James Maksymetz1, Max E Joffe1, Sean P Moran2, Branden J Stansley1, Brianna Li3, Kayla Temple4, Darren W Engers1, J Josh Lawrence5, Craig W Lindsley6, P Jeffrey Conn7. 1. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee. 2. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee. 3. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee. 4. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee. 5. Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, Texas. 6. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee; Department of Chemistry, Vanderbilt University, Nashville, Tennessee. 7. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee. Electronic address: jeff.conn@vanderbilt.edu.
Abstract
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 M1 mAChRs in conditioned fear extinction in control mice and in the stress-enhanced fear-learning model. RESULTS: M1 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 M1 mAChR antagonism impaired contextual fear extinction. Treatment with an M1 positive allosteric modulator enhanced contextual fear extinction consolidation in stress-enhanced fear learning-conditioned mice. CONCLUSIONS: M1 mAChRs dynamically modulate synaptic transmission at two PFC inputs whose activity is necessary for fear extinction, and M1 mAChR function is required for proper contextual fear extinction. Furthermore, an M1 positive allosteric modulator enhanced the consolidation of fear extinction in the stress-enhanced fear-learning model, suggesting that M1 positive allosteric modulators may provide a novel treatment strategy to facilitate exposure therapy in the clinic for the treatment of posttraumatic stress disorder.
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 M1 mAChRs in conditioned fear extinction in control mice and in the stress-enhanced fear-learning model. RESULTS: M1 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 M1 mAChR antagonism impaired contextual fear extinction. Treatment with an M1 positive allosteric modulator enhanced contextual fear extinction consolidation in stress-enhanced fear learning-conditioned mice. CONCLUSIONS: M1 mAChRs dynamically modulate synaptic transmission at two PFC inputs whose activity is necessary for fear extinction, and M1 mAChR function is required for proper contextual fear extinction. Furthermore, an M1 positive allosteric modulator enhanced the consolidation of fear extinction in the stress-enhanced fear-learning model, suggesting that M1 positive allosteric modulators may provide a novel treatment strategy to facilitate exposure therapy in the clinic for the treatment of posttraumatic stress disorder.
Authors: A Ghoshal; J M Rook; J W Dickerson; G N Roop; R D Morrison; N Jalan-Sakrikar; A Lamsal; M J Noetzel; M S Poslusney; M R Wood; B J Melancon; S R Stauffer; Z Xiang; J S Daniels; C M Niswender; C K Jones; C W Lindsley; P J Conn Journal: Neuropsychopharmacology Date: 2015-06-25 Impact factor: 7.853
Authors: Jana K Shirey; Ashley E Brady; Paulianda J Jones; Albert A Davis; Thomas M Bridges; J Phillip Kennedy; Satyawan B Jadhav; Usha N Menon; Zixiu Xiang; Mona L Watson; Edward P Christian; James J Doherty; Michael C Quirk; Dean H Snyder; James J Lah; Allan I Levey; Michelle M Nicolle; Craig W Lindsley; P Jeffrey Conn Journal: J Neurosci Date: 2009-11-11 Impact factor: 6.167
Authors: Jennifer N Perusini; Edward M Meyer; Virginia A Long; Vinuta Rau; Nathaniel Nocera; Jacob Avershal; James Maksymetz; Igor Spigelman; Michael S Fanselow Journal: Neuropsychopharmacology Date: 2015-08-06 Impact factor: 7.853
Authors: Mohammed R Milad; Gregory J Quirk; Roger K Pitman; Scott P Orr; Bruce Fischl; Scott L Rauch Journal: Biol Psychiatry Date: 2007-08-20 Impact factor: 13.382
Authors: Sean P Moran; Jonathan W Dickerson; Hyekyung P Cho; Zixiu Xiang; James Maksymetz; Daniel H Remke; Xiaohui Lv; Catherine A Doyle; Deepa H Rajan; Colleen M Niswender; Darren W Engers; Craig W Lindsley; Jerri M Rook; P Jeffrey Conn Journal: Neuropsychopharmacology Date: 2018-03-14 Impact factor: 7.853
Authors: Sean P Moran; Zixiu Xiang; Catherine A Doyle; James Maksymetz; Xiaohui Lv; Sehr Faltin; Nicole M Fisher; Colleen M Niswender; Jerri M Rook; Craig W Lindsley; P Jeffrey Conn Journal: Sci Signal Date: 2019-12-03 Impact factor: 8.192
Authors: Max E Joffe; James Maksymetz; Joseph R Luschinger; Shalini Dogra; Anthony S Ferranti; Deborah J Luessen; Isabel M Gallinger; Zixiu Xiang; Hannah Branthwaite; Patrick R Melugin; Kellie M Williford; Samuel W Centanni; Brenda C Shields; Craig W Lindsley; Erin S Calipari; Cody A Siciliano; Colleen M Niswender; Michael R Tadross; Danny G Winder; P Jeffrey Conn Journal: Neuron Date: 2022-01-18 Impact factor: 17.173
Authors: Murray B Stein; Joel Gelernter; Daniel F Levey; Zhongshan Cheng; Frank R Wendt; Kelly Harrington; Gita A Pathak; Kelly Cho; Rachel Quaden; Krishnan Radhakrishnan; Matthew J Girgenti; Yuk-Lam Anne Ho; Daniel Posner; Mihaela Aslan; Ronald S Duman; Hongyu Zhao; Renato Polimanti; John Concato Journal: Nat Genet Date: 2021-01-28 Impact factor: 38.330
Authors: James Maksymetz; Nellie E Byun; Deborah J Luessen; Brianna Li; Robert L Barry; John C Gore; Colleen M Niswender; Craig W Lindsley; Max E Joffe; P Jeffrey Conn Journal: Cell Rep Date: 2021-11-02 Impact factor: 9.423