Sex differences in response to an immune challenge

青春期是发育的关键时期，在此期间性腺激素重组和重塑大脑，为大脑的长期功能奠定基础。青春期也是压力反应发生改变的时期，在青春期暴露于压力源会破坏正常的大脑发育，并在成年后产生持久的行为影响。例如，处于发育期（6周大）的雌性小鼠暴露在运输压力下，即使在完全注入雌二醇和黄体酮之后，与更年轻或更年长的雌性小鼠相比，它们的性接受能力也会持续下降。由于航运是一个多因素可变的压力源，一项对受控实验室压力源的研究表明，标准的实验室压力源，已知会激活压力反应，都无法复制航运对性接受度持续下降的影响，除了一个。与海运一样，与对照组相比，腹腔注射脂多糖（LPS）会导致6周龄小鼠的性接受性长期下降。这种效应在年轻或年老的老鼠身上都不存在。青春期LPS注射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LPS治疗总体上改变了性腺激素依赖的行为。然而，青春期免疫挑战导致这些行为改变的机制仍有待研究。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，但这仍有待研究。上面提到的关于发育期免疫挑战影响的研究仅在雌性小鼠中进行，因此寻找发育期和成年雄性之间免疫反应的差异也很重要，因为众所周知，一种性别的结果并不容易转化为另一种性别。我实验室的初步研究结果表明，LPS治疗后的疾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腺激素依赖行为长期改变的潜在机制。该研究计划的短期目标是使用一种新颖的多学科方法，首先表征小鼠急性免疫反应的年龄和性别相关差异。其次，我将检查性腺激素的作用和潜在的遗传和表观遗传机制的性腺功能在年龄和性别差异的急性反应免疫挑战。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。在青春期暴露于免疫挑战可以永久改变对性腺激素的反应的想法是一个新的和原始的概念，对中介机制知之甚少。该研究计划采用多学科方法来表征免疫反应的年龄和性别相关差异，以及性腺激素在青春期免疫挑战脆弱性中的作用。这个研究项目还将显示青春期暴露于免疫挑战是否会对压力和免疫反应产生长期的改变。这项工作将通过检查青春期神经内分泌、压力和免疫系统之间的相互作用，扩大对压力源影响发育中的大脑的基本机制的研究，并在敏感的发育时期对神经系统的结构和功能造成长期的改变。

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.