Researchers from Emory University investigated whether chronic adolescent stress (CAS) modulates immune responses within the brain to promote depression and anxiety during adulthood and suggest that males and females are uniquely affected by CAS.

By Angelica Michelle-Fimbres Garcia

Researchers from Emory University investigated the influence of chronic adolescent stress (CAS) on immune responses within the brain and how those responses vary according to biological sex. Scientists believe that CAS has an immune-priming effect on the body, meaning that adversity during adolescence causes the immune system to prepare for action in response to secondary stressors later on. Given the hypothesized role for the immune system in the development of certain adult psychiatric illnesses, this may be one reason why CAS is a well-known precursor to depression and anxiety, among other disorders. Additionally, since women are twice as likely to be afflicted by mood disorders than men, the effects of CAS on the immune response may vary between males and females.

Previously, researchers showed that CAS increases depressive behaviors in adult rats and can contribute to long-lasting alterations in the hypothalamic-pituitary-adrenal (HPA) axis, a pathway that controls the release of important stress hormones and whose dysregulation has been associated with psychiatric illness. They also discovered that CAS causes changes in the release of inflammation-triggering cytokines in the hippocampus, a structure in the temporal lobe of the brain that is highly susceptible to stress effects mediated by the HPA axis, and therefore an appropriate region to address in studies of chronic stress.

The researchers’ recent study investigated whether the CAS immune-priming takes place in the peripheral organs, where adaptive immune responses frequently originate, or in the brain. They evaluated the expression of genes associated with the pro-inflammatory NFκB pathway whose over-activation is a marker for the progression of CAS, examining whether males and females responded differently to stress.

Rats were either placed under stressful conditions or exposed to no stress at all during adolescence. Upon reaching adulthood, the rats that experienced stressful conditions were injected with lipopolysaccharide, which acted as a secondary stressor, and were subsequently tested for the expression of genes involved in the NFκB pathway in the hippocampus and periphery. The levels of corticosterone, a stress hormone involved in the HPA axis, were also assessed. The results demonstrated that CAS generates immune-priming effects and that there is indeed a distinct inflammatory response between males and females.

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While the expression of NFκB pathway-associated genes increased in the hippocampus of both male and female rats following CAS, the types of genes expressed differed between sexes. For example, the expression of mRNA for the cytokine IL1B was exaggerated only in female rat hippocampi. However, IL-1B was found in higher levels in the plasma of male rats, an indicator of peripheral immune response activation. Male rats also experienced decreased levels of corticosterone—the primary stress hormone in rats which has anti-inflammatory properties—two hours after lipopolysaccharide injection while females experienced no change. Therefore, the male rats’ reduced levels of corticosterone and elevated peripheral inflammatory responses may indicate that the immune system of male rats would be better equipped to resolve infection or injury in the periphery. In summary, while the CAS-triggered inflammatory responses of female rats were isolated primarily to the hippocampus, males experienced changes in both the hippocampus and periphery.

The findings of this study are consistent with the idea that CAS may alter the immune system within the brain and body, but it seems to do so differently between males and females. These variations may hold the key to understanding the mechanisms underlying the sex differences that are characteristic of mood disorders.

Bekhbat M, Howell PA, Rowson SA, et al. (2019) Chronic adolescent stress sex-specifically alters central and peripheral neuro-immune reactivity in rats. Brain, Behavior, and Immunity, 76, 248-257. https://www.sciencedirect.com/science/article/pii/S0889159118303180











