Crh receptor priming in the bed nucleus of the stria terminalis (BNST) induces tph2 gene expression in the dorsomedial dorsal raphe nucleus and chronic anxiety

Nina C. Donner, Sofia M. Davies, Stephanie D. Fitz, Drake M. Kienzle, Anantha Shekhar, Christopher A. Lowry

Research output: Contribution to journalArticle

Abstract

The bed nucleus of the stria terminalis (BNST) is a nodal structure in neural circuits controlling anxiety-related defensive behavioral responses. It contains neurons expressing the stress- and anxiety-related neuropeptide corticotropin-releasing hormone (Crh) as well as Crh receptors. Repeated daily subthreshold activation of Crh receptors in the BNST is known to induce a chronic anxiety-like state, but how this affects neurotransmitter-relevant gene expression in target regions of the BNST is still unclear. Since the BNST projects heavily to the dorsal raphe nucleus (DR), the main source of brain serotonin, we here tested the hypothesis that such repeated, anxiety-inducing activation of Crh receptors in the BNST alters the expression of serotonergic genes in the DR, including tph2, the gene encoding the rate-limiting enzyme for brain serotonin synthesis, and slc6a4, the gene encoding the serotonin transporter (SERT). For 5 days, adult male Wistar rats received daily, bilateral, intra-BNST microinjections of vehicle (1% bovine serum albumin in 0.9% saline, n = 11) or behaviorally subthreshold doses of urocortin 1 (Ucn1, n = 11), a potent Crh receptor agonist. Priming with Ucn1 increased tph2 mRNA expression selectively within the anxiety-related dorsal part of the DR (DRD) and decreased social interaction (SI) time, a measure of anxiety-related defensive behavioral responses in rodents. Decreased social interaction was strongly correlated with increased tph2 mRNA expression in the DRD. Together with previous studies, our data are consistent with the hypothesis that Crh-mediated control of the BNST/DRD-serotonergic system plays a key role in the development of chronic anxiety states, possibly also contributing to stress-induced relapses in drug abuse and addiction behavior.

Original languageEnglish (US)
Article number109730
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume96
DOIs
StatePublished - Jan 10 2020

Fingerprint

Corticotropin-Releasing Hormone Receptors
Septal Nuclei
Anxiety
Gene Expression
Corticotropin-Releasing Hormone
Interpersonal Relations
Substance-Related Disorders
Serotonin
Urocortins
Serotonin Plasma Membrane Transport Proteins
Messenger RNA
Brain
Microinjections
Bovine Serum Albumin
Dorsal Raphe Nucleus
Neuropeptides
Genes
Neurotransmitter Agents
Wistar Rats
Rodentia

Keywords

  • Anxiety
  • Chronic anxiety
  • Dorsal raphe nucleus
  • Serotonin transporter
  • tph2
  • Tryptophan hydroxylase 2

ASJC Scopus subject areas

  • Pharmacology
  • Biological Psychiatry

Cite this

Crh receptor priming in the bed nucleus of the stria terminalis (BNST) induces tph2 gene expression in the dorsomedial dorsal raphe nucleus and chronic anxiety. / Donner, Nina C.; Davies, Sofia M.; Fitz, Stephanie D.; Kienzle, Drake M.; Shekhar, Anantha; Lowry, Christopher A.

In: Progress in Neuro-Psychopharmacology and Biological Psychiatry, Vol. 96, 109730, 10.01.2020.

Research output: Contribution to journalArticle

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abstract = "The bed nucleus of the stria terminalis (BNST) is a nodal structure in neural circuits controlling anxiety-related defensive behavioral responses. It contains neurons expressing the stress- and anxiety-related neuropeptide corticotropin-releasing hormone (Crh) as well as Crh receptors. Repeated daily subthreshold activation of Crh receptors in the BNST is known to induce a chronic anxiety-like state, but how this affects neurotransmitter-relevant gene expression in target regions of the BNST is still unclear. Since the BNST projects heavily to the dorsal raphe nucleus (DR), the main source of brain serotonin, we here tested the hypothesis that such repeated, anxiety-inducing activation of Crh receptors in the BNST alters the expression of serotonergic genes in the DR, including tph2, the gene encoding the rate-limiting enzyme for brain serotonin synthesis, and slc6a4, the gene encoding the serotonin transporter (SERT). For 5 days, adult male Wistar rats received daily, bilateral, intra-BNST microinjections of vehicle (1{\%} bovine serum albumin in 0.9{\%} saline, n = 11) or behaviorally subthreshold doses of urocortin 1 (Ucn1, n = 11), a potent Crh receptor agonist. Priming with Ucn1 increased tph2 mRNA expression selectively within the anxiety-related dorsal part of the DR (DRD) and decreased social interaction (SI) time, a measure of anxiety-related defensive behavioral responses in rodents. Decreased social interaction was strongly correlated with increased tph2 mRNA expression in the DRD. Together with previous studies, our data are consistent with the hypothesis that Crh-mediated control of the BNST/DRD-serotonergic system plays a key role in the development of chronic anxiety states, possibly also contributing to stress-induced relapses in drug abuse and addiction behavior.",
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AU - Shekhar, Anantha

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