Antidepressants may mitigate the effects of prenatal maternal anxiety on infant auditory sensory gating.

OBJECTIVE: Prenatal maternal anxiety has detrimental effects on the offspring's neurocognitive development, including impaired attentional function. Antidepressants are commonly used during pregnancy, yet their impact on offspring attention and their interaction with maternal anxiety has not been assessed. The authors used P50 auditory sensory gating, a putative marker of early attentional processes measurable in young infants, to assess the impact of maternal anxiety and antidepressant use. METHOD: A total of 242 mother-infant dyads were classified relative to maternal history of anxiety and maternal prenatal antidepressant use. Infant P50 auditory sensory gating was recorded during active sleep at a mean age of 76 days (SD=38). RESULTS: In the absence of prenatal antidepressant exposure, infants whose mothers had a history of anxiety diagnoses had diminished P50 sensory gating. Prenatal antidepressant exposure mitigated the effect of anxiety. The effect of maternal anxiety was limited to amplitude of response to the second stimulus, while antidepressant exposure had an impact on the amplitude of response to both the first and second stimulus. CONCLUSIONS: Maternal anxiety disorders are associated with less inhibition during infant sensory gating, a performance deficit mitigated by prenatal antidepressant exposure. This effect may be important in considering the risks and benefits of antidepressant use during pregnancy. Cholinergic mechanisms are hypothesized for both anxiety and antidepressant effects, although the cholinergic receptors involved are likely different for anxiety and antidepressant effects.

The occurrence of preterm delivery is linked to pregnancy-specific distress and elevated inflammatory markers across gestation.

There is mounting evidence that stress during pregnancy can have detrimental effects on gestation and birth. Existing studies indicate that prenatal stress may increase levels of circulating inflammatory markers that are associated with prematurity and pregnancy complications, suggesting that stress-related changes in the cytokine milieu may increase the risk of poor pregnancy outcome. Previous studies, however, have not clearly connected stress during pregnancy to changes in inflammatory mediators and, in turn, to clinically-relevant outcomes such as premature delivery. The present study sought to directly connect prenatal stress and changes in inflammatory markers to preterm delivery and gestational age at birth (GAB). A sample of 173 women was recruited during the first trimester of pregnancy and followed through delivery. Overall stress, pregnancy-specific distress, and inflammatory markers were assessed early and later in pregnancy, and the predictive value of these measures for preterm birth and GAB was determined. There were significant differences in pregnancy-specific distress, IL-6, and TNF-α between women who delivered prematurely versus those who delivered at term, and elevated levels of pregnancy-specific distress, IL-6, and TNF-α were predictive of shortened GAB overall. Importantly, in many cases, the effects of overall stress and pregnancy-specific distress on GAB were mediated by levels of circulating inflammatory markers. Collectively, these data provide strong evidence that prenatal stress experiences can affect the timing of parturition via alterations in circulating inflammatory mediators, and underscore the need for ongoing research aimed at further understanding the mechanisms and effects of prenatal stress on maternal and infant health.

Activation of corticotropin-releasing factor receptor 2 in lateral septum negatively regulates maternal defense.

Maternal defense (also known as maternal aggression) is impaired by corticotropin-releasing factor-(CRF) related peptides, but where these peptides inhibit defense is unknown. Lateral septum (LS) gates reactivity to stressors, contains receptors to CRF-related peptides, and during lactation shows a decreased response to CRF, suggesting LS is a key site for regulating maternal aggression. In this study, the authors examined the effects of CRF-related peptides in LS on maternal defense. LS injections of CRF (0.2 microg), urocortin (Ucn) 1 (0.2 microg), and Ucn 3 (0.25 microg) all significantly impaired maternal defense behavior. However, LS injections of CRF receptor 2 antagonist astressin-2B, but not a CRF receptor 1 antagonist, reversed the inhibitory effects of both septal CRF and Ucn 3. After intra-LS injection of peptides, c-Fos immunoreactivity was increased in ventromedial hypothalamus, lateral hypothalamus, and parabrachial nucleus, identifying these brain regions as possible downstream mediators of altered LS activity. Together, these findings indicate that CRF-related peptides similarly modulate maternal defense via CRF receptor 2, and that LS is a critical site for the negative regulation of maternal defense behavior.

Maternal profiling of corticotropin-releasing factor receptor 2 deficient mice in association with restraint stress.

Mice deficient in corticotropin-releasing factor receptor 2 (CRF2) (C57BL/6J:129Sv background) exhibit impaired maternal defense (protection of offspring) and are more reactive to stressors than wild-type mice. To further understand CRF2's role in maternal behavior, we crossed the knockout mice with a line bred for high maternal defense that also has elevated maternal care relative to inbred lines. Maternal care was normal in knockout mice (relative to wild-type). Maternal defense was impaired as previously observed. Exposure to a mild stressor (15 min restraint) did not trigger deficits in maternal defense in either genotype as determined by a two-way repeated measures ANOVA analysis. However, when examining difference scores between unrestrained and restrained conditions, knockout mice exhibited significant decreases in maternal defense with stress, suggesting knockouts are more susceptible to a mild stressor's effects. To gain possible insights into brain activity differences between WT and KO mice, we examined c-Fos expression in association with stress. Unrestrained KO mice exhibited significantly lower c-Fos levels relative to unrestrained WT mice in 9 regions, including lateral septum and periaqueductal gray. For WT mice, restraint stress triggered c-Fos activity increases in 3 regions while for KO mice, restraint stress triggered c-Fos increases in 16 regions. Taken together, our results suggest both altered behavioral and c-Fos responses to stress in lactating CRF2 KO mice.

