Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory
Background Prior exposure to stress is a risk factor for developing posttraumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon....
| Main Authors: | , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/102424 https://orcid.org/0000-0003-2218-7489 https://orcid.org/0000-0002-0419-3351 |
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| author | Baratta, Michael V. Monahan, Patrick E. Yao, Junmei Weber, Michael D. Lin, Pei-Ann Gisabella, Barbara Petrossian, Natalie Amat, Jose Kim, Kyungman Yang, Aimei Forest, Craig R. Goosens, Ki Ann Kodandaramaiah, Suhasa Bangalo Boyden, Edward |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Baratta, Michael V. Monahan, Patrick E. Yao, Junmei Weber, Michael D. Lin, Pei-Ann Gisabella, Barbara Petrossian, Natalie Amat, Jose Kim, Kyungman Yang, Aimei Forest, Craig R. Goosens, Ki Ann Kodandaramaiah, Suhasa Bangalo Boyden, Edward |
| author_sort | Baratta, Michael V. |
| collection | MIT |
| description | Background
Prior exposure to stress is a risk factor for developing posttraumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon.
Methods
Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacologic manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior.
Results
Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2C receptor (5-HT2CR) activity during memory consolidation were necessary for stress enhancement of fear memory, but neither process affected fear memory in unstressed mice. Additionally, prior stress increased amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also showed that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning.
Conclusions
Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD. |
| first_indexed | 2024-09-23T13:03:00Z |
| format | Article |
| id | mit-1721.1/102424 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:03:00Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1024242022-10-01T12:46:36Z Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory Baratta, Michael V. Monahan, Patrick E. Yao, Junmei Weber, Michael D. Lin, Pei-Ann Gisabella, Barbara Petrossian, Natalie Amat, Jose Kim, Kyungman Yang, Aimei Forest, Craig R. Goosens, Ki Ann Kodandaramaiah, Suhasa Bangalo Boyden, Edward Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Massachusetts Institute of Technology. Media Laboratory McGovern Institute for Brain Research at MIT MIT Intelligence Initiative Program in Media Arts and Sciences (Massachusetts Institute of Technology) Baratta, Michael V. Kodandaramaiah, Suhasa B. Monahan, Patrick E. Yao, Junmei Lin, Pei-Ann Gisabella, Barbara Petrossian, Natalie Kim, Kyungman Yang, Aimei Boyden, Edward Stuart Goosens, Ki Ann Background Prior exposure to stress is a risk factor for developing posttraumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon. Methods Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacologic manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior. Results Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2C receptor (5-HT2CR) activity during memory consolidation were necessary for stress enhancement of fear memory, but neither process affected fear memory in unstressed mice. Additionally, prior stress increased amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also showed that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning. Conclusions Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD. United States. Dept. of Defense. Congressionally Directed Medical Research Programs Posttraumatic Stress Disorder Program Human Frontier Science Program (Strasbourg, France) McGovern Institute for Brain Research at MIT McGovern Institute for Brain Research at MIT. Neurotechnology Program Massachusetts Institute of Technology. Media Laboratory Massachusetts Institute of Technology. Mind-Machine Project National Alliance for Research on Schizophrenia and Depression National Institutes of Health (U.S.) (Director's New Innovator Award 1DP2OD002002) National Institutes of Health (U.S.) (Grant 1R01DA029639) National Institutes of Health (U.S.) (Grant 1R43NS070453) National Institutes of Health (U.S.) (Grant 1RC1MH088182) Alfred P. Sloan Foundation National Institute of Mental Health (U.S.) (R01 MH084966) United States. Army Research Laboratory United States. Army Research Office (Grant 58076-LS-DRP) 2016-05-09T13:51:44Z 2016-05-09T13:51:44Z 2015-07 2015-06 Article http://purl.org/eprint/type/JournalArticle 00063223 http://hdl.handle.net/1721.1/102424 Baratta, Michael V., Suhasa B. Kodandaramaiah, Patrick E. Monahan, Junmei Yao, Michael D. Weber, Pei-Ann Lin, Barbara Gisabella, et al. “Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory.” Biological Psychiatry 79, no. 10 (May 2016): 814–22. https://orcid.org/0000-0003-2218-7489 https://orcid.org/0000-0002-0419-3351 en_US http://dx.doi.org/10.1016/j.biopsych.2015.06.025 Biological Psychiatry Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier Elsevier |
| spellingShingle | Baratta, Michael V. Monahan, Patrick E. Yao, Junmei Weber, Michael D. Lin, Pei-Ann Gisabella, Barbara Petrossian, Natalie Amat, Jose Kim, Kyungman Yang, Aimei Forest, Craig R. Goosens, Ki Ann Kodandaramaiah, Suhasa Bangalo Boyden, Edward Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory |
| title | Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory |
| title_full | Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory |
| title_fullStr | Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory |
| title_full_unstemmed | Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory |
| title_short | Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory |
| title_sort | stress enables reinforcement elicited serotonergic consolidation of fear memory |
| url | http://hdl.handle.net/1721.1/102424 https://orcid.org/0000-0003-2218-7489 https://orcid.org/0000-0002-0419-3351 |
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