Impacts of neonatal methylmercury on behavioral flexibility and learning in spatial discrimination reversal and visual signal detection tasks.

Early postnatal development in rodents is sensitive to neurotoxic effects of the environmental contaminant, methylmercury. While juvenile and adolescent exposure also produce long-term impairments in behavior, the outcome of neonatal exposure is less understood. Neural development during the neonatal period in rodents is akin to that seen in humans during the third trimester of pregnancy but methylmercury exposure occurring during the neonatal period has not been modeled, partly because breast milk is a poor source of bioavailable methylmercury. To examine this developmental period, male Long-Evans rats were exposed to 0, 80, or 350 µg/kg/day methylmercuric chloride from postnatal days