Sex differences in response to an immune challenge

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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.