Issler Orna, Carter Roderick N, Paul Evan D, Kelly Paul At, Olverman Henry J, Neufeld-Cohen Adi, Kuperman Yael, Lowry Christopher A, Seckl Jonathan R, Chen Alon, Jamieson Pauline M
Centre for Cardiovascular Science, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Biol Mood Anxiety Disord. 2014 Jan 21;4(1):1. doi: 10.1186/2045-5380-4-1.
Corticotropin-releasing factor type 2 receptors (CRFR2) are suggested to facilitate successful recovery from stress to maintain mental health. They are abundant in the midbrain raphe nuclei, where they regulate serotonergic neuronal activity and have been demonstrated to mediate behavioural consequences of stress. Here, we describe behavioural and serotonergic responses consistent with maladaptive recovery from stressful challenge in CRFR2-null mice.
CRFR2-null mice showed similar anxiety levels to control mice before and immediately after acute restraint stress, and also after cessation of chronic stress. However, they showed increased anxiety by 24 hours after restraint, whether or not they had been chronically stressed.Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) contents were quantified and the level of 5-HIAA in the caudal dorsal raphe nucleus (DRN) was increased under basal conditions in CRFR2-null mice, indicating increased 5-HT turnover. Twenty-four hours following restraint, 5-HIAA was decreased only in CRFR2-null mice, suggesting that they had not fully recovered from the challenge. In efferent limbic structures, CRFR2-null mice showed lower levels of basal 5-HT in the lateral septum and subiculum, and again showed a differential response to restraint stress from controls.Local cerebral glucose utilization (LCMRglu) revealed decreased neuronal activity in the DRN of CRFR2-null mice under basal conditions. Following 5-HT receptor agonist challenge, LCMRglu responses indicated that 5-HT1A receptor responses in the DRN were attenuated in CRFR2-null mice. However, postsynaptic 5-HT receptor responses in forebrain regions were intact.
These results suggest that CRFR2 are required for proper functionality of 5-HT1A receptors in the raphe nuclei, and are key to successful recovery from stress. This disrupted serotonergic function in CRFR2-null mice likely contributes to their stress-sensitive phenotype. The 5-HT content in lateral septum and subiculum was notably altered. These areas are important for anxiety, and are also implicated in reward and the pathophysiology of addiction. The role of CRFR2 in stress-related psychopathologies deserves further consideration.
促肾上腺皮质激素释放因子2型受体（CRFR2）被认为有助于从应激中成功恢复以维持心理健康。它们在中脑缝核中大量存在，在那里调节血清素能神经元活动，并已被证明介导应激的行为后果。在此，我们描述了与CRFR2基因敲除小鼠应激挑战后适应不良恢复一致的行为和血清素能反应。
CRFR2基因敲除小鼠在急性束缚应激前、应激后立即以及慢性应激停止后，焦虑水平与对照小鼠相似。然而，无论是否经历过慢性应激，它们在束缚后24小时焦虑增加。对血清素（5-HT）和5-羟吲哚乙酸（5-HIAA）含量进行定量分析，发现CRFR2基因敲除小鼠在基础条件下尾侧背缝核（DRN）中的5-HIAA水平升高，表明5-HT周转增加。束缚后24小时，只有CRFR2基因敲除小鼠的5-HIAA降低，这表明它们尚未从挑战中完全恢复。在传出边缘结构中，CRFR2基因敲除小鼠在外侧隔区和海马下托中的基础5-HT水平较低，并且再次表现出与对照小鼠对束缚应激的不同反应。局部脑葡萄糖利用（LCMRglu）显示，CRFR2基因敲除小鼠在基础条件下DRN中的神经元活动降低。给予5-HT受体激动剂刺激后，LCMRglu反应表明，CRFR2基因敲除小鼠DRN中的5-HT1A受体反应减弱。然而，前脑区域的突触后5-HT受体反应是完整的。
这些结果表明，CRFR2是缝核中5-HT1A受体正常功能所必需的，并且是从应激中成功恢复的关键。CRFR2基因敲除小鼠中这种血清素能功能的破坏可能导致了它们的应激敏感表型。外侧隔区和海马下托中的5-HT含量明显改变。这些区域对焦虑很重要，并且也与奖赏和成瘾的病理生理学有关。CRFR2在应激相关精神病理学中的作用值得进一步研究。
