Our results, showing that prenatal stress increases IL1β mRNA levels in the hippocampi of ovariectomized female mice, are in agreement with previous findings for adolescent female rats, which show that prenatal stress increases pro-inflammatory status  and elevates splenic and brain IL1β levels . However, a previous study did not detect changes in IL1β levels in hippocampi of prenatally stressed female mice . This discrepancy may be due to the fact that females were ovariectomized in our experiment, therefore, preventing the antiinflammatory effects of ovarian hormones [20, 21, 34, 35].
The increased mRNA levels for IL1β in the hippocampi of prenatally stressed animals detected in the present study may contribute to the increased activity of HPA axis observed in adulthood in these animals , since IL1β is known to decrease the affinity of corticosteroid receptors in the hippocampus . In addition, the hyper-secretion of pro-inflammatory cytokines, such as IL1β, is an index of stress and psychopathology . Therefore, the increased expression of IL1β in the hippocampi of prenatally stressed animals may also be related to the depressive-like behaviors observed in these animals . In accordance with these data, it has been described that external stress-induced depression-like behaviors are associated with increased levels of certain cytokines, such as IL1β .
In addition, prenatal stress produces an inhibition of neurogenesis in the dentate gyrus of the hippocampi in rats [31, 32] and monkeys . In turn, decreased hippocampal neurogenesis related to stress-induced increases in plasma glucocorticoids may be involved in mediating depressive affect [46, 47]. Since it has been described that elevation of hippocampal IL1β can markedly suppress hippocampal neurogenesis and since IL1β is induced by stress, it is probable that IL1β mediates the anti-neurogenic effect of stress [26, 48–50].
The increase in mRNA levels for IL1β in hippocampi of prenatally stressed animals was accompanied by a significant increase in the number of cells immunoreactive for Iba1, a marker of both resting and reactive microglia. In addition, prenatal stress caused a decrease in the number of Iba1-immunoreactive cells showing three to five short branches (type II) and an increase in the proportion of Iba1-immunoreactive cells with numerous cell processes (type III). This observation is in agreement with accelerated microglial differentiation into a ramified form in prenatally stressed pups of 10 days of age . The significance of these morphological changes in microglia is unknown, but they may reflect a transition of resting microglia towards a pre-activated phenotype. In addition, in prenatally stressed animals there was a higher proportion of Iba1-immunoreactive cells with large somas and retracted and thicker processes (type IV); morphology that is characteristic of activated microglia.
Systemic LPS administration induces peripheral inflammation and central neuroinflammation involving microglial activation, resulting in chronically elevated inflammatory, oxidative and nitrosative stress pathways [38, 44]. Induction of the proinflammatory cytokines IL-1β, IL-6 and TNF-α within the CNS leads to a variety of behavioral, physiological and neurological alterations, including fever, diminished feeding behavior, decreased social behavior and decreased exploration (collectively termed “sickness behavior”) . In agreement with this, LPS administration induces fever response in prenatally stressed animals [17, 18]. LPS administration also causes deficits in performance and spatial learning and increased corticosterone and IL-1β levels. .
Our findings indicate that prenatal stress not only affects mRNA levels for IL1β and Iba1 immunoreactivity in the hippocampus under basal conditions, but also modifies the inflammatory response after the administration of LPS. LPS induced significantly greater increases in the mRNA for IL6, TNF-α and IP10 in hippocampus of prenatally stressed mice compared to non-stressed animals. The enhanced LPS-induced expression of IL6 and TNFα in prenatally stressed animals may increase inflammatory damage  and dysfunction of the blood–brain barrier . Furthermore, increased expression of IP10 after LPS could result in differences in the recruitment of T lymphocytes, natural killer cells and monocytes into the central nervous system [55, 56]. The expression of these proinflammatory molecules is also associated with increased microglia reactivity  and may, therefore, be involved in the higher proportion of Iba1-immunoreactive cells with morphological characteristics of activated microglia (types IV and V) induced by LPS in prenatally stressed animals compared to non-stressed animals. In this regard, although under quiescent condition, microglia may be involved in facilitation of neurogenesis ; inflammation-induced microglial activation has been implicated in neurogenesis suppression [59, 60]. In addition, the number of activated microglial cells shows a direct correlation with impairment of neurogenesis . Therefore, the increased number of Iba1-immunoreactive cells in the prenatally stressed group could be involved in decreased neurogenesis and in behavioral alterations observed in this animal model [4, 31]. Also, the exacerbated increase of IL6 and TNFα observed in prenatally stressed mice after LPS administration could directly affect neurogenesis, since IL-6 and TNFα are known to inhibit neurogenesis [26, 62, 63].
The inflammatory response to LPS is mediated by TLR4, a member of the IL1 receptor/TLR superfamily that is expressed by astrocytes [64–67] and microglia . In agreement with our results, previous studies have shown that expression of TLR4 is increased in hippocampus of mice after systemic administration of LPS [69, 70]. The significance of an increased central expression of TLR4 during systemic inflammation remains to be determined. However, our data show that prenatally stressed and non-stressed mice showed similar changes in the expression of TLR4 in hippocampus after LPS administration. This indicates that the different responses of hippocampus of these animals to LPS are not mediated by differences in TLR4 expression. The different responses of the hippocampi of prenatally stressed and non-stressed animals to LPS may be an indirect effect of deregulation of the HPA axis by prenatal stress . This deregulation of the HPA axis may affect the release of ACTH and glucocorticoids in response to LPS [72–74] and the regulation of the immune response by these molecules [75, 76].