Fear response-based prediction for stress susceptibility to PTSD-like phenotypes

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Abstract

Most individuals undergo traumatic stresses at some points in their life, but only a small proportion develop stress-related disorders such as anxiety diseases and posttraumatic stress disorder (PTSD). Although stress susceptibility is one determinant of mental disorders, the underlying mechanisms and functional implication remain unclear yet. We found that an increased amount of freezing that animals exhibited in the intertrial interval (ITI) of a stress-enhanced fear learning paradigm, predicts ensuing PTSD-like symptoms whereas resilient mice show ITI freezing comparable to that of unstressed mice. To examine the behavioral features, we developed a systematic analytical approach for ITI freezing and stress susceptibility. Thus, we provide a behavioral parameter for prognosis to stress susceptibility of individuals in the development of PTSD-like symptoms as well as a new mathematical means to scrutinize freezing behavior.

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MicroRNA as repressors of stress-induced anxiety: the case of amygdalar miR-34.

Sharon Haramati, Inbal Navon, Orna Issler … (2011)

The etiology and pathophysiology of anxiety and mood disorders is linked to inappropriate regulation of the central stress response. To determine whether microRNAs have a functional role in the regulation of the stress response, we inactivated microRNA processing by a lentiviral-induced local ablation of the Dicer gene in the central amygdala (CeA) of adult mice. CeA Dicer ablation induced a robust increase in anxiety-like behavior, whereas manipulated neurons survive and appear to exhibit normal gross morphology in the time period examined. We also observed that acute stress in wild-type mice induced a differential expression profile of microRNAs in the amygdala. Bioinformatic analysis identified putative gene targets for these stress-responsive microRNAs, some of which are known to be associated with stress. One of the prominent stress-induced microRNAs found in this screen, miR-34c, was further confirmed to be upregulated after acute and chronic stressful challenge and downregulated in Dicer ablated cells. Lentivirally mediated overexpression of miR34c specifically within the adult CeA induced anxiolytic behavior after challenge. Of particular interest, one of the miR-34c targets is the stress-related corticotropin releasing factor receptor type 1 (CRFR1) mRNA, regulated via a single evolutionary conserved seed complementary site on its 3' UTR. Additional in vitro studies demonstrated that miR-34c reduces the responsiveness of cells to CRF in neuronal cells endogenously expressing CRFR1. Our results suggest a physiological role for microRNAs in regulating the central stress response and position them as potential targets for treatment of stress-related disorders.

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Single prolonged stress disrupts retention of extinguished fear in rats.

S. George, Christine Rabinak, Christopher J Fitzpatrick … (2012)

Clinical research has linked post-traumatic stress disorder (PTSD) with deficits in fear extinction. However, it is not clear whether these deficits result from stress-related changes in the acquisition or retention of extinction or in the regulation of extinction memories by context, for example. In this study, we used the single prolonged stress (SPS) animal model of PTSD and fear conditioning procedures to examine the effects of prior traumatic stress on the acquisition, retention, and context-specificity of extinction. SPS administered one week prior to fear conditioning had no effect on the acquisition of fear conditioning or extinction but disrupted the retention of extinction memories for both contextual and cued fear. This SPS effect required a post-stress incubation period to manifest. The results demonstrate that SPS disrupts extinction retention, leading to enhanced fear renewal; further research is needed to identify the neurobiological processes through which SPS induces these effects.

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Neuronal encoding of the switch from specific to generalized fear.

Supriya Ghosh, Sumantra Chattarji (2015)

Fear memories are crucial for survival. However, excessive generalization of such memories, characterized by a failure to discriminate dangerous from safe stimuli, is common in anxiety disorders. Neuronal encoding of the transition from cue-specific to generalized fear is poorly understood. We identified distinct neuronal populations in the lateral amygdala (LA) of rats that signaled generalized versus cue-specific associations and determined how their distributions switched during fear generalization. Notably, the same LA neurons that were cue specific before the behavioral shift to generalized fear lost their specificity afterwards, thereby tilting the balance of activity toward a greater proportion of generalizing neurons. Neuronal activity in the LA, but not the auditory cortex, was necessary for fear generalization. Furthermore, targeted activation of cAMP-PKA signaling in the LA increased neuronal excitability of LA neurons and led to generalized fear. These results provide a cellular basis in the amygdala for the alteration of emotional states from normal to pathological fear.

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Author and article information

Contributors

Joung-Hun Kim: joungkim@postech.ac.kr

Journal

Journal ID (nlm-ta): Mol Brain

Journal ID (iso-abbrev): Mol Brain

Title: Molecular Brain

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-6606

Publication date (Electronic): 7 October 2020

Publication date PMC-release: 7 October 2020

Publication date Collection: 2020

Volume: 13

Electronic Location Identifier: 134

Affiliations

[1 ]GRID grid.49100.3c, ISNI 0000 0001 0742 4007, Department of Life Sciences, , Pohang University of Science and Technology (POSTECH), ; Pohang, Gyungbuk 37673 Republic of Korea

[2 ]GRID grid.49100.3c, ISNI 0000 0001 0742 4007, Department of Mathematics, , Pohang University of Science and Technology (POSTECH), ; Pohang, Gyungbuk 37673 Republic of Korea

[3 ]GRID grid.42327.30, ISNI 0000 0004 0473 9646, Program in Neurosciences and Mental Health, , Hospital for Sick Children, ; Toronto, Ontario Canada

Article

Publisher ID: 667

DOI: 10.1186/s13041-020-00667-5

PMC ID: 7539418

SO-VID: 050f8fcf-1be7-409b-ac3c-dcce7420a587

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 19 July 2020

Date accepted : 8 September 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100003725, National Research Foundation of Korea;

Award ID: 2018R1A3B1052079

Award ID: 2018M3C7A1024152

Award Recipient : Joung-Hun Kim

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ScienceOpen disciplines: Neurosciences

Keywords: ptsd,stress,fear conditioning,iti

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ScienceOpen disciplines: Neurosciences

Keywords: ptsd, stress, fear conditioning, iti

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Fear response-based prediction for stress susceptibility to PTSD-like phenotypes

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Most cited references 24

MicroRNA as repressors of stress-induced anxiety: the case of amygdalar miR-34.

Single prolonged stress disrupts retention of extinguished fear in rats.

Neuronal encoding of the switch from specific to generalized fear.

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