Incerto-thalamic modulation of fear via GABA and dopamine

• Type of Material: Article
• Authors: Archana Venkataraman, Emory University; Sarah C. Hunter, Emory University; Maria Dhinojwala, Emory University; Diana Ghebrezadik, Agnes Scott College; Jidong Guo, Emory University; Kiyoshi Inoue, Emory University; Larry Young, Emory University; Brian Dias, Emory University
• Language: English
• Date: 2021-08-01
• Publisher: Springer Nature [academic journals on nature.com]
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41386-021-01006-5
• Title of Journal or Parent Work: NEUROPSYCHOPHARMACOLOGY
• Volume: 46
• Issue: 9
• Start Page: 1658
• End Page: 1668
• Grant/Funding Information: Funding for this study was provided to BGD by the US National Institute of Health (R01MH120133) which included support of AV and JG. Support to BGD was also provided by the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine, the Yerkes National Primate Research Center (YNPRC), the Department of Pediatrics at USC Keck School of Medicine, the Division of Research on Children, Youth & Families at Children’s Hospital Los Angeles, and the Developmental Neuroscience and Neurogenetics Program at The Saban Research Institute. AV was also supported by the Emory University Women’s Club Memorial Fellowship Award. LJY and KI were supported by P50MH100023 to LJY. JG’s contributions were also supported by R01MH072908 to LJY. Additional funding was provided to Yerkes National Primate Research Center by Office of Research Infrastructure Programs ODP51OD11132. The authors have no competing financial interests or potential conflicts of interest.
• Keywords: Classical conditioning; Behavioural methods
• Research Categories: Biology, Neuroscience; Psychology, Cognitive

Abstract

Fear generalization and deficits in extinction learning are debilitating dimensions of Post-Traumatic Stress Disorder (PTSD). Most understanding of the neurobiology underlying these dimensions comes from studies of cortical and limbic brain regions. While thalamic and subthalamic regions have been implicated in modulating fear, the potential for incerto-thalamic pathways to suppress fear generalization and rescue deficits in extinction recall remains unexplored. We first used patch-clamp electrophysiology to examine functional connections between the subthalamic zona incerta and thalamic reuniens (RE). Optogenetic stimulation of GABAergic ZI → RE cell terminals in vitro induced inhibitory post-synaptic currents (IPSCs) in the RE. We then combined high-intensity discriminative auditory fear conditioning with cell-type-specific and projection-specific optogenetics in mice to assess functional roles of GABAergic ZI → RE cell projections in modulating fear generalization and extinction recall. In addition, we used a similar approach to test the possibility of fear generalization and extinction recall being modulated by a smaller subset of GABAergic ZI → RE cells, the A13 dopaminergic cell population. Optogenetic stimulation of GABAergic ZI → RE cell terminals attenuated fear generalization and enhanced extinction recall. In contrast, optogenetic stimulation of dopaminergic ZI → RE cell terminals had no effect on fear generalization but enhanced extinction recall in a dopamine receptor D1-dependent manner. Our findings shed new light on the neuroanatomy and neurochemistry of ZI-located cells that contribute to adaptive fear by increasing the precision and extinction of learned associations. In so doing, these data reveal novel neuroanatomical substrates that could be therapeutically targeted for treatment of PTSD.