Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee.
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee.
Biol Psychiatry. 2019 Jun 15;85(12):989-1000. doi: 10.1016/j.biopsych.2019.02.020. Epub 2019 Mar 7.
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.
前额叶皮层（PFC）整合来自多个输入的信息，以发挥自上而下的控制作用，从而在给定的情境下做出适当的反应。在创伤后应激障碍等精神疾病中，PFC 的过度活跃与在安全情况下的不适当恐惧有关。我们之前报道了一种 PFC 中的毒蕈碱型乙酰胆碱受体（mAChR）依赖性长时程抑制，我们假设它参与了适当的恐惧反应，并可能有助于减少应激后的皮质过度活跃。然而，目前尚不清楚这种长时程抑制是否发生在与恐惧相关的输入中。
我们使用光遗传学和细胞外及全细胞电生理学来评估 mAChR 激活对特定 PFC 输入的突触强度的影响。我们使用选择性药理学工具来评估 M mAChR 在对照小鼠和应激增强的恐惧学习模型中的条件性恐惧消退中的作用。
M mAChR 激活诱导了来自腹侧海马体和基底外侧杏仁核的输入的长时程抑制，但来自丘脑背内侧核的输入则没有。我们发现，全身 M mAChR 拮抗剂会损害情境性恐惧消退。在应激增强的恐惧学习条件下，用 M 正变构调节剂治疗可增强情境性恐惧消退的巩固。
M mAChR 动态调节两个 PFC 输入的突触传递，这两个输入的活动对于恐惧消退是必要的，而 M mAChR 的功能对于适当的情境性恐惧消退是必需的。此外，M 正变构调节剂增强了应激增强的恐惧学习模型中恐惧消退的巩固，这表明 M 正变构调节剂可能为在临床上进行创伤后应激障碍的暴露疗法提供一种新的治疗策略。
