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Gastrin-releasing peptide regulates fear learning under stressed conditions via activation of the amygdalostriatal transition area

Molecular Psychiatry volume 27, pages 1694–1703 (2022)Cite this article

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Abstract

The amygdala, a critical brain region responsible for emotional behavior, is crucially involved in the regulation of the effects of stress on emotional behavior. In the mammalian forebrain, gastrin-releasing peptide (GRP), a 27-amino-acid mammalian neuropeptide, which is a homolog of the 14-amino-acid amidated amphibian peptide bombesin, is highly expressed in the amygdala. The levels of GRP are markedly increased in the amygdala after acute stress; therefore, it is known as a stress-activated modulator. To determine the role of GRP in emotional behavior under stress, we conducted some behavioral and biochemical experiments with GRP-knockout (KO) mice. GRP-KO mice exhibited a longer freezing response than wild-type (WT) littermates in both contextual and auditory fear (also known as threat) conditioning tests only when they were subjected to acute restraint stress 20 min before the conditioning. To identify the critical neural circuits associated with the regulation of emotional memory by GRP, we conducted Arc/Arg3.1-reporter mapping in the amygdala with an Arc-Venus reporter transgenic mouse line. In the amygdalostriatal transition area (AST) and the lateral side of the basal nuclei, fear conditioning after restraint stress increased neuronal activity significantly in WT mice, and GRP KO was found to negate this potentiation only in the AST. These results indicate that the GRP-activated neurons in the AST are likely to suppress excessive fear expression through the regulation of downstream circuits related to fear learning following acute stress.

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Fig. 1: Contextual and auditory fear learning in GRP-KO mice with or without prior stress.
Fig. 2: Neuronal activity in the amygdaloid complex examined using Arc-Venus mice.
Fig. 3: Analysis of Venus fluorescence intensities with Arc-Venus mice using bubble charts.
Fig. 4: Analysis of Venus-positive neurons in the AST.
Fig. 5: Characteristics of AST neurons.

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Acknowledgements

We thank S. Sato, N. Numata, M. Nagai, Y. Watanabe, and R. Shiojiri for maintaining mouse colonies and R.S. Suzuki for technical assistances. This work was supported by JSPS KAKENHI Grant Number 21200006, 15K01848 and 19K07799 to YK; 18H05127, 19H03328 and 20H05068 to HO; 15H02358, 17K19442, and 17H06312 to HB; 18100003, 23220008, 25116505, 15K14309, 19H03321 and 19H04876 to TM.

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Authors and Affiliations

  1. Division of Neuronal Network, Department of Basic Medical Sciences, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan

    Fumiko Goto, Yuji Kiyama, Itone Ogawa & Toshiya Manabe

  2. Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, 153-8904, Japan

    Yuji Kiyama, Motonobu Anai & Tatsuhiko Kodama

  3. Department of Biochemistry and Molecular Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8544, Japan

    Yuji Kiyama & Hiroyuki Okuno

  4. Department of Neurochemistry, Graduate School of Medicine, University of Tokyo, Tokyo, 113-0033, Japan

    Hiroyuki Okuno & Haruhiko Bito

  5. Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan

    Taeko Ichise, Hirotake Ichise & Nobuaki Yoshida

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  1. Fumiko Goto
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Contributions

YK and TM conceived the idea and coordinated the study. IO, TI, HI, and NY generated GRP-KO mice. FG and YK performed the behavioral experiments. HO and HB generated Arc-Venus reporter transgenic mouse. FG, YK, and IO performed histological analysis. MA and TK provided support for paper writing. FG, YK, and TM participated in paper writing.

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Correspondence to Yuji Kiyama or Toshiya Manabe.

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Goto, F., Kiyama, Y., Ogawa, I. et al. Gastrin-releasing peptide regulates fear learning under stressed conditions via activation of the amygdalostriatal transition area. Mol Psychiatry 27, 1694–1703 (2022). https://doi.org/10.1038/s41380-021-01408-3

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