Deficient maternal care resulting from immunological stress during pregnancy is associated with a sex-dependent enhancement of conditioned fear in the offspring

Activation of maternal stress response systems during pregnancy has been associated with altered postpartum maternal care and subsequent abnormalities in the offspring’s brain and behavioral development. It remains unknown, however, whether similar effects may be induced by exposure to immunological stress during pregnancy. The present study was designed to address this issue in a mouse model of prenatal immune activation by the viral mimic polyriboinosinic–polyribocytidilic acid (PolyI:C). Pregnant mice were exposed to PolyI:C-induced immune challenge or sham treatment, and offspring born to PolyI:C- and sham-treated dams were simultaneously cross-fostered to surrogate rearing mothers, which had either experienced inflammatory or vehicle treatment during pregnancy. We evaluated the effects of the maternal immunological manipulation on postpartum maternal behavior, and we assessed the prenatal and postnatal maternal influences on anxiety- and fear-related behavior in the offspring at the peri-adolescent and adult stage of development. We found that PolyI:C treatment during pregnancy led to changes in postpartum maternal behavior in the form of reduced pup licking/grooming and increased nest building activity. Furthermore, the adoption of neonates by surrogate rearing mothers, which had experienced PolyI:C-induced immunological stress during pregnancy, led to enhanced conditioned fear in the peri-adolescent and adult offspring, an effect that was exclusively seen in female but not male subjects. Unconditioned (innate) anxiety-related behavior as assessed in the elevated plus maze and open field explorations tests were not affected by the prenatal and postnatal manipulations. Our results thus highlight that being raised by gestationally immune-challenged surrogate mothers increases the vulnerability for specific forms of fear-related behavioral pathology in later life, and that this association may be mediated by deficits in postpartum maternal care. This may have important implications for the identification and characterization of early-life risk factors involved in the developmental etiology of fear-related neuropsychiatric disorders

Long-term effects of early life deprivation on brain glia in Fischer rats

Both clinical and experimental studies have indicated that depression and depression-like animal conditions are associated with disruption of the intrinsic plasticity of the brain, resulting in neuronal atrophy. However, little is known about the brain glia in these conditions. Early life stress in the form of infant abuse or neglect constitutes a risk factor in the aetiology of major depressive disorder in later life. It is possible to model this relation between early life stress and depression in the rat through maternal deprivation; in adulthood, this postnatal manipulation is known to lead to depression-like behaviour. In the stress-hyperresponsive Fischer strain, P1-14 pups were isolated for 4 h/day (early deprivation, ED, n=6) or were nonhandled (NH, n=6); they were left undisturbed until adulthood. Postmortem quantitative analysis of regional astroglial distribution and morphology based on glial fibrillary acidic protein (GFAP) immunohistochemistry indicated a significant effect of ED on the density of GFAP-reactive astrocytes in brain areas implicated in stress-related behaviour. A moderate (10-22%) but consistent reduction in GFAP-reactive astrocyte density was seen in dorsal dentate gyrus, prefrontal cortex, ventral hippocampal CA1, cingulate cortex, dorsal hippocampal CA1 and basolateral amygdala. The ED-related reduction in GFAP-immunoreactive astrocyte density was more marked than the reduction in total cell density, which suggests that GFAP immunoreactivity, rather than the number of astrocytes, was reduced. This study provides evidence that early life stress leads to long-term changes in the density of astroglia in the brain regions involved in stress responses in the rat

Discriminative stimulus effects of L-838,417 (7-tert-butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine): Role of GABAA receptor subtypes

Previous reports suggest that γ-aminobutyric acid type A (GABAA) receptors containing α1 subunits may play a pivotal role in mediating the discriminative stimulus effects of benzodiazepines (BZs). L-838,417 (7-tert-Butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine) is a GABAA receptor modulator with intrinsic efficacy in vitro at α2, α3, and α5 subunit-containing GABAA receptors, and little demonstrable intrinsic efficacy in vitro at α1 subunit-containing GABAA receptors. The present study evaluated the discriminative stimulus effects of L-838,417 in order to determine the extent to which the α2, α3, and α5 subunit-containing GABAA receptors contribute to the interoceptive effects of BZ-type drugs. Squirrel monkeys (Saimiri sciureus) were trained to discriminate L-838,417 (0.3 mg/kg, i.v.) from vehicle under a 5-response fixed-ratio schedule of food reinforcement. Under test conditions, L-838,417 administration resulted in dose-dependent increases in drug-lever responding that were antagonized by the BZ-site antagonist, flumazenil. Administration of non-selective BZs, compounds with 10-fold greater affinity for α1 subunit-containing GABAA receptors compared to α2, α3, and α5 subunit-containing GABAA receptors, barbiturates and ethanol (which modulate the GABAA receptor via a non-BZ site), all resulted in a majority of responses on the L-838,417-paired lever (65–100% drug-lever responding). βCCT, an antagonist that binds with 20-fold greater affinity for α1 subunit-containing GABAA receptors relative to α2, α3, and α5-containing GABAA receptors, had no significant effect on the discriminative stimulus effects of L-838,417 or the L-838,417-like effects of diazepam or zolpidem. These data suggest that efficacy at α2, α3, and/or α5 subunit-containing GABAA receptors likely are sufficient for engendering BZ-like discriminative stimulus effects