PAC1 receptor modulation of freezing and flight behavior in periaqueductal gray.
PAC1 receptor modulation of freezing and flight behavior in periaqueductal gray.
复制标题
DOI：
10.1111/gbb.12873
复制
发表时间：
2023-12
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
中脑导水管周围灰质（PAG）区域是恐惧相关物种特异性防御反应（SSDR）的关键解剖调节器。垂体腺苷酸环化酶激活多肽（PACAP）及其主要受体 PAC1 在恐惧相关行为和焦虑症中发挥重要作用。然而，PAG 内的 PACAP-PAC1 系统在 SSDR 方面的功能却很少受到关注。为了解决这一差距，我们使用转基因 PAC1flox/flox 小鼠来检查条件和非条件防御反应。我们使用编码 Cre 重组酶的腺相关病毒 (AAV) 在 PAC1flox/flox 小鼠的腹外侧 (vl)PAG 内进行了条件性 PAC1 基因删除。病毒表达后，我们使用了白噪声恐惧调节制剂，该制剂产生无条件活动爆发到噪声发作，然后是有条件冻结。第一天，小鼠接受五次白噪声足部电击配对，而在第二天，它们在没有电击的情况下暴露于白噪声五次，我们对白噪声的活动爆发和冻结进行评分。行为测试后，进行免疫荧光分析的组织学，以分别识别 PACAP 阳性细胞和应激诱导的 c-fos 活性。我们发现 vlPAG 中 PAC1 的缺失增加了无条件活性爆发反应，但破坏了条件冻结。行为实验后，PAC1 缺失伴随着更高的 c-fos 活性。此外，PACAP-EGFP 阳性细胞的很大一部分显示出与 VGAT 重叠的表达，表明它们与抑制性神经元相关。研究结果表明，完整的 PACAP-PAC1 机制对于 vlPAG 中的 SSDR 至关重要。因此，中脑 PACAP 有助于调节恐惧反应的潜在分子机制。从 PACAP 阳性细胞主要位于的腹外侧 PAG 有条件删除 PAC1 受体，并进行了恐惧调节实验。缺乏 PAC1 受体会表现出不适合当前情况的防御反应，例如冻结、活动爆发和猛冲。研究结果表明，完整的 PACAP-PAC1 机制对于腹外侧 PAG 中完整的物种特异性防御反应至关重要。
The midbrain periaqueductal gray (PAG) region is a critical anatomical regulator of fear‐related species‐specific defensive reactions (SSDRs). Pituitary adenylate‐cyclase‐activating polypeptide (PACAP), and its main receptor PAC1, play an important role in fear‐related behavior and anxiety disorders. However, the function of the PACAP‐PAC1 system within the PAG with regards to SSDRs has received little attention. To address this gap, we used transgenic PAC1flox/flox mice to examine both conditional and unconditional defensive reactions. We performed conditional PAC1 gene deletion within the ventrolateral(vl)PAG of PAC1flox/flox mice using an adeno‐associated virus (AAV) coding for Cre recombinase. Following viral expression, we used a white noise fear conditioning preparation that produces both an unconditional activity burst to the onset of noise that is followed by conditional freezing. On Day 1, mice received five white noise foot‐shock pairings, whereas on Day 2, they were exposed to white noise five times without shock and we scored the activity burst and freezing to the white noise. Following behavioral testing, histology for immunofluorescent analysis was conducted in order to identify PACAP positive cells and stress‐induced c‐fos activity respectively. We found that PAC1 deletion in vlPAG increased the unconditional activity burst response but disrupted conditional freezing. PAC1 deletion was accompanied by higher c‐fos activity following the behavioral experiments. Furthermore, a significant portion of PACAP‐EGFP positive cells showed overlapping expression with VGAT, indicating their association with inhibitory neurons. The findings suggested that intact PACAP‐PAC1 mechanisms are essential for SSDRs in vlPAG. Therefore, midbrain PACAP contributes to the underlying molecular mechanisms regulating fear responses. PAC1 receptors were conditionally deleted from the ventrolateral PAG where PACAP‐positive cells are primarily located, performed fear conditioning experiments were conducted. Lacking PAC1 receptors showed defensive responses inappropriate to the situation such as freezing, activity burst and darting. The findings suggested that intact PACAP‐PAC1 mechanisms are essential for intact species‐specific defensive reactions in ventrolateral PAG.
登录
查看更多内容
影响因子：
7.6
作者：
Dore, Riccardo;Iemolo, Attilio;Sabino, Valentina
通讯作者：
Sabino, Valentina
影响因子：
5.2
作者：
Khodai T;Nunn N;Worth AA;Feetham CH;Belle MDC;Piggins HD;Luckman SM
通讯作者：
Luckman SM
影响因子：
7.7
作者：
Gruene, Tina M.;Flick, Katelyn;Shansky, Rebecca M.
通讯作者：
Shansky, Rebecca M.
影响因子：
8
作者：
HUANG, LK;WANG, MJJ
通讯作者：
WANG, MJJ
影响因子：
1.3
作者：
Fanselow, Michael S.;Hoffman, Ann N.;Zhuravka, Irina
通讯作者：
Zhuravka, Irina