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

亲和性社会接触、青春期压力和催产素对成年大鼠恐惧行为的共同作用

• 批准号: RGPIN-2019-04790
• 负责人: Menard, Janet
• 金额: $ 2.04万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=764084
• 关键词: Joint; contributions; affiliative; social; contact

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.

恐惧或许是我们最原始的情感。适当程度的恐惧会产生适应性防御反应，从而促进生存。过度的恐惧反应可能是不适应的。我感兴趣的是恐惧表达的神经调节，以及这一过程是如何由先前的经验塑造的。在婴儿期和/或儿童早期经历压力，在某些情况下，可以增强(而不是阻碍)以后的生活韧性。我想知道，经验诱导的韧性增加是否也可以在青春期开始。我们最近的发现表明，获得从属社交联系可能会将青春期压力的持久结果转变为增强韧性，这从成年后较低水平的恐惧表达中可见一斑。我们现在想要扩大这些发现。我们将在青春期早期或中期将单人和成对的雄性和雌性大鼠置于间歇性物理应激(IPS)下，然后测试它们在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将表现出比无应激/成对居住的对照组大鼠更低的行为恐惧水平，而在单独居住/IPS的大鼠中则相反。其他实验将探索神经肽催产素(OT)在经验诱导的弹性中的潜在参与。这包括通过我们的青春期应激方案处理大鼠(如上所述)，然后用OT的标记标记它们的成年脑组织。我们预计配对饲养的/IPS大鼠将在富含催产素细胞的下丘脑区显示出最多的催产素阳性细胞。这些大鼠还将在与防御行为有关的两个相互关联的脑区--外侧隔区(LS)和下丘脑前部(AHA)--显示最高密度的催产素阳性纤维。为了进一步探索OT在减少恐惧中的作用，我们将在青春期将有IPS病史的单人和成对饲养的大鼠暴露在一个严重的威胁下，成年后进行休克探头埋葬测试(SPBT)。在SPBT之后，我们将通过处理产生OT的细胞的脑组织进行双重免疫标记，使用神经元活动标记物CFOS和OT的抗体来评估威胁诱导的激活。我们预计，配对饲养的/IPS大鼠在SPBT中表现出最低水平的恐惧表达，这将与下丘脑中最高数量的双标记细胞有关。一系列免费的实验旨在确定将OT直接注入LS或AHA是否能减少大鼠在各种行为测试中的恐惧表达。这项研究将提供有关因素(附属社会联系、逆境年龄、性别、催产素)的新信息，这些因素可能相互作用，塑造青春期逆境的持久结果，从而赋予人们对以后生活中不利事件的更大敏感度或韧性。最终，这些发现可能会为旨在支持加拿大弱势青年的努力提供参考。