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.

Exposure to Methylmercury at Juvenile Stage Worsens Autism-like Symptoms in Adult BTBR T+tf/J Mice Due to Lack of Nuclear Factor Erythroid 2-Related Factor 2 Signaling Upregulation in Periphery and Brain

“…Abnormal neuron development, elevated oxidative stress, and the release of pro-inflammatory cytokines can cause neuroinflammation and damage the brain tissue in individuals with autism spectrum disorder [ 26 , 27 , 28 , 29 ]. Since the condition is a neurological problem, it is thought that genetic or environmental factors may play a vital role in affecting brain functioning [ 22 , 30 ]. For instance, a study showed that environmental factors account for a 55% probability of having autism spectrum disorder, whereas genetic factors account for only 37% [ 31 ].…”

“…To examine the impact of the environmental contaminant methylmercury chloride (MeHgCl) on autism-like symptoms in BTBR mice, they were administered with MeHgCl at a dose of 0.3 ppm in their drinking water for a duration of three weeks, starting at the age of 3 weeks [ 22 ]. At the age of 6 weeks, the mice were switched to normal tap water for a period of 4 weeks followed by behavioral tests in week 10.…”

d-Amphetamine and methylmercury exposure during adolescence alters sensitivity to monoamine uptake inhibitors in adult mice

“…A theoretically-driven model called Mathematical Principles of Reinforcement (MPR) (Killeen, 1994) can be especially helpful in parsing the behavioral effects of exposure (Boomhower and Newland, 2019). MPR posits that three processes govern voluntary behavior: (a) the value or specific activation of a reinforcer, (b) the maximal rate of a target response (e.g., lever pressing), which is the inverse of the minimum response time required to complete that behavior, and (c) the rate at which coupling of reinforcers to preceding responses increases, called the saturation rate (Table 1).…”