Altered dopamine signaling in naturally occurring maternal neglect.

BACKGROUND: Child neglect is the most common form of child maltreatment, yet the biological basis of maternal neglect is poorly understood and a rodent model is lacking. METHODOLOGY/PRINCIPAL FINDINGS: The current study characterizes a population of mice (MaD1) which naturally exhibit maternal neglect (little or no care of offspring) at an average rate of 17% per generation. We identified a set of risk factors that can predict future neglect of offspring, including decreased self-grooming and elevated activity. At the time of neglect, neglectful mothers swam significantly more in a forced swim test relative to nurturing mothers. Cross-fostered offspring raised by neglectful mothers in turn exhibit increased expression of risk factors for maternal neglect and decreased maternal care as adults, suggestive of possible epigenetic contributions to neglect. Unexpectedly, offspring from neglectful mothers elicited maternal neglect from cross-fostered nurturing mothers, suggesting that factors regulating neglect are not solely within the mother. To identify a neurological pathway underlying maternal neglect, we examined brain activity in neglectful and nurturing mice. c-Fos expression was significantly elevated in neglectful relative to nurturing mothers in the CNS, particularly within dopamine associated areas, such as the zona incerta (ZI), ventral tegmental area (VTA), and nucleus accumbens. Phosphorylated tyrosine hydroxylase (a marker for dopamine production) was significantly elevated in ZI and higher in VTA (although not significantly) in neglectful mice. Tyrosine hydroxylase levels were unaltered, suggesting a dysregulation of dopamine activity rather than cell number. Phosphorylation of DARPP-32, a marker for dopamine D1-like receptor activation, was elevated within nucleus accumbens and caudate-putamen in neglectful versus nurturing dams. CONCLUSIONS/SIGNIFICANCE: These findings suggest that atypical dopamine activity within the maternal brain, especially within regions involved in reward, is involved in naturally occurring neglect and that MaD1 mice are a useful model for understanding the basis of naturally occurring neglect.

Urocortin 1 and 3 impair maternal defense behavior in mice.

Lactating female mice fiercely defend offspring while exhibiting decreased fear and anxiety. Recent work (J. S. Lonstein & S. C. Gammie, 2002) found that intracerebroventricular (icv) injections of corticotropin releasing factor (CRF), a putative anxiogenic peptide, inhibit maternal defense behavior. This study examines effects of CRF-related peptides, urocortin (Ucn) 1 and Ucn 3, on maternal aggression in mice. Intracerebroventricular injections of both Ucn 1 (0.2 microg) and Ucn 3 (0.5 microg) reduced aggression but not pup retrieval. c-Fos levels were elevated by intracerebroventricular injections of Ucn 1 (0.2 microg) and Ucn 3 (0.5 microg) in 2 and 6 brain regions, respectively; however, both triggered increases in bed nucleus of the stria terminalis dorsal (BNSTd) and lateral septum (LS). These findings suggest that CRF-related peptides similarly modulate maternal aggression and that BNSTd/LS may be critical sites for negative regulation of maternal aggression.

Elevated stress sensitivity in corticotropin-releasing factor receptor 2 deficient mice decreases maternal, but not intermale aggression.

Maternal aggression is a form of aggression towards intruders by lactating females that is critical for defense of offspring. During lactation, fear and anxiety are reduced, the CNS is less responsive to the anxiogenic neuropeptide, corticotropin-releasing factor (CRF), and central injections of CRF inhibit maternal aggression. Together, these previous findings suggest that decreased CRF neurotransmission during lactation supports normal maternal aggression expression. Recent work indicates that mice deficient in CRF receptor 2 (CRFR2) display increased anxiety-like behaviors, have a hypersensitive stress response, and overproduce CRF. In this study, we examined both maternal and intermale aggression in wild-type (WT) and CRFR2-deficient mice. CRFR2-mutant mice exhibited significant deficits in maternal aggression on postpartum Day 4 relative to WT mice in terms of percentage displaying aggression, mean number of attacks, and mean time in aggressive encounters. However, time sniffing male intruder, pup retrieval, number of pups, and performance on the elevated plus maze were similar between genotypes. In contrast, intermale aggression did not differ between genotype in any measure on any of three consecutive test days. For neither form of aggression did sites of attacks on the intruder differ between genotype. Taken together, the results suggest that differences in stress sensitivity and the overproduction of CRF of the knockout (KO) mice specifically affects maternal, but not intermale aggression.