期刊
BIOLOGICAL PSYCHIATRY
卷 85, 期 12, 页码 989-1000出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2019.02.020
关键词
Fear extinction; M-1 muscarinic receptor; Positive allosteric modulator; Posttraumatic stress disorder; Prefrontal cortex; Synaptic plasticity
资金
- Canadian Institutes for Health Research [CIHR DFS146189]
- Vanderbilt International Scholars Program
- National Institutes of Health [R01 NS069689, R01 MH073676]
- Johnson and Johnson
- BristolMyers Squibb
- AstraZeneca
- Michael J. Fox Foundation
- Seaside Therapeutics
- Dystonia Medical Research Foundation
- CHDI Foundation
BACKGROUND: The prefrontal cortex (PFC) integrates information from multiple inputs to exert top-down control allowing for appropriate responses in a given context. In psychiatric disorders such as posttraumatic stress disorder, PFC hyperactivity is associated with inappropriate fear in safe situations. We previously reported a form of muscarinic acetylcholine receptor (mAChR)-dependent long-term depression in the PFC that we hypothesize is involved in appropriate fear responding and could serve to reduce cortical hyperactivity following stress. However, it is unknown whether this long-term depression occurs at fear-related inputs. METHODS: Using optogenetics with extracellular and whole-cell electrophysiology, we assessed the effect of mAChR activation on the synaptic strength of specific PFC inputs. We used selective pharmacological tools to assess the involvement of M-1 mAChRs in conditioned fear extinction in control mice and in the stress-enhanced fear-learning model. RESULTS: M-1 mAChR activation induced long-term depression at inputs from the ventral hippocampus and basolateral amygdala but not from the mediodorsal nucleus of the thalamus. We found that systemic M-1 mAChR antagonism impaired contextual fear extinction. Treatment with an M-1 positive allosteric modulator enhanced contextual fear extinction consolidation in stress-enhanced fear learning-conditioned mice. CONCLUSIONS: M-1 mAChRs dynamically modulate synaptic transmission at two PFC inputs whose activity is necessary for fear extinction, and M-1 mAChR function is required for proper contextual fear extinction. Furthermore, an M-1 positive allosteric modulator enhanced the consolidation of fear extinction in the stress-enhanced fear-learning model, suggesting that M-1 positive allosteric modulators may provide a novel treatment strategy to facilitate exposure therapy in the clinic for the treatment of posttraumatic stress disorder.
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