Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

Abstract

Humans are exposed to potentially harmful agents (bacteria, viruses, toxins) throughout our lifespan; the consequences of such exposure can alter central nervous system development. Exposure to immunogens during pregnancy increases the risk of developing neurological disorders such as schizophrenia and autism. Further, sex hormones, such as estrogen, have strong modulatory effects on immune function and have also been implicated in the development of neuropathologies (e.g., schizophrenia and depression). Similarly, animal studies have demonstrated that immunogen exposure in utero or during the neonatal period, at a time when the brain is undergoing maturation, can induce changes in learning and memory, as well as dopaminemediated behaviors in a sex-specific manner. Literature that covers the effects of immunogens on innate immune activation and ultimately the development of the adult brain and behavior is riddled with contradictory findings, and the addition of sex as a factor only adds to the complexity. This review provides evidence that innate immune activation during critical periods of development may have effects on the adult brain in a sex-specific manner. Issues regarding sex bias in research as well as variability in animal models of immune function are discussed.

Neonatal lipopolysaccharide exposure induces sexually dimorphic sickness behavior in adult rats.

“…These discrepancies could be attributable to the different periods of neonatal LPS exposure and different doses used for the LPS challenge. The type of immunogen (e.g., LPS, polyriboinosinic-polyribocytidylic acid, and cytokines), dose, and time of administration (e.g., early vs. late gestation, neonatal period) may interact with sex and play significant roles in the observed variability (Rana, Aavani, & Pittman, 2012).…”

The cytokine hypothesis: A neurodevelopmental explanation for the emergence of schizophrenia later in life

“…Additional experiments revealed that PPI abnormalities were lowest during estrus in female rats. This is mirrored in women; symptoms of schizophrenia are most severe when estrogen is low [22]. These findings indicate that there is an interaction between sex, the CNS, and the immune system, that results in different outcomes of schizophrenia.…”

“…Different areas of the brain develop at different times; therefore immune dysfunction can have varied developmental outcomes depending on what stage in development infection occurs [21]. Furthermore, considering that cytokines have different, even opposite effects depending on developmental stage, outcomes can vary immensely based on time [22].…”

Developmental immune activation programs adult behavior: insight from research on birds

“…Male zebra finches challenged with the endotoxin lipopolysaccharide (LPS) early in life exhibited reduced performance on a novel foraging task when tested approximately one year later, whereas female performance was not impacted by this endotoxin challenge [10]. As with the effects of immune challenge on neophobia, this demonstrates that immune activation may have sex-specific effects on behavior and future research should explicitly test for sex differences [25]. …”