Joint contributions of affiliative social contact, stress in adolescence and oxytocin to fear behaviour in adult rats

恐惧也许是我们最原始的情感。适当程度的恐惧会产生适应性的防御反应，从而促进生存。过度的恐惧反应可能是不适应的。我对恐惧表达的神经调节以及这个过程是如何被先前的经验塑造的很感兴趣。在某些情况下，在婴儿期和/或幼儿期经历压力可以增强（而不是阻碍）以后生活的适应力。我想知道由经验引起的适应力增强是否也可以在青春期开始。我们最近的研究结果表明，获得亲和性社会接触可能会将青少年压力的持久结果转变为增强的复原力，正如成年后较低水平的恐惧表达所证明的那样。我们现在想扩展这些发现。我们将在青春期早期或中期将单鼠和成对饲养的雄性和雌性大鼠暴露在间歇性身体应激（IPS）下，然后测试它们成年后对急性威胁的行为反应。我们预计，在青春期有IPS病史的成对饲养的大鼠与无应激/成对饲养的对照大鼠相比，表现出较低的行为恐惧水平，而在单舍/IPS大鼠中则相反。其他的实验将探索神经肽催产素（OT）在经验诱导的恢复力中的潜在作用。这包括通过我们的青春期压力方案（如上所述）处理大鼠，然后用OT标记它们的成年脑组织。我们预计成对饲养/IPS大鼠在富含OT产生细胞的下丘脑区域显示出最多的OT阳性细胞。这些大鼠在涉及防御行为的两个相互连接的大脑区域，外侧隔（LS）和下丘脑前部（AHA），也会显示出最高密度的OT阳性纤维。为了进一步探讨OT在减少恐惧中的作用，我们将青春期有IPS病史的单鼠和成对饲养的大鼠暴露在成年期的急性威胁中，即休克探针掩埋试验（SPBT）。在SPBT之后，我们将评估威胁诱导的OT产生细胞的激活，方法是处理它们的脑组织，使用神经元活性标记物、cfo和OT的抗体进行双重免疫标记。我们预计成对饲养/IPS大鼠在SPBT中表现出最低水平的恐惧表达，这将与下丘脑中最多的双标记细胞有关。一系列附加实验旨在确定在各种行为测试中，将OT直接注入LS或AHA是否会减少大鼠的恐惧表达。这项研究将提供有关因素的新信息（从属社会联系、逆境年龄、性别、催产素），这些因素可能相互作用，形成青春期逆境的持久结果，从而赋予他们对以后生活中的不良事件更大的敏感性或复原力。最终，这些发现可能会为支持加拿大弱势青年的努力提供信息。

Fear is perhaps our most primal emotion. Appropriate levels of fear yield adaptive defensive responses that promote survival. Excessive fear reactions can be maladaptive. I am interested in the neural regulation of fear expression and how this process is shaped by prior experience. Experiencing stress in infancy and/or early childhood can, in certain instances, enhance (rather than impede) resilience in later life. I want to know if experience-induced increases in resilience can also be initiated in adolescence. Our recent findings suggest that access to affiliative social contact might shift the lasting outcomes of adolescent stress toward enhanced resilience, as evidenced by lower levels of fear expression in adulthood. We now want to extend those findings. We will expose single and pair-housed, male and female rats to intermittent physical stress (IPS) in early or mid-adolescence and then test their behavioural responses to acute threats in adulthood. We expect that pair-housed rats with a history of IPS in adolescence will display lower levels of behavioural fearfulness relative to no-stress/pair-housed control rats, whereas the reverse will be found in single-housed/IPS rats. Additional experiments will explore the potential involvement of the neuropeptide, oxytocin (OT) in experience-induced resilience. This involves processing rats through our adolescent stress protocol (as described above) and then labelling their adult brain tissue with a marker for OT. We expect that pair-housed/IPS rats will display the highest number of OT positive cells in hypothalamic areas rich in OT-producing cells. These same rats will also display the highest density of OT positive fibers in two interconnected brain regions implicated in defensive behaviour, the lateral septum (LS) and anterior hypothalamus (AHA). To further explore the involvement of OT in fear reduction, we will expose single and pair-housed rats with a history of IPS in adolescence to an acute threat, the shock-probe burying test (SPBT) in adulthood. After the SPBT, we will evaluate threat-induced activation of OT-producing cells by processing their brain tissue for double immuno-labelling using antibodies for the neuronal activity marker, cFos and OT. We expect that pair-housed/IPS rats will display the lowest levels of fear expression in the SPBT, and this will be associated with the highest number of double labelled cells in the hypothalamus. A complimentary series of experiments aims to determine whether infusing OT directly into the LS or AHA reduces rats' fear expression in various behavioural tests. This research will provide novel information about factors (affiliative social contact, age at adversity, sex, oxytocin) that potentially interact to shape the lasting outcomes of adversity in adolescence, thus conferring either greater sensitivity or resilience to adverse events in later life. Ultimately, the findings might inform endeavors aimed at supporting vulnerable youth in Canada.