Prostaglandin E Induces Long-Lasting Inhibition of Noradrenergic Neurons in the Locus Coeruleus and Moderates the Behavioral Response to Stressors

Overview

Journal J Neurosci

Specialty Neurology

Date 2023 Sep 21

PMID 37734949

Authors

Yasutaka Mukai

Tatsuo S Okubo

Michael Lazarus

Daisuke Ono

Kenji F Tanaka

Akihiro Yamanaka

Affiliations

Soon will be listed here.

Abstract

Neuronal activity is modulated not only by inputs from other neurons but also by various factors, such as bioactive substances. Noradrenergic (NA) neurons in the locus coeruleus (LC-NA neurons) are involved in diverse physiological functions, including sleep/wakefulness and stress responses. Previous studies have identified various substances and receptors that modulate LC-NA neuronal activity through techniques including electrophysiology, calcium imaging, and single-cell RNA sequencing. However, many substances with unknown physiological significance have been overlooked. Here, we established an efficient screening method for identifying substances that modulate LC-NA neuronal activity through intracellular calcium ([Ca]) imaging using brain slices. Using both sexes of mice, we screened 53 bioactive substances, and identified five novel substances: gastrin-releasing peptide, neuromedin U, and angiotensin II, which increase [Ca], and pancreatic polypeptide and prostaglandin D, which decrease [Ca] Among them, neuromedin U induced the greatest response in female mice. In terms of the duration of [Ca] change, we focused on prostaglandin E (PGE), since it induces a long-lasting decrease in [Ca] via the EP receptor. Conditional knock-out of the receptor in LC-NA neurons resulted in increased depression-like behavior, prolonged wakefulness in the dark period, and increased [Ca] after stress exposure. Our results demonstrate the effectiveness of our screening method for identifying substances that modulate a specific neuronal population in an unbiased manner and suggest that stress-induced prostaglandin E can suppress LC-NA neuronal activity to moderate the behavioral response to stressors. Our screening method will contribute to uncovering previously unknown physiological functions of uncharacterized bioactive substances in specific neuronal populations. Bioactive substances modulate the activity of specific neuronal populations. However, since only a limited number of substances with predicted effects have been investigated, many substances that may modulate neuronal activity have gone unrecognized. Here, we established an unbiased method for identifying modulatory substances by measuring the intracellular calcium signal, which reflects neuronal activity. We examined noradrenergic (NA) neurons in the locus coeruleus (LC-NA neurons), which are involved in diverse physiological functions. We identified five novel substances that modulate LC-NA neuronal activity. We also found that stress-induced prostaglandin E (PGE) may suppress LC-NA neuronal activity and influence behavioral outcomes. Our screening method will help uncover previously overlooked functions of bioactive substances and provide insight into unrecognized roles of specific neuronal populations.

References

Mukai Y, Li Y, Nakamura A, Fukatsu N, Iijima D, Abe M . Cre-dependent ACR2-expressing reporter mouse strain for efficient long-lasting inhibition of neuronal activity. Sci Rep. 2023; 13(1):3966. PMC: 9998869. DOI: 10.1038/s41598-023-30907-2. View

Grove K, Campbell R, ffrench-Mullen J, Cowley M, Smith M . Neuropeptide Y Y5 receptor protein in the cortical/limbic system and brainstem of the rat: expression on gamma-aminobutyric acid and corticotropin-releasing hormone neurons. Neuroscience. 2000; 100(4):731-40. DOI: 10.1016/s0306-4522(00)00308-0. View

Szekeres P, Muir A, Spinage L, Miller J, Butler S, Smith A . Neuromedin U is a potent agonist at the orphan G protein-coupled receptor FM3. J Biol Chem. 2000; 275(27):20247-50. DOI: 10.1074/jbc.C000244200. View

Szabadi E . Functional neuroanatomy of the central noradrenergic system. J Psychopharmacol. 2013; 27(8):659-93. DOI: 10.1177/0269881113490326. View

Theisen C, Reyes B, Sabban E, Van Bockstaele E . Ultrastructural Characterization of Corticotropin-Releasing Factor and Neuropeptide Y in the Rat Locus Coeruleus: Anatomical Evidence for Putative Interactions. Neuroscience. 2018; 384:21-40. DOI: 10.1016/j.neuroscience.2018.04.043. View

Boie Y, Stocco R, Sawyer N, Slipetz D, Ungrin M, Neuschafer-Rube F . Molecular cloning and characterization of the four rat prostaglandin E2 prostanoid receptor subtypes. Eur J Pharmacol. 1998; 340(2-3):227-41. DOI: 10.1016/s0014-2999(97)01383-6. View

