M 1 Muscarinic Receptors Modulate Fear-Related Inputs to the Prefrontal Cortex: Implications for Novel Treatments of Posttraumatic Stress Disorder
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 prev...
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Published in | Biological psychiatry (1969) Vol. 85; no. 12; p. 989 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
15.06.2019
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Subjects | |
Online Access | Get full text |
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Summary: | 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.
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
mAChRs in conditioned fear extinction in control mice and in the stress-enhanced fear-learning model.
M
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
mAChR antagonism impaired contextual fear extinction. Treatment with an M
positive allosteric modulator enhanced contextual fear extinction consolidation in stress-enhanced fear learning-conditioned mice.
M
mAChRs dynamically modulate synaptic transmission at two PFC inputs whose activity is necessary for fear extinction, and M
mAChR function is required for proper contextual fear extinction. Furthermore, an M
positive allosteric modulator enhanced the consolidation of fear extinction in the stress-enhanced fear-learning model, suggesting that M
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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ISSN: | 1873-2402 |
DOI: | 10.1016/j.biopsych.2019.02.020 |