Modulation of fear generalization by the zona incerta

• Type of Material: Article
• Authors: Archana Venkataraman, Emory University; Natalia Brody, Yerkes National Primate Research Center; Preethi Reddi, Yerkes National Primate Research Center; Jidong Guo, Emory University; Donald Rainnie, Emory University; Brian Dias, Emory University
• Language: English
• Date: 2019-04-30
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2019 National Academy of Sciences. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1820541116
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• Volume: 116
• Issue: 18
• Start Page: 9072
• End Page: 9077
• Grant/Funding Information: Additional funding was provided to the YNPRC by the Office of Research Infrastructure Programs (Grant ODP51OD11132).; Funding was provided to B.G.D. by the Department of Psychiatry and Behavioral Sciences, the Brain Health Center, the Yerkes National Primate Research Center (YNPRC), a Canadian Institute for Advanced Research (CIFAR) Azrieli Global Scholar Award, and the Catherine Shopshire Hardman Fund.
• Keywords: MEMORY; ANXIETY; LESIONS; Science & Technology; anxiety; STRIA TERMINALIS; CONTEXT FEAR; AUDITORY THALAMUS; posttraumatic stress disorder; Multidisciplinary Sciences; subthalamic; AMYGDALA; NEURONS; BED NUCLEUS; fear inhibition; CONDITIONED FEAR; Science & Technology - Other Topics; trauma
• Research Categories: Biology, Neuroscience; Psychology, Behavioral

Abstract

Fear expressed toward threat-associated stimuli is an adaptive behavioral response. In contrast, the generalization of fear responses toward nonthreatening cues is a maladaptive and debilitating dimension of trauma- and anxiety-related disorders. Expressing fear to appropriate stimuli and suppressing fear generalization require integration of relevant sensory information and motor output. While thalamic and subthalamic brain regions play important roles in sensorimotor integration, very little is known about the contribution of these regions to the phenomenon of fear generalization. In this study, we sought to determine whether fear generalization could be modulated by the zona incerta (ZI), a subthalamic brain region that influences sensory discrimination, defensive responses, and retrieval of fear memories. To do so, we combined differential intensity-based auditory fear conditioning protocols in mice with C-FOS immunohistochemistry and designer receptors exclusively activated by designer drugs (DREADDs)-based manipulation of neuronal activity in the ZI. C-FOS immunohistochemistry revealed an inverse relationship between ZI activation and fear generalization: The ZI was less active in animals that generalized fear. In agreement with this relationship, chemogenetic inhibition of the ZI resulted in fear generalization, while chemogenetic activation of the ZI suppressed fear generalization. Furthermore, targeted stimulation of GABAergic cells in the ZI reduced fear generalization. To conclude, our data suggest that stimulation of the ZI could be used to treat fear generalization in the context of trauma- and anxiety-related disorders.