■社会失败范式是研究社交焦虑障碍(SAD)及其潜在神经元机制的最具代表性的动物模型。我们以前曾报道过,在雌性草原田鼠(Microtusochogaster)的八周时间内,失败会逐渐减少大脑边缘区域的催产素受体(OXTR)。催产素受体激活丝裂原活化蛋白激酶(MAPK)途径,以前与催产素的抗焦虑作用有关。这里,我们评估了OXTR在应激诱导的社交回避和MAPK信号通路在伏隔核(NAc)的反应中的功能意义,前扣带皮质(ACC),雌性草原田鼠的基底外侧杏仁核(BLA)。
■在实验1中,性天真成年雌性草原田鼠连续三天被击败,并在一周后进行社交偏好/回避(SPA)测试。对照受试者在没有失败条件的情况下进行类似处理。在实验2中,性和压力幼稚的成年雌性草原田鼠被双侧注射到NAc中,ACC,或具有靶向Oxtr编码序列的CRISPR/Cas9病毒的BLA诱导OXTR敲低。手术后两周,对受试者进行SPA行为测试。类似地处理病毒对照组,但注射对照病毒。在两个实验中来自每种条件的一组动物被类似地处理和安乐死,而不测试SPA行为。采集大脑进行OXTR放射自显影,MAPK蛋白的蛋白质印迹分析和NAc中局部催产素含量的定量,BLA,ACC,和PVN通过ELISA。
■社会失败减少了NAc中OXTR的结合,并影响了MAPK途径的活性和催产素的可用性。这些结果是区域特异性的并且对暴露于SPA测试敏感。此外,在NAc中OXTR击倒,ACC,和BLA诱导NAc中的社交回避和基础MAPK活性降低。最后,我们发现,这些区域的OXTR敲低与PVN中催产素的可用性降低相关.
■NAc中催产素系统和MAPK信号通路的失调,ACC,和BLA在女性田鼠的社会行为中断中很重要。这种失调可能,因此,在女性SAD的病因中起着重要作用。
UNASSIGNED: The social defeat paradigm is the most representative animal model to study social anxiety disorder (SAD) and its underlying neuronal mechanisms. We have previously reported that defeat progressively reduces oxytocin receptors (OXTR) in limbic regions of the brain over an eight-week period in female prairie voles (Microtus ochrogaster). Oxytocin receptors activate the mitogen-activated protein kinase (MAPK) pathway, which has been previously associated with the anxiolytic effects of oxytocin. Here, we assessed the functional significance of OXTR in stress-induced social avoidance and the response of the MAPK signaling pathway in the nucleus accumbens (NAc), anterior cingulate cortex (ACC), and basolateral amygdala (BLA) of female prairie voles.
UNASSIGNED: In experiment 1, Sexually naïve adult female prairie voles were defeated for three consecutive days and tested a week after for social preference/avoidance (SPA) test. Control subjects were similarly handled without defeat conditioning. In experiment 2, sexually and stress naïve adult female prairie voles were bilaterally injected into the NAc, ACC, or the BLA with a CRISPR/Cas9 virus targeting the Oxtr coding sequence to induce OXTR knockdown. Two weeks post-surgery, subjects were tested for SPA behavior. Viral control groups were similarly handled but injected with a control virus. A subgroup of animals from each condition in both experiments were similarly treated and euthanized without being tested for SPA behavior. Brains were harvested for OXTR autoradiography, western blot analysis of MAPK proteins and quantification of local oxytocin content in the NAc, BLA, ACC, and PVN through ELISA.
UNASSIGNED: Social defeat reduced OXTR binding in the NAc and affected MAPK pathway activity and oxytocin availability. These results were region-specific and sensitive to exposure to the SPA test. Additionally, OXTR knockdown in the NAc, ACC, and BLA induced social avoidance and decreased basal MAPK activity in the NAc. Finally, we found that OXTR knockdown in these regions was associated with less availability of oxytocin in the PVN.
UNASSIGNED: Dysregulation of the oxytocin system and MAPK signaling pathway in the NAc, ACC, and BLA are important in social behavior disruptions in female voles. This dysregulation could, therefore, play an important role in the etiology of SAD in women.