■肾素-血管紧张素系统已被确定为创伤后应激障碍的潜在治疗靶点,虽然它的机制还没有很好的理解。脑血管紧张素2型受体(AT2R)是位于应激和焦虑相关区域的血管紧张素II受体的亚型,包括内侧前额叶皮层(mPFC),但它们在mPFC中的功能和机制仍未被探索。因此,我们使用了成像的组合,cre/lox,和行为方法研究恐惧和stess相关行为中表达mPFC-AT2R的神经元。
■为了表征mPFC中表达mPFC-AT2R的神经元,AT2R-Cre/td番茄雄性和雌性小鼠用于免疫组织化学。mPFC脑切片用谷氨酸能或中间神经元标记染色,和AT2R+细胞的密度以及与每个标记物的共定位被定量。为了评估AT2R-flox小鼠的恐惧相关行为,我们使用表达Cre的腺相关病毒从mPFC神经元中选择性删除AT2R。然后小鼠接受巴甫洛夫听觉恐惧调节,高架加上迷宫,和开放式现场测试。
■免疫组织化学结果表明,AT2R在整个mPFC中密集表达,并主要以性别依赖性方式在生长抑素中间神经元中表达。在恐惧调理之后,mPFC-AT2RCre-lox缺失损害了雌性小鼠而不是雄性小鼠的灭绝和探索行为增加,而两性的mPFC-AT2R缺失均未改变运动能力。
■这些结果将mPFC-AT2R+神经元确定为生长抑素中间神经元的新亚组,并揭示了它们在以性别依赖方式调节恐惧学习中的作用,可能为创伤后应激障碍的新治疗靶点提供见解。
创伤后应激障碍(PTSD)是心血管疾病(CVD)的重要预测因子,尽管对潜在的机制知之甚少。脑肾素-血管紧张素系统(RAS)对于心血管和情绪压力调节很重要,可能有助于更好地了解PTSD与CVD风险之间的联系。我们的研究表明,脑血管紧张素II2型受体(AT2R)亚型位于内侧前额叶皮质(mPFC)的特定生长抑素(SOM)中间神经元上,并在恐惧记忆消退中起作用,尤其是女性。这些发现揭示了mPFC-AT2R在基于恐惧的学习和记忆中的作用,提供对PTSD-CVD关联和治疗策略的潜在机制的潜在见解。
UNASSIGNED: The renin-angiotensin system has been identified as a potential therapeutic target for posttraumatic stress disorder, although its mechanisms are not well understood. Brain angiotensin type 2 receptors (AT2Rs) are a subtype of angiotensin II receptors located in stress and anxiety-related regions, including the medial prefrontal cortex (mPFC), but their function and mechanism in the mPFC remain unexplored. Therefore, we used a combination of imaging, cre/lox, and behavioral methods to investigate mPFC-AT2R-expressing neurons in fear and stess related behavior.
UNASSIGNED: To characterize mPFC-AT2R-expressing neurons in the mPFC, AT2R-Cre/tdTomato male and female mice were used for immunohistochemistry. mPFC brain sections were stained with glutamatergic or
interneuron markers, and density of AT2R+ cells and colocalization with each marker were quantified. To assess fear-related behaviors in AT2R-flox mice, we selectively deleted AT2R from mPFC neurons using a Cre-expressing adeno-associated virus. Mice then underwent Pavlovian auditory fear conditioning, elevated plus maze, and open field testing.
UNASSIGNED: Immunohistochemistry results revealed that AT2R was densely expressed throughout the mPFC and primarily expressed in somatostatin interneurons in a sex-dependent manner. Following fear conditioning, mPFC-AT2R Cre-lox deletion impaired extinction and increased exploratory behavior in female but not male mice, while locomotion was unaltered by mPFC-AT2R deletion in both sexes.
UNASSIGNED: These results identify mPFC-AT2R+ neurons as a novel subgroup of somatostatin interneurons and reveal their role in regulating fear learning in a sex-dependent manner, potentially offering insights into novel therapeutic targets for posttraumatic stress disorder.
Posttraumatic stress disorder (PTSD) is a significant predictor of cardiovascular disease (CVD), although the underlying mechanisms are poorly understood. The brain renin-angiotensin system (RAS) is important for cardiovascular and emotional stress regulation and may better help understand the link between PTSD and CVD risk. Our research reveals that the brain angiotensin II type 2 receptor (AT2R) subtype is located on specific somatostatin (SOM+) interneurons in the medial prefrontal cortex (mPFC) and plays a role in fear memory extinction, particularly in females. These findings reveal a role for the mPFC-AT2R in fear-based learning and memory, offering potential insights into the mechanisms underlying the PTSD-CVD association and therapeutic strategies.