Adolescent methylmercury exposure: Behavioral mechanisms and effects of sodium butyrate in mice

Abstract

Methylmercury (MeHg), an environmental neurotoxicant primarily found in fish, produces neurobehavioral impairment when exposure occurs during gestation. Whether other developmental periods, such as adolescence, display enhanced vulnerability to the behavioral effects of MeHg exposure is only beginning to be explored. Further, little is known about the effects of repeated administration of lysine deacetylase inhibitors, such as sodium butyrate (NaB), on operant behavior. In Experiment 1, male C57BL6/n mice were exposed to 0, 0.3, and 3.0 ppm MeHg (n = 12 each) via drinking water from postnatal days 21 to 60 (murine adolescence). As adults, mice were trained to lever press under an ascending series of fixed-ratio schedules of milk reinforcement selected to enable the analysis of three important parameters of operant behavior using the framework provided by Mathematical Principles of Reinforcement. Adolescent MeHg exposure dose-dependently increased saturation rate, a measure of the retroactive reach of a reinforcer, and decreased minimum response time relative to controls. In Experiment 2, the behavioral effects of repeated NaB administration both alone and following adolescent MeHg exposure were examined. Male C57BL6/n mice were given either 0 or 3.0 ppm MeHg during adolescence and, before behavioral testing, two weeks of once daily i.p. injections of saline or 0.6 g/kg NaB (n = 12 in each cell). Adolescent MeHg exposure again increased saturation rate but did not significantly alter minimum response time. NaB also increased saturation rate in both MeHg exposure groups. These data suggest that the behavioral mechanisms of adolescent MeHg exposure and NaB may be related to the impact of reinforcement on prior responses. Specifically, MeHg and NaB concentrated the effects of reinforcers onto the most recent responses.

Keywords: Adolescence; Fixed ratio; Lysine deacetylase inhibitor; Mathematical principles of reinforcement; Methylmercury; Sodium butyrate.

Figure 1.

The effects of changes in minimum response time (δ), specific activation (a), and saturation rate (λ) on the shape of the MPR function drawn by Eq. 1. The base function (solid line) in each panel is drawn with δ = .50, a = 300, and λ = .10. An increase in minimum response time to δ = .80 (left panel) is evident in a reduction in the maximum response rate (1/δ), which is the extrapolated Y-intercept of the descending limb of the function (dotted lines, left panel). A reduction in specific activation to a = 200 (middle panel) is reflected as a decrease in the X-intercept of the descending limb of the function. Finally, an increase in saturation rate to λ = .75 shifts the peak of the function to the left. The vertical dotted lines (right panel) indicate that an FR 54 maximizes response rates when λ = .10 whereas an FR 12 maximizes response rates when λ = .75.

Figure 2.

Timeline of events for Experiment 1 and Experiment 2. Mice arrived at PND 21 (Experiment 1) or PND 23 (Experiment 2) and were exposed to MeHg during adolescence for 39 days. In Experiment 2, sodium butyrate (NaB; 0.6 g/kg, i.p.) or saline vehicle were injected daily for two weeks prior to behavioral testing. Behavioral testing began in adulthood (PND 90 in Experiment 1, PND 100 in Experiment 2). MeHg = methylmercury, PND = postnatal day, NaB = sodium butyrate

Figure 3.

Left panel: Mean response rate as a function of fixed ratio for mice exposed to MeHg in adolescence. Lines represent mean predictions of Eq. 1. Right panel: Response rate (symbols) and predictions of Eq. 1 (lines) as a function of fixed ratio for individual mice. The left column shows data from mice with the best-fitting curves, and the right column shows data from mice with the worst-fitting curves. Note the Y-axis scaling in the lower-right panel. MeHg = methylmercury

Figure 4.

Mean (±SD) parameter estimates from Eq. 1 as a function of dose of MeHg in adolescence. An outlier in the 3.0 ppm group is denoted as an open circle. MeHg = methylmercury *p < .05 relative to control

Figure 5.

Mean (±SD) dose of MeHg as a function of postnatal day for each MeHg-exposure group in Experiment 2. Note the error bars may be obscured by the symbols in some cases. MeHg = methylmercury, NaB = sodium butyrate

Figure 6.

Mean response rate as a function of fixed ratio for mice exposed to 0 or 3 ppm MeHg in adolescence and treated with control (left panel), sodium butyrate (middle panel), or environmental enrichment (right panel) before behavioral testing. Lines represent mean predictions of Eq. 1. MeHg = methylmercury

Figure 7.

Mean (+SD) parameter estimates from Eq. 1 for each treatment group. MeHg = methylmercury, NaB = sodium butyrate. *p < .05