotransporter KCC2 that is required for the generation of classical hyperpolarizing inhibitory postsynaptic potentials (IPSPs) (10).A wealth of electrophysiological evidence dating back to the work in vivo by Eccles and coworkers (11) has provided evidence for active regulation of [Cl − ] i in mammalian central neurons and its crucial effect on the driving force of Cl − in inhibitory synapses (1). However, thus far, there are no direct data on neuronal [Cl − ] i measured in vivo at the single-cell level in the living brain, and for in...

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“…Considering that parvocellular neurosecretory neurons of the PVN send their nerve terminals into the external zone of the ME ( 26 , 27 ), we intraperitoneally injected Fluorogold (FG), a retrograde axonal tracer, to examine whether the axons of PVN insulin neurons terminate in the ME. FG circulating in the blood is taken up by nerve terminals lying outside the blood-brain barrier and is retrogradely transported to neuronal somata, resulting in the labeling of neurons projecting to the external zone of the ME ( 28 – 30 ). Five days after i.p.…”

Section: Resultsmentioning

confidence: 99%

Insulin synthesized in the paraventricular nucleus of the hypothalamus regulates pituitary growth hormone production

Lee¹,

Kim²,

Cho³

et al. 2020

JCI Insight

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Evidence has mounted that insulin can be synthesized in various brain regions, including the hypothalamus. However, the distribution and functions of insulin-expressing cells in the hypothalamus remain elusive. Herein, we show that in the mouse hypothalamus, the perikarya of insulin-positive neurons are located in the paraventricular nucleus (PVN) and their axons project to the median eminence; these findings define parvocellular neurosecretory PVN insulin neurons. Contrary to corticotropin-releasing hormone expression, insulin expression in the PVN was inhibited by restraint stress (RS) in both adult and young mice. Acute RS–induced inhibition of PVN insulin expression in adult mice decreased both pituitary growth hormone ( Gh ) mRNA level and serum GH concentration, which were attenuated by overexpression of PVN insulin. Notably, PVN insulin knockdown or chronic RS in young mice hindered normal growth via the downregulation of GH gene expression and secretion, whereas PVN insulin overexpression in young mice prevented chronic RS–induced growth retardation by elevating GH production. Our results suggest that in both normal and stressful conditions, insulin synthesized in the parvocellular PVN neurons plays an important role in the regulation of pituitary GH production and body length, unveiling a physiological function of brain-derived insulin.

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A novel GABA-mediated corticotropin-releasing hormone secretory mechanism in the median eminence

Abstract: Excitatory GABAergic input from arcuate nucleus maintains steady-state CRH release from axon terminals with NKCC1-driven high [Cl−]i.

Cited by 44 publications

References 71 publications

Tanycytes control the hormonal output of the hypothalamic-pituitary-thyroid axis

Tanycytes control the hormonal output of the hypothalamic-pituitary-thyroid axis

Simultaneous two-photon imaging of intracellular chloride concentration and pH in mouse pyramidal neurons in vivo

Insulin synthesized in the paraventricular nucleus of the hypothalamus regulates pituitary growth hormone production

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