Impaired Endogenous Neurosteroid Signaling Contributes to Behavioral Deficits Associated With Chronic Stress.

Mice Animals Pregnanolone Receptors, GABA-A / metabolism Neurosteroids Signal Transduction gamma-Aminobutyric Acid
Allopregnanolone Depression GABA Neurosteroidogenesis Neurosteroids Stress

Journal

Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264

Informations de publication

Date de publication:
01 08 2023
Historique:
received: 15 06 2022
revised: 21 11 2022
accepted: 14 01 2023
pmc-release: 01 08 2024
medline: 14 7 2023
pubmed: 4 2 2023
entrez: 3 2 2023
Statut: ppublish

Résumé

Chronic stress is a major risk factor for psychiatric illnesses, including depression. However, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. Allopregnanolone acts as a positive allosteric modulator preferentially on δ subunit-containing GABA We utilized a chronic unpredictable stress (CUS) mouse model, followed by behavioral and biochemical assays, to examine whether altered neurosteroid signaling contributes to behavioral outcomes following CUS. We subsequently performed in vivo CRISPR (clustered regularly interspaced short palindromic repeats) knockdown of rate-limiting enzymes involved in allopregnanolone synthesis, 5α-reductase type 1 and 2 (5α1/2), in addition to lentiviral overexpression of 5α1/2 in the basolateral amygdala (BLA) of mice that underwent CUS to assess the impact of 5α1/2 on behavioral outcomes. The expression of δ subunit-containing GABA Our findings demonstrate that chronic stress impairs endogenous neurosteroid signaling in the BLA, which is sufficient to induce behavioral deficits. Further, these studies suggest that allopregnanolone-based treatments may directly target the underlying pathophysiology of mood disorders suggesting that targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy.

Sections du résumé

BACKGROUND
Chronic stress is a major risk factor for psychiatric illnesses, including depression. However, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. Allopregnanolone acts as a positive allosteric modulator preferentially on δ subunit-containing GABA
METHODS
We utilized a chronic unpredictable stress (CUS) mouse model, followed by behavioral and biochemical assays, to examine whether altered neurosteroid signaling contributes to behavioral outcomes following CUS. We subsequently performed in vivo CRISPR (clustered regularly interspaced short palindromic repeats) knockdown of rate-limiting enzymes involved in allopregnanolone synthesis, 5α-reductase type 1 and 2 (5α1/2), in addition to lentiviral overexpression of 5α1/2 in the basolateral amygdala (BLA) of mice that underwent CUS to assess the impact of 5α1/2 on behavioral outcomes.
RESULTS
The expression of δ subunit-containing GABA
CONCLUSIONS
Our findings demonstrate that chronic stress impairs endogenous neurosteroid signaling in the BLA, which is sufficient to induce behavioral deficits. Further, these studies suggest that allopregnanolone-based treatments may directly target the underlying pathophysiology of mood disorders suggesting that targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy.

Identifiants

DOI: 10.1016/j.biopsych.2023.01.022 PMID: 36736870 PMC: PMC10363189
pubmed: 36736870
pii: S0006-3223(23)00050-1
doi: 10.1016/j.biopsych.2023.01.022
pmc: PMC10363189
mid: NIHMS1870438
pii:
doi:

Substances chimiques

Pregnanolone BXO86P3XXW
Receptors, GABA-A 0
Neurosteroids 0
gamma-Aminobutyric Acid 56-12-2

Types de publication

Journal Article Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

249-261

Subventions

Organisme : NINDS NIH HHS
ID : R01 NS102937
Pays : United States
Organisme : NIMH NIH HHS
ID : P50 MH122379
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK046200
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK108797
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH128235
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK124170
Pays : United States
Organisme : NICHD NIH HHS
ID : R21 HD098056
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA026256
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS105628
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS107315
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Références

Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18736-41
pubmed: 18003893
Neurobiol Stress. 2019 Oct 24;11:100198
pubmed: 31709278
Neurobiol Stress. 2019 Sep 27;11:100196
pubmed: 31649968
Nat Commun. 2020 Aug 31;11(1):4358
pubmed: 32868768
J Neurosci. 2020 Jan 2;40(1):12-21
pubmed: 31896560
Chronic Stress (Thousand Oaks). 2017 Jan-Dec;1:
pubmed: 28856337
Nat Commun. 2022 Mar 11;13(1):1290
pubmed: 35277502
Stress. 2005 Jun;8(2):85-93
pubmed: 16019600
Neuron. 2008 Jul 31;59(2):207-13
pubmed: 18667149
Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):504-9
pubmed: 24344272
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2849-54
pubmed: 11226329
Biomol Concepts. 2013 Feb;4(1):29-42
pubmed: 25436563
Neurobiol Stress. 2016 Aug 24;6:78-93
pubmed: 28229111
Biol Psychiatry. 2022 Feb 1;91(3):283-293
pubmed: 34561029
J Neurosci. 2021 Nov 3;41(44):9223-9234
pubmed: 34561234
Neurosci Biobehav Rev. 2010 Sep;35(1):2-16
pubmed: 19822172
J Neurosci. 2011 Dec 14;31(50):18198-210
pubmed: 22171026
Lancet. 2018 Sep 22;392(10152):1058-1070
pubmed: 30177236
Psychopharmacology (Berl). 2003 Jan;165(2):97-110
pubmed: 12420152
Nat Rev Neurosci. 2005 Jul;6(7):565-75
pubmed: 15959466
PLoS Biol. 2019 Mar 7;17(3):e3000157
pubmed: 30845142
Psychoneuroendocrinology. 2018 Apr;90:182-193
pubmed: 29274662
CNS Drug Rev. 2006 Spring;12(1):53-76
pubmed: 16834758
Psychopharmacology (Berl). 2014 Sep;231(17):3557-67
pubmed: 24846476
J Neurochem. 2006 Jul;98(1):122-33
pubmed: 16805802
Ann N Y Acad Sci. 1998 May 1;840:33-44
pubmed: 9629234
N Engl J Med. 2019 Sep 5;381(10):903-911
pubmed: 31483961
Nature. 2018 Apr;556(7702):505-509
pubmed: 29670283
Neurosci Biobehav Rev. 2013 Jan;37(1):109-22
pubmed: 23085210
Nat Neurosci. 2017 Nov;20(11):1624-1633
pubmed: 28967909
J Neurochem. 2000 Aug;75(2):732-40
pubmed: 10899949
Psychoneuroendocrinology. 2014 Mar;41:75-88
pubmed: 24495609
Neuropharmacology. 2002 Sep;43(4):651-61
pubmed: 12367610
J Sex Med. 2013 Oct;10(10):2598-603
pubmed: 23890183
Neural Plast. 2016;2016:2762518
pubmed: 26819762

Auteurs

Najah L Walton (NL)

Department of Neuroscience, Program of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts.

Pantelis Antonoudiou (P)

Department of Neuroscience, Program of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts.

Lea Barros (L)

Department of Neuroscience, Program of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts; Building Diversity in Biomedical Sciences Program, Tufts University School of Medicine, Boston, Massachusetts; Department of Biology, Hamilton College, Clinton, New York.

Tauryn Dargan (T)

Department of Neuroscience, Program of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts.

Alyssa DiLeo (A)

Department of Neuroscience, Program of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts.

Aidan Evans-Strong (A)

Department of Neuroscience, Program of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts.

Jenah Gabby (J)

Department of Neuroscience, Program of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts; Building Diversity in Biomedical Sciences Program, Tufts University School of Medicine, Boston, Massachusetts; Louis Stokes Alliance for Minority Participation, Tufts University, Medford, Massachusetts.

Samantha Howard (S)

Department of Neuroscience, Program of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts; Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.

Rumzah Paracha (R)

Department of Neuroscience, Program of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts.

Edgardo J Sánchez (EJ)

Department of Neuroscience, Program of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts; Building Diversity in Biomedical Sciences Program, Tufts University School of Medicine, Boston, Massachusetts; Department of Chemistry, University of Puerto Rico, Cayey, Puerto Rico.

Grant L Weiss (GL)

Department of Neuroscience, Program of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts.

Dong Kong (D)

Department of Neuroscience, Program of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts; Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.

Jamie L Maguire (JL)

Department of Neuroscience, Program of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts. Electronic address: Jamie.Maguire@tufts.edu.

Articles similaires

Evaluating the efficacy of telesurgery with dual console SSI Mantra Surgical Robotic System: experiment on animal model and clinical trials.

Sudhir Prem Srivastava, Vishwajyoti Pascual Srivastava, Avinesh Singh et al.
1.00
Robotic Surgical Procedures Animals Humans Telemedicine Models, Animal

Odour generalisation and detection dog training.

Lyn Caldicott, Thomas W Pike, Helen E Zulch et al.
1.00
Animals Odorants Dogs Generalization, Psychological Smell

FBXO22 inhibits colitis and colorectal carcinogenesis by regulating the degradation of the S2448-phosphorylated form of mTOR.

Minle Li, Xuan Chen, Pengfei Qu et al.
1.00
Animals TOR Serine-Threonine Kinases Colorectal Neoplasms Colitis Mice

Use of organic material provided by an automatic enrichment device by weaner pigs and its influence on tail lesions.

Philipp Heseker, Jeanette Probst, Stefanie Ammer et al.
1.00
Animals Tail Swine Behavior, Animal Animal Husbandry

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Impaired Endogenous Neurosteroid Signaling...
questionsmedicales.fr › Eucaryotes › Animaux › Impaired Endogenous Neurosteroid Signaling...
questionsmedicales.fr › Composés polycycliques › Composés à cycles fusionnés › Stéroïdes › Prégnanes › Prégnanolone › Impaired Endogenous Neurosteroid Signaling...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs aux acides aminés › Récepteurs GABA › Récepteurs GABA-A › Impaired Endogenous Neurosteroid Signaling...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Agents neuromédiateurs › Neurostéroïdes › Impaired Endogenous Neurosteroid Signaling...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Impaired Endogenous Neurosteroid Signaling...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Amino-butyrates › Acide gamma-amino-butyrique › Impaired Endogenous Neurosteroid Signaling...