Cargando…
Incerto-thalamic modulation of fear via GABA and dopamine
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 i...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280196/ https://www.ncbi.nlm.nih.gov/pubmed/33864008 http://dx.doi.org/10.1038/s41386-021-01006-5 |
_version_ | 1783722601220145152 |
---|---|
author | Venkataraman, Archana Hunter, Sarah C. Dhinojwala, Maria Ghebrezadik, Diana Guo, JiDong Inoue, Kiyoshi Young, Larry J. Dias, Brian George |
author_facet | Venkataraman, Archana Hunter, Sarah C. Dhinojwala, Maria Ghebrezadik, Diana Guo, JiDong Inoue, Kiyoshi Young, Larry J. Dias, Brian George |
author_sort | Venkataraman, Archana |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8280196 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-82801962021-07-23 Incerto-thalamic modulation of fear via GABA and dopamine Venkataraman, Archana Hunter, Sarah C. Dhinojwala, Maria Ghebrezadik, Diana Guo, JiDong Inoue, Kiyoshi Young, Larry J. Dias, Brian George Neuropsychopharmacology Article 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. Springer International Publishing 2021-04-16 2021-08 /pmc/articles/PMC8280196/ /pubmed/33864008 http://dx.doi.org/10.1038/s41386-021-01006-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Venkataraman, Archana Hunter, Sarah C. Dhinojwala, Maria Ghebrezadik, Diana Guo, JiDong Inoue, Kiyoshi Young, Larry J. Dias, Brian George Incerto-thalamic modulation of fear via GABA and dopamine |
title | Incerto-thalamic modulation of fear via GABA and dopamine |
title_full | Incerto-thalamic modulation of fear via GABA and dopamine |
title_fullStr | Incerto-thalamic modulation of fear via GABA and dopamine |
title_full_unstemmed | Incerto-thalamic modulation of fear via GABA and dopamine |
title_short | Incerto-thalamic modulation of fear via GABA and dopamine |
title_sort | incerto-thalamic modulation of fear via gaba and dopamine |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280196/ https://www.ncbi.nlm.nih.gov/pubmed/33864008 http://dx.doi.org/10.1038/s41386-021-01006-5 |
work_keys_str_mv | AT venkataramanarchana incertothalamicmodulationoffearviagabaanddopamine AT huntersarahc incertothalamicmodulationoffearviagabaanddopamine AT dhinojwalamaria incertothalamicmodulationoffearviagabaanddopamine AT ghebrezadikdiana incertothalamicmodulationoffearviagabaanddopamine AT guojidong incertothalamicmodulationoffearviagabaanddopamine AT inouekiyoshi incertothalamicmodulationoffearviagabaanddopamine AT younglarryj incertothalamicmodulationoffearviagabaanddopamine AT diasbriangeorge incertothalamicmodulationoffearviagabaanddopamine |