Loomba Niharika, Cao Anyu, Charles Senna, Kandil Isaac, Kwon Michelle, Patel Sachin
Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA.
Department of Psychiatry and Behavioral Sciences, Stephen M. Stahl Centre for Psychiatric Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Psychopharmacology (Berl). 2025 May 24. doi: 10.1007/s00213-025-06812-z.
A hallmark of many psychiatric disorders is maladaptive and heightened fear responses to non-threatening stimuli. Adaptive defensive responses to threats involve transitions between passive behaviors, such as freezing, and active escape strategies, such as darting or fleeing. The endocannabinoid (eCB) system, particularly 2-arachidonoylglycerol (2-AG), plays a crucial role in modulating fear and stress responses. However, the extent to which 2-AG influences defensive behavioral state transitions to fear responses remains unclear. To address this, we investigated the role of 2-AG in shaping defensive behaviors to learned and innate threats using pharmacological manipulations in both the serial compound stimulus (SCS) and the looming shadow paradigm. During SCS, inhibition of 2-AG synthesis enhanced freezing to early cues and promoted active responses during cues associated with heightened threat imminence. In the looming shadow paradigm, 2-AG depletion biased defensive behavior toward freezing and increased time spent in a safe zone, suggesting a shift toward passive responses. These findings demonstrate that 2-AG signaling critically regulates the balance and transitions between passive and active defensive strategies in both learned and innate fear contexts. Thus, 2-AG plays a key role in the scaling of defensive response transitions and the promotion of active defensive responses to threats.
许多精神疾病的一个标志是对无威胁刺激产生适应不良且增强的恐惧反应。对威胁的适应性防御反应包括被动行为（如僵住）和主动逃避策略（如飞奔或逃离）之间的转换。内源性大麻素（eCB）系统，尤其是2-花生四烯酸甘油酯（2-AG），在调节恐惧和应激反应中起关键作用。然而，2-AG影响防御行为状态向恐惧反应转换的程度仍不清楚。为了解决这个问题，我们在序列复合刺激（SCS）和逼近阴影范式中使用药理学操作，研究了2-AG在塑造对习得性和先天性威胁的防御行为中的作用。在SCS期间，抑制2-AG合成增强了对早期线索的僵住反应，并促进了在与更高威胁紧迫性相关的线索期间的主动反应。在逼近阴影范式中，2-AG耗竭使防御行为偏向僵住，并增加了在安全区停留的时间，表明转向被动反应。这些发现表明，2-AG信号传导在习得性和先天性恐惧情境中关键地调节被动和主动防御策略之间的平衡和转换。因此，2-AG在防御反应转换的调节以及促进对威胁的主动防御反应中起关键作用。