Merali Z, Kent P, Du L, Hrdina P, Palkovits M, Faludi G . Corticotropin-releasing hormone, arginine vasopressin, gastrin-releasing peptide, and neuromedin B alterations in stress-relevant brain regions of suicides and control subjects. Biol Psychiatry. 2005; 59(7):594-602. DOI: 10.1016/j.biopsych.2005.08.008. View

Tabuchi S, Tsunematsu T, Black S, Tominaga M, Maruyama M, Takagi K . Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system function. J Neurosci. 2014; 34(19):6495-509. PMC: 4012309. DOI: 10.1523/JNEUROSCI.0073-14.2014. View

Pawlyk A, Morrison A, Ross R, Brennan F . Stress-induced changes in sleep in rodents: models and mechanisms. Neurosci Biobehav Rev. 2007; 32(1):99-117. PMC: 2215737. DOI: 10.1016/j.neubiorev.2007.06.001. View

10.

Ohmura Y, Tanaka K, Tsunematsu T, Yamanaka A, Yoshioka M . Optogenetic activation of serotonergic neurons enhances anxiety-like behaviour in mice. Int J Neuropsychopharmacol. 2014; 17(11):1777-83. DOI: 10.1017/S1461145714000637. View

11.

Sabban E, Serova L, Newman E, Aisenberg N, Akirav I . Changes in Gene Expression in the Locus Coeruleus-Amygdala Circuitry in Inhibitory Avoidance PTSD Model. Cell Mol Neurobiol. 2017; 38(1):273-280. PMC: 11481846. DOI: 10.1007/s10571-017-0548-3. View

12.

Inutsuka A, Yamashita A, Chowdhury S, Nakai J, Ohkura M, Taguchi T . The integrative role of orexin/hypocretin neurons in nociceptive perception and analgesic regulation. Sci Rep. 2016; 6:29480. PMC: 4935841. DOI: 10.1038/srep29480. View

13.

Poe G, Foote S, Eschenko O, Johansen J, Bouret S, Aston-Jones G . Locus coeruleus: a new look at the blue spot. Nat Rev Neurosci. 2020; 21(11):644-659. PMC: 8991985. DOI: 10.1038/s41583-020-0360-9. View

14.

Dumont Y, Moyse E, Fournier A, Quirion R . Distribution of peripherally injected peptide YY ([125I] PYY (3-36)) and pancreatic polypeptide ([125I] hPP) in the CNS: enrichment in the area postrema. J Mol Neurosci. 2007; 33(3):294-304. DOI: 10.1007/s12031-007-9007-9. View

15.

Chandler D, Jensen P, McCall J, Pickering A, Schwarz L, Totah N . Redefining Noradrenergic Neuromodulation of Behavior: Impacts of a Modular Locus Coeruleus Architecture. J Neurosci. 2019; 39(42):8239-8249. PMC: 6794927. DOI: 10.1523/JNEUROSCI.1164-19.2019. View

16.

Horikawa K, Yamada Y, Matsuda T, Kobayashi K, Hashimoto M, Matsu-Ura T . Spontaneous network activity visualized by ultrasensitive Ca(2+) indicators, yellow Cameleon-Nano. Nat Methods. 2010; 7(9):729-32. DOI: 10.1038/nmeth.1488. View

17.

Pedragosa-Badia X, Stichel J, Beck-Sickinger A . Neuropeptide Y receptors: how to get subtype selectivity. Front Endocrinol (Lausanne). 2013; 4:5. PMC: 3563083. DOI: 10.3389/fendo.2013.00005. View

18.

Valentino R, Van Bockstaele E . Convergent regulation of locus coeruleus activity as an adaptive response to stress. Eur J Pharmacol. 2008; 583(2-3):194-203. PMC: 2349983. DOI: 10.1016/j.ejphar.2007.11.062. View

19.

Zeisel A, Munoz-Manchado A, Codeluppi S, Lonnerberg P, La Manno G, Jureus A . Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science. 2015; 347(6226):1138-42. DOI: 10.1126/science.aaa1934. View

20.

Bregonzio C, Seltzer A, Armando I, Pavel J, Saavedra J . Angiotensin II AT(1) receptor blockade selectively enhances brain AT(2) receptor expression, and abolishes the cold-restraint stress-induced increase in tyrosine hydroxylase mRNA in the locus coeruleus of spontaneously hypertensive rats. Stress. 2008; 11(6):457-66. PMC: 2742314. DOI: 10.1080/10253890801892040. View