Amygdala DCX and blood Cdk14 are implicated as cross-species indicators of individual differences in fear, extinction, and resilience to trauma exposure

• Type of Material: Article
• Authors: ME Maheu, McLean Hospital; Sanjay Sharma, Emory University; G King, The University of New South Wales; SA Maddox, McLean Hospital; Aliza Wingo, Emory University; Adriana Lori, Emory University; Vasiliki Michopoulos, Emory University; R Richardson, The University of New South Wales; Kerry Ressler, Emory University
• Language: English
• Date: 2021-11-02
• Publisher: SPRINGERNATURE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021, The Author(s), under exclusive licence to Springer Nature Limited
• Final Published Version (URL): http://dx.doi.org/10.1038/s41380-021-01353-1
• Title of Journal or Parent Work: MOLECULAR PSYCHIATRY
• Volume: 27
• Issue: 2
• Start Page: 956
• End Page: 966
• Grant/Funding Information: Dr. Ressler has performed scientific consultation for Bioxcel, Bionomics, and Jazz Pharma; served on Scientific Advisory Boards for Janssen, Sage, Acer Therapeutics, Verily, and the Brain Research Foundation, and he has received sponsored research support from Takeda, Alto Neuroscience, and Brainsway. None of these relationships are related to this manuscript. He receives funding from NIH and the Brain and Behavior Research Fund.; MEM is supported by a fellowship from the Canadian Institutes of Health Research. Support was also provided by the American Heart Association, AHA Award #15CSA2430001, the Australian Research Council, DP150104835, and the National Institutes of Health: MH108665, MH110441, MH100122, HD088931 and MH115874.
• Keywords: NEURONS; DOUBLECORTIN; MIGRATION; Biochemistry & Molecular Biology; Neurosciences; PLASTICITY; EXPRESSION; Science & Technology; STRESS; MEMORY; Psychiatry; KINASE; Neurosciences & Neurology; Life Sciences & Biomedicine; SURVIVAL; TASK-DIFFICULTY

Abstract

Doublecortin (DCX) has long been implicated in, and employed as a marker for, neurogenesis, yet little is known about its function in non-neurogenic brain regions, including the amygdala. This study sought first to explore, in rodents, whether fear learning and extinction modulate amygdala DCX expression and, second, to assess the utility of peripheral DCX correlates as predictive biomarkers of trauma response in rodents and humans. Pavlovian conditioning was found to alter DCX protein levels in mice 24 h later, resulting in higher DCX expression associated with enhanced learning in paradigms examining both the acquisition and extinction of fear (p < 0.001). This, in turn, is associated with differences in freezing on subsequent fear expression tests, and the same relationship between DCX and fear extinction was replicated in rats (p < 0.001), with higher amygdala DCX levels associated with more rapid extinction of fear. RNAseq of amygdala and blood from mice identified 388 amygdala genes that correlated with DCX (q < 0.001) and which gene ontology analyses revealed were significantly over-represented for neurodevelopmental processes. In blood, DCX-correlated genes included the Wnt signaling molecule Cdk14 which was found to predict freezing during both fear acquisition (p < 0.05) and brief extinction protocols (p < 0.001). High Cdk14 measured in blood immediately after testing was also associated with less freezing during fear expression testing (p < 0.01). Finally, in humans, Cdk14 expression in blood taken shortly after trauma was found to predict resilience in males for up to a year post-trauma (p < 0.0001). These data implicate amygdala DCX in fear learning and suggest that Cdk14 may serve as a predictive biomarker of trauma response.