Enhanced stimulus sequence-dependent repeated learning in male offspring after prenatal stress alone or in conjunction with lead exposure

Abstract

Both lead (Pb) exposure and prenatal stress (PS) can produce cognitive deficits, and in a prior study we demonstrated enhanced cognitive deficits in repeated learning of female rats exposed to both of these developmental insults (Cory-Slechta et al., 2010). However, PS can also lead to improved cognitive outcomes that are both gender-and context-dependent. Thus, the current study examined whether Pb ± PS likewise produced repeated learning deficits in males, either after maternal or lifetime Pb exposure. Repeated learning was evaluated using a multiple schedule of repeated learning and performance that required learning 3-response sequences in male offspring that had been subjected to either maternal Pb (0 or 150 ppm) or lifetime Pb exposure (0 or 50 ppm) beginning two mos prior to dam breeding, to prenatal immobilization restraint stress (gestational days 16–17), or to both Pb and PS. Blood Pb, corticosterone, hippocampal glucocorticoid receptor density and brain monoamines were also measured. In contrast to outcomes in females, sequence-specific enhancements of repeated learning accuracy were produced by PS, particularly when combined with Pb, results that appeared to be more robust in combination with lifetime than maternal Pb exposure. A common behavioral mechanism of these improvements appears to be an increase reinforcement density associated with increased response rates and shorter session times seen with PS ± Pb that could both shorten time to reinforcement. Trends towards lower levels of nucleus accumbens dopamine activity seen after both maternal Pb and lifetime Pb combined with PS suggest a possible role for this region/neurotransmitter in enhanced accuracy, whereas PS ± Pb-induced corticosterone changes did not exhibit an obvious systematic relationship to accuracy enhancements. While PS ± Pb-based increases in accuracy appear to be an improved outcome, the benefits of increased response rate are by no means universal, but highly context-dependent and can lead to adverse behavioral effects in other conditions.

Sex-dependent impacts of low-level lead exposure and prenatal stress on impulsive choice behavior and associated biochemical and neurochemical manifestations

“…Dependent upon ANOVA outcomes, subsequent Fishers least protected differences post-hoc tests were carried out. Our prior studies have repeatedly demonstrated clear sex differences in the consequences of Pb ± PS (Cory-Slechta et al, 2012a; Cory-Slechta et al, 2010; Cory-Slechta et al, 2012b; Cory-Slechta et al, 2008; Cory-Slechta et al, 2009; Cory-Slechta et al, 2004; Cory-Slechta et al, 2013b; Rossi-George et al, 2009; Rossi-George et al, 2011; Virgolini et al, 2005; Virgolini et al, 2008); similar consequences were apparent in an initial overall analyses of percent long delay choice by session in the current study, as characterized by a significant interaction of Pb × sex (F(47,3666)=2.16, p<0.0001). Consequently, all analyses were carried out separately for each sex.…”

Developmental stress and lead (Pb): Effects of maternal separation and/or Pb on corticosterone, monoamines, and blood Pb in rats

“…Of those in the nucleus accumbens, DOPAC was reduced in the 50 ppm Pb-stress group but not in the 150 ppm Pb-stress group; DA utilization was increased in the no Pb-prenatal stress group; and NE was increased in the no Pb-prenatal stress group. The interaction in the striatum was in the 150 ppm Pb no stress group in which DOPAC was higher than the no Pb no stress control group (Cory-Slechta et al, 2012). In the next experiment using the same model but only the 50 ppm Pb dose, no interactions were found in the frontal cortex on monoamines, but reductions in the Pb-stress group were found in frontal cortex glutamate and GABA (not measured in previous studies) and in midbrain 5-HT and 5-HIAA.…”

“…Restraint in these experiments was given on gestational days (G)16 and G17 three times, 45 min each time, spaced 3 h apart (where G1 = embryonic day E0, hence G16–17 is the same as E15–16). In these studies a number of Pb and prenatal stress effects were reported on behavior, corticosterone, and monoamines, but relatively few stress × Pb interactions were found (Cory-Slechta et al, 2004;Virgolini et al, 2008a;Cory-Slechta et al, 2009;Rossi-George et al, 2009;Cory-Slechta et al, 2010;Rossi-George et al, 2011;Cory-Slechta et al, 2012;Cory-Slechta et al, 2013b;Cory-Slechta et al, 2013a;Weston et al, 2014). In the first study, interactions between prenatal restraint stress and monoamines were found in the high dose group Pb Group (150 ppm/day Pb) on frontal cortex DA utilization (DA/HVA but not DA/DOPAC) and in nucleus accumbens (increased DOPAC and HVA) and reduced 5-HT (Cory-Slechta et al, 2004).…”

“…Interactions between Pb and stress have been reported in children (Tong et al, 2000) and in animals (Weston et al, 2014;Cory-Slechta et al, 2013b;Cory-Slechta et al, 2010;Cory-Slechta et al, 2012;Cory-Slechta et al, 2009;Cory-Slechta et al, 2013a;Rossi-George et al, 2009;Rossi-George et al, 2011;Virgolini et al, 2006;Virgolini et al, 2008b;Virgolini et al, 2008a;Cory-Slechta et al, 2004). The latter are from a laboratory primarily using a paradigm in which female Long-Evans rats are given Pb (50 or 150 ppm in drinking water) for 2 months prior to mating, throughout gestation, and up to weaning or through adulthood.…”

Maternal stress modifies the effect of exposure to lead during pregnancy and 24-month old children's neurodevelopment

“…This sex-dependent effect of the lead-stress association has been mostly investigated by animal studies where females show worse outcomes than males and the suggested mechanism involves the role of oestrogen in the mediation of pre- and post-natal effects of this association (Cory-Slechta et al 2012). …”