Gunn et al. GABAA receptors, neurosteroids, and stress defeat of a female rat during the last week of pregnancy by a resident lactating rat). In this model, both male and female adult offspring displayed exaggerated adrenocorticotropic hor- mone (ACTH) and corticosterone responses to an acute stress challenge, i.e., interleukin-1β (IL-1β) administration (Brunton and Russell, 2010). Interestingly, prior treatment (2 and 20 h before the IL-1β challenge) with 5α3α-THPROG normalized the exagger- ated (approximately threefold) ACTH response in female, but not male adult rats exposed prenatally (i.e., during the last week of pregnancy) to social PNS (Brunton and Russell, 2011). However, the testosterone metabolite androstanediol, which also enhances GABAAR function (Gee et al., 1988; Reddy and Jian, 2010), nor- malized the HPA response to IL-1β of male PNS rats (Brunton and Russell, 2011). These observations are consistent with the proposal that neurosteroidogenesis may be compromised in the adult brain of rats exposed to PNS. Yet, the mechanism whereby these neurosteroids restore the neuroendocrine response to IL-1β administration is currently unclear, although given the prominent role of GABAAR-mediated inhibition in the stress neurocircuitry (Cullinan et al., 2008), potentiation of GABAAR function is likely to contribute. For example, neurosteroid administration to PNS adult rats may restore HPA sensitivity through a mechanism sim- ilar to that previously described in dams during the ﬁnal stage of pregnancy (Brunton et al., 2009). Thus, during late pregnancy (pregnancy day 21), the maternal response to an IL-1β challenge is reduced due to the inhibition of noradrenergic inputs to the PVN. This effect appears consequent to an increased expression of enkephalin and presynaptic μ-opioid receptors, an adaptation that is critically dependent on 5α3α-THPROG (Brunton et al., 2009). An attractive possibility worthy of investigation is that neu- rosteroids such as 5α3α-THPROG and androstanediol may induce similar adaptations in adult PNS rats to normalize the endocrine response to IL-1β administration (see Brunton and Russell, 2011). While the speciﬁc mechanism whereby 5α3α-THPROG induces increased enkephalin and opioid receptor expression in pregnant rats remains to be elucidated, the “glucocorticoid-like” effects of neurosteroids upon CRH and vasopressin (AVP) expression within the PVN (Patchev et al., 1994, 1996) and the modulation of PVN neuropeptide expression by GABAARs (Cole and Sawchenko, 2002; Bali and Kovacs, 2003) warrant further investigation. Of fur- ther note, the fetal neuroprotective actions of 5α3α-THPROG may not be exclusively associated with direct effects within the fetal brain, as elevated maternal levels of this neurosteroid during the latter stages of pregnancy act to reduce the sensitivity of maternal HPA axis to stressful challenges, and hence, the exposure of the fetus to maternally derived glucocorticoids (reviewed in Brunton and Russell, 2008). Perturbations in neurosteroid levels have also been reported in the fetal brain following an acute hypoxic challenge induced by constriction of the umbilical cord, a response, which may result from increased 5α-reductase and cytochrome P450scc expression within the brain (Nguyen et al., 2004). The observed elevation in central neurosteroid levels in response to hypoxia may repre- sent an endogenous neuroprotective mechanism in the develop- ing brain. In agreement, binding studies, using [35S] TBPS have revealed that by late gestation GABAARs are signiﬁcantly more sensitive to 5α3α-THPROG modulation than in the adult brain (Crossley et al., 2000). In contrast, exposure to chronic hypoxic stress (induced through the injection of inert microspheres into the fetal circulation) increased the expression of the neurosteroid synthesizing enzyme 5α-reductase in most brain regions, but had no effect upon the amount of 5α3α-THPROG in the fetal brain after 20 days of hypoxemia (Nguyen et al., 2003). The reduced capacity of the fetus to synthesize 5α3α-THPROG in response to a chronic hypoxic challenge may result from a reduction in the sup- ply of maternally derived 5α3α-THPROG and/or the impaired metabolism of progesterone to other neurosteroid precursors. However, the ability of the fetal brain to synthesize other neu- roactive steroids and the impact that acute and chronic stress have upon this remains unknown. Collectively, these observations suggest that neurosteroids such as 5α3α-THPROG may be impor- tant neuroprotective agents within the fetal brain (reviewed in Hirst et al., 2009). In this context, it is conceivable that the doc- umented excitatory and trophic actions of GABA in the prenatal CNS (Represa and Ben-Ari, 2005) are not incidental to the neuro- protective actions of neurosteroids. However, it should be noted that the excitatory actions of GABA, observed during development have also been associated with neuronal damage (e.g., epilepsy-see Dzhala et al., 2005). Few studies have measured changes in brain function associated with PNS in humans. However, children of mothers who during pregnancy experienced stress, depression, or anxiety, or who were treated with glucocorticoids, exhibit increased basal HPA activ- ity, thus indicating that there are long-lasting alterations affecting the child’s normal development of the stress response (reviewed in Lupien et al., 2009). This altered HPA programming may con- tribute to the increased vulnerability of the progeny to affective disorders in later life (Bale et al., 2010). POSTNATAL STRESS Endogenous neurosteroids have also been implicated in the post- natal maturation of the HPA axis. The early postnatal period is crucial in the development and maturation of the HPA axis and is characterized in rodents, by a period (PN4–14) of marked hypore- sponsivity (Sapolsky and Meaney, 1986). As this period coincides with stages of axonal growth, synaptogenesis, and myelination of key brain circuits, it has been postulated that this hyporesponsive phenotype protects the developing brain from excessive glucocor- ticoid exposure. Adverse early life events are known to result in profound and long-lasting alterations in the mature organism’s behavioral and neuroendocrine response to stress (Francis and Meaney, 1999). Speciﬁcally, the mother–pup interaction has been shown to strongly inﬂuence the maturation of the stress neuro- circuitry, as both in rodents and in primates reduced maternal care is associated with impaired behavioral and neuroendocrine responses to stress in adulthood (Sanchez et al., 2001). Conversely, enhanced maternal care increases the ability to cope with stressful experiences in later life (Francis et al., 1999). Suggesting a possible role for neurosteroids in the program- ming of the stress response, 5α3α-THPROG reduced the number of ultrasonic vocalizations (USVs), a measure of an anxious-like phenotype, in neonatal (PN7) rat pups previously exposed to maternal separation (Zimmerberg et al., 1994, 1999), while mater- nally separated (between PN 2 and 7) neonatal rats displayed a www.frontiersin.org December 2011 | Volume 5 | Article 131 | 9