Sex differences in response to an immune challenge

青春期是发育的关键时期，性腺激素在此期间重组和重塑大脑，为大脑的长期功能奠定基础。青春期也是压力反应发生变化的时期，青春期暴露在压力源下会扰乱正常的大脑发育，并在成年后产生持久的行为影响。例如，暴露在运输压力下的青春期(六周大)雌性小鼠与年龄较小或年龄较大的雌性小鼠相比，性接受性下降，即使在用雌二醇和孕酮完全启动激素后也是如此。由于运输是一种多因素变量应激源，对受控实验室应激源的搜索表明，除了一个例外，标准的实验室应激源都未能复制运输对性接受能力持续下降的影响。与航运一样，与对照组相比，腹膜内注射脂多糖(LPS)会导致六周龄小鼠的性接受能力长期下降。这种影响在较年轻或较年长的小鼠中不存在。青春期注射脂多糖的持久影响也延伸到非生殖行为，并影响认知和情感功能。这些发现表明，青春期的内毒素治疗在全球范围内改变了性腺激素依赖的行为。然而，青春期免疫攻击导致这些行为变化的机制仍有待研究。对于这些发现，有几种可能的解释。一种可能性是性腺类固醇激素在青春期增强免疫反应，但这一点仍有待研究。上面提到的关于青春期免疫挑战的影响的工作仅在雌性小鼠中进行，重要的是也要寻找青春期和成年雄性之间的免疫反应差异，因为众所周知，一种性别的结果不容易转化为另一种性别。我的实验室的初步发现表明，在接受内毒素治疗后，患者的患病行为存在年龄和性别差异。我的研究计划的长期愿景是确定青春期免疫挑战导致性激素依赖行为长期变化的潜在机制。拟议研究计划的短期目标是使用一种原创性和多学科的方法首先确定小鼠急性免疫反应中与年龄和性别相关的差异。其次，我将研究性腺激素的作用以及性腺功能在年龄和性别差异中对免疫挑战的急性反应的潜在遗传和表观遗传机制。最后，我将研究经验和青春期成熟对长期免疫反应和应激反应的作用。青春期暴露在免疫挑战下会永久性地改变对性腺激素的反应，这是一个新的原创概念，对其调节机制知之甚少。拟议的研究计划使用多学科方法来表征与年龄和性别相关的免疫反应差异，以及性腺激素在青春期对免疫挑战的脆弱性中的作用。这项研究计划还将展示青春期暴露在免疫挑战中是否会对压力和免疫反应产生长期的改变。这项工作将通过研究青春期神经内分泌、应激和免疫系统之间的相互作用，扩大对压力源暴露在发育敏感时期塑造发育中的大脑并导致神经系统结构和功能长期变化的基本机制的研究。

Puberty is a critical period of development during which gonadal hormones reorganize and remodel the brain and set the stage for long-term brain functioning. Puberty is also a period during which the stress response is altered and exposure to stressors during puberty can disrupt normal brain development and exert lasting behavioural effects in adulthood. For example, pubertal (six weeks old) female mice exposed to shipping stress display enduring decreases in sexual receptivity compared to females shipped younger or older, even after complete hormonal priming with estradiol and progesterone. Since shipping is a multifactor variable stressor, a search for a controlled laboratory stressor showed that standard laboratories stressors, known to activate the stress response, all failed to replicate the effect of shipping on the enduring decrease in sexual receptivity, expect for one. Like shipping, intraperitoneal injection of lipopolysaccharide (LPS) causes long-lasting decreases in sexual receptivity in six-week old mice compared to controls. This effect is not present in younger or older mice. The enduring effect of pubertal LPS injection also extends to non-reproductive behaviours and affects cognitive and emotional functioning. These findings show that pubertal LPS treatment globally alters behaviors that are gonadal hormone-dependant. However, the mechanism through which pubertal immune challenge causes these behavioral changes remains to be investigated. There are several possible explanations for these findings. One possibility is that gonadal steroid hormones potentiate immune response during puberty, but this remains to be investigated. The work mentioned above on the effects of pubertal immune challenge was carried out solely in female mice, it would be important to also look for differences in immune response between pubertal and adult males as well, since it is well known that results in one sex do not readily translate to the other sex. Preliminary findings from my laboratory suggest that there are age and sex differences in sickness behavior following LPS treatment. The long-term vision of my research program is to identify the potential mechanisms through which pubertal immune challenge causes long-term alterations in gonadal hormone-dependent behavior. The short-term objectives of the proposed research program are to use an original and multidisciplinary approach to first characterize the age- and sex-related differences in acute immune response in mice. Second, I will examine the role of gonadal hormones and the underlying genetic and epigenetic mechanisms of gonadal function in the age and sex differences in the acute response to an immune challenge. Lastly, I will examine the role of experience and pubertal maturation on long-term immune response and stress reactivity. The idea that exposure to an immune challenge during puberty can permanently alter the response to gonadal hormones is a new and original concept and little is known about the mediating mechanisms. The proposed research program uses a multidisciplinary approach to characterize age- and sex-related differences in immune response and the effect of gonadal hormones in the vulnerability of the pubertal period to immune challenge. This research program will also show whether pubertal exposure to an immune challenge exerts long-term alterations to stress and immune responses. This work will expand the investigation of the basic mechanisms through which exposure to stressors shapes the developing brain and causes long-lasting alterations on the structure and function of the nervous system during sensitive periods of development by examining the interactions between the neuroendocrine, stress and immune systems during the pubertal period.