Anxiety and trauma-related disorders are highly prevalent worldwide, and are associated with altered associative fear learning. Despite the effectiveness of exposure therapy, which aims to reduce associative fear responses, relapse rates remain high. This is due, in part, to the context specificity of exposure therapy, which is a form of extinction. Many studies show that fear relapses when mice are tested outside the extinction context, and this is known as fear renewal. Using Pavlovian fear conditioning and extinction, we can study the mechanisms underlying extinction and renewal. The aim of the current experiment was to identify the role of presynaptic GABA_B receptors in these two processes. Previous work from our lab showed that genetic deletion or pharmacological inhibition of GABA_B(1a) receptors that provide presynaptic inhibition on glutamatergic terminals reduces context specificity and leads to generalization. We therefore hypothesized that inactivation of these presynaptic GABA_B receptors could be used to reduce the context specificity associated with fear extinction training and suppress renewal when mice are tested outside of the extinction context. Using CGP 36216, an antagonist specific for presynaptic GABA_B receptors, we blocked presynaptic GABA_B receptors using intracerebroventricular injections during various time points of extinction learning in male and female mice. Results showed that blocking these receptors pre- and post-extinction training led to enhanced extinction learning in male mice only. We also found that post-extinction infusions of CGP reduced renewal rates in male mice when they were tested outside of the extinction context. In an attempt to localize the function of presynaptic GABA_B receptors within regions of the extinction circuit, we infused CGP locally within the basolateral amygdala or dorsal hippocampus. We failed to reduce renewal when CGP was infused directly within these regions, suggesting that presynaptic inhibition within these regions per se may not be necessary for driving context specificity during extinction learning. Together, these results show an important sex-dependent role of presynaptic GABA_B receptors in extinction and renewal processes and identify a novel receptor target that may be used to design pharmacotherapies to enhance the effectiveness of exposure therapy.

焦虑和创伤相关疾病在世界范围内非常普遍，并且与联想恐惧学习的改变有关。尽管旨在减少联想恐惧反应的暴露疗法很有效，但复发率仍然很高。这在一定程度上是由于暴露疗法的背景特殊性，暴露疗法是一种灭绝形式。许多研究表明，当老鼠在灭绝背景之外进行测试时，恐惧会复发，这被称为恐惧再现。利用巴甫洛夫恐惧调节和灭绝，我们可以研究灭绝和更新的机制。当前实验的目的是确定突触前 GABA _B受体在这两个过程中的作用。我们实验室之前的工作表明，对谷氨酸能末端提供突触前抑制的 GABA _B(1a)受体的基因删除或药理学抑制会降低背景特异性并导致泛化。因此，我们假设这些突触前 GABA _B受体的失活可用于减少与恐惧消退训练相关的环境特异性，并在小鼠在消退环境之外进行测试时抑制恐惧更新。使用 CGP 36216（一种突触前 GABA _B受体特异性拮抗剂），我们在雄性和雌性小鼠的消退学习的不同时间点通过侧脑室注射来阻断突触前 GABA _B受体。结果表明，在消退前和消退后的训练中阻断这些受体只会增强雄性小鼠的消退学习能力。我们还发现，在灭绝背景之外进行测试时，灭绝后注射 CGP 会降低雄性小鼠的更新率。 为了将突触前 GABA _B受体的功能定位在消退回路区域内，我们将 CGP 局部注入基底外侧杏仁核或背侧海马内。当 CGP 直接注入这些区域时，我们未能减少更新，这表明这些区域内的突触前抑制本身对于驱动消退学习期间的情境特异性可能不是必需的。总之，这些结果表明突触前 GABA _B受体在消退和更新过程中具有重要的性别依赖性作用，并确定了一个新的受体靶点，可用于设计药物疗法以增强暴露疗法的有效性。