Substance P-Mediated Enhancement of Salience for Cues Predicting Aversive Outcomes

项目摘要 适应不良的恐惧加剧了对厌恶刺激的反应，并增强了压力和焦虑。然而，驱动这些厌恶反应和增强厌恶刺激的显着性的大脑机制尚不清楚。兴奋肽P物质在伏隔核核心神经元的一个子集上产生空间受限的长时程增强作用，已知该神经元促进厌恶。此外，这种长时程增强发生在恐惧条件反射后的伏隔核核心中，并且可以通过阻断P物质信号传导来抑制。对这个子区域的谷氨酸能输入，特别是边缘系统输入，是对提示进行显着性编码的几个大脑系统之一，这表明P物质可能会驱动这些细胞上显着性相关信号的整合，以促进对进行行为动作的厌恶刺激的学习。本项目采用多层次的方法，包括切片电生理学、光遗传学和纤维光度学，旨在了解P物质介导的对丘脑核核心的显著性相关输入的增强作用如何促进对预测厌恶结果的线索的显著性，并旨在开发脑刺激范式来抑制恐惧反应。

Project Summary Maladaptive fear exacerbates responses to aversive stimuli and enhances stress and anxiety. However, brain mechanisms that drive these aversive responses and enhance salience of aversive stimuli are not known. The excitatory peptide substance P produces a spatially restricted, glutamatergic long-term potentiation on a subset of Nucleus Accumbens core neurons that are known to promote aversion. Furthermore, this long-term potentiation occurs in the Nucleus Accumbens core following fear conditioning and can be suppressed by blocking substance P signaling. Glutamatergic inputs, particularly limbic inputs, to this sub-region are among several brain systems that encode salience to cues, suggesting substance P may drive integration of salience-related signals on these cells to promote learning about aversive stimuli that proceeds behavioral action. Using a multi-level approach including slice electrophysiology, optogenetics, and fiber photometry, this project aims to understand how substance P-mediated potentiation of saliencerelated inputs to the nucleus accumbens core promotes salience to cues predicting aversive outcomes and aims to develop brain stimulation paradigms to suppress fear responding.