Orexin receptor-1 in the locus coeruleus plays an important role in cue-dependent fear memory consolidation

Shingo Soya, Hirotaka Shoji, Emi Hasegawa, Mari Hondo, Tsuyoshi Miyakawa, Masashi Yanagisawa, Michihiro Mieda, Takeshi Sakurai

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

The noradrenergic (NA) projections arising from the locus ceruleus (LC) to the amygdala and bed nucleus of the stria terminalis have been implicated in the formation of emotional memory. Since NA neurons in the LC (LC-NA neurons) abundantly express orexin receptor-1 (OX1R) and receive prominent innervation by orexin-producing neurons, we hypothesized that an OX1R-mediated pathway is involved in the physiological fear learning process via regulation of LC-NA neurons. To evaluate this hypothesis, we examined the phenotype of Ox1r-/- mice in the classic cued and contextual fear-conditioning test. We found that Ox1r-/- mice showed impaired freezing responses in both cued and contextual fear-conditioning paradigms. In contrast, Ox2r-/- mice showed normal freezing behavior in the cued fear-conditioning test, while they exhibited shorter freezing time in the contextual fear-conditioning test. Double immunolabeling of Fos and tyrosine hydroxylase showed that double-positive LC-NA neurons after test sessions of both cued and contextual stimuli were significantly fewer in Ox1r-/- mice. AAV-mediated expression of OX1R in LC-NA neurons in Ox1r-/- mice restored the freezing behavior to the auditory cue to a comparable level to that in wild-type mice in the test session. Decreased freezing time during the contextual fear test was not affected by restoring OX1R expression in LC-NA neurons. These observations support the hypothesis that the orexin system modulates the formation and expression of fear memory via OX1R in multiple pathways. Especially, OX1R in LC-NA neurons plays an important role in cue-dependent fear memory formation and/or retrieval.

Original languageEnglish
Pages (from-to)14549-14557
Number of pages9
JournalJournal of Neuroscience
Volume33
Issue number36
DOIs
Publication statusPublished - 09-09-2013

Fingerprint

Orexin Receptors
Locus Coeruleus
Adrenergic Neurons
Fear
Cues
Freezing
Septal Nuclei
Memory Consolidation
Tyrosine 3-Monooxygenase
Amygdala
Learning
Phenotype
Neurons

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Soya, Shingo ; Shoji, Hirotaka ; Hasegawa, Emi ; Hondo, Mari ; Miyakawa, Tsuyoshi ; Yanagisawa, Masashi ; Mieda, Michihiro ; Sakurai, Takeshi. / Orexin receptor-1 in the locus coeruleus plays an important role in cue-dependent fear memory consolidation. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 36. pp. 14549-14557.
@article{70df753287694652a8aaeae548348c76,
title = "Orexin receptor-1 in the locus coeruleus plays an important role in cue-dependent fear memory consolidation",
abstract = "The noradrenergic (NA) projections arising from the locus ceruleus (LC) to the amygdala and bed nucleus of the stria terminalis have been implicated in the formation of emotional memory. Since NA neurons in the LC (LC-NA neurons) abundantly express orexin receptor-1 (OX1R) and receive prominent innervation by orexin-producing neurons, we hypothesized that an OX1R-mediated pathway is involved in the physiological fear learning process via regulation of LC-NA neurons. To evaluate this hypothesis, we examined the phenotype of Ox1r-/- mice in the classic cued and contextual fear-conditioning test. We found that Ox1r-/- mice showed impaired freezing responses in both cued and contextual fear-conditioning paradigms. In contrast, Ox2r-/- mice showed normal freezing behavior in the cued fear-conditioning test, while they exhibited shorter freezing time in the contextual fear-conditioning test. Double immunolabeling of Fos and tyrosine hydroxylase showed that double-positive LC-NA neurons after test sessions of both cued and contextual stimuli were significantly fewer in Ox1r-/- mice. AAV-mediated expression of OX1R in LC-NA neurons in Ox1r-/- mice restored the freezing behavior to the auditory cue to a comparable level to that in wild-type mice in the test session. Decreased freezing time during the contextual fear test was not affected by restoring OX1R expression in LC-NA neurons. These observations support the hypothesis that the orexin system modulates the formation and expression of fear memory via OX1R in multiple pathways. Especially, OX1R in LC-NA neurons plays an important role in cue-dependent fear memory formation and/or retrieval.",
author = "Shingo Soya and Hirotaka Shoji and Emi Hasegawa and Mari Hondo and Tsuyoshi Miyakawa and Masashi Yanagisawa and Michihiro Mieda and Takeshi Sakurai",
year = "2013",
month = "9",
day = "9",
doi = "10.1523/JNEUROSCI.1130-13.2013",
language = "English",
volume = "33",
pages = "14549--14557",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "36",

}

Orexin receptor-1 in the locus coeruleus plays an important role in cue-dependent fear memory consolidation. / Soya, Shingo; Shoji, Hirotaka; Hasegawa, Emi; Hondo, Mari; Miyakawa, Tsuyoshi; Yanagisawa, Masashi; Mieda, Michihiro; Sakurai, Takeshi.

In: Journal of Neuroscience, Vol. 33, No. 36, 09.09.2013, p. 14549-14557.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Orexin receptor-1 in the locus coeruleus plays an important role in cue-dependent fear memory consolidation

AU - Soya, Shingo

AU - Shoji, Hirotaka

AU - Hasegawa, Emi

AU - Hondo, Mari

AU - Miyakawa, Tsuyoshi

AU - Yanagisawa, Masashi

AU - Mieda, Michihiro

AU - Sakurai, Takeshi

PY - 2013/9/9

Y1 - 2013/9/9

N2 - The noradrenergic (NA) projections arising from the locus ceruleus (LC) to the amygdala and bed nucleus of the stria terminalis have been implicated in the formation of emotional memory. Since NA neurons in the LC (LC-NA neurons) abundantly express orexin receptor-1 (OX1R) and receive prominent innervation by orexin-producing neurons, we hypothesized that an OX1R-mediated pathway is involved in the physiological fear learning process via regulation of LC-NA neurons. To evaluate this hypothesis, we examined the phenotype of Ox1r-/- mice in the classic cued and contextual fear-conditioning test. We found that Ox1r-/- mice showed impaired freezing responses in both cued and contextual fear-conditioning paradigms. In contrast, Ox2r-/- mice showed normal freezing behavior in the cued fear-conditioning test, while they exhibited shorter freezing time in the contextual fear-conditioning test. Double immunolabeling of Fos and tyrosine hydroxylase showed that double-positive LC-NA neurons after test sessions of both cued and contextual stimuli were significantly fewer in Ox1r-/- mice. AAV-mediated expression of OX1R in LC-NA neurons in Ox1r-/- mice restored the freezing behavior to the auditory cue to a comparable level to that in wild-type mice in the test session. Decreased freezing time during the contextual fear test was not affected by restoring OX1R expression in LC-NA neurons. These observations support the hypothesis that the orexin system modulates the formation and expression of fear memory via OX1R in multiple pathways. Especially, OX1R in LC-NA neurons plays an important role in cue-dependent fear memory formation and/or retrieval.

AB - The noradrenergic (NA) projections arising from the locus ceruleus (LC) to the amygdala and bed nucleus of the stria terminalis have been implicated in the formation of emotional memory. Since NA neurons in the LC (LC-NA neurons) abundantly express orexin receptor-1 (OX1R) and receive prominent innervation by orexin-producing neurons, we hypothesized that an OX1R-mediated pathway is involved in the physiological fear learning process via regulation of LC-NA neurons. To evaluate this hypothesis, we examined the phenotype of Ox1r-/- mice in the classic cued and contextual fear-conditioning test. We found that Ox1r-/- mice showed impaired freezing responses in both cued and contextual fear-conditioning paradigms. In contrast, Ox2r-/- mice showed normal freezing behavior in the cued fear-conditioning test, while they exhibited shorter freezing time in the contextual fear-conditioning test. Double immunolabeling of Fos and tyrosine hydroxylase showed that double-positive LC-NA neurons after test sessions of both cued and contextual stimuli were significantly fewer in Ox1r-/- mice. AAV-mediated expression of OX1R in LC-NA neurons in Ox1r-/- mice restored the freezing behavior to the auditory cue to a comparable level to that in wild-type mice in the test session. Decreased freezing time during the contextual fear test was not affected by restoring OX1R expression in LC-NA neurons. These observations support the hypothesis that the orexin system modulates the formation and expression of fear memory via OX1R in multiple pathways. Especially, OX1R in LC-NA neurons plays an important role in cue-dependent fear memory formation and/or retrieval.

UR - http://www.scopus.com/inward/record.url?scp=84883441101&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84883441101&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.1130-13.2013

DO - 10.1523/JNEUROSCI.1130-13.2013

M3 - Article

VL - 33

SP - 14549

EP - 14557

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 36

ER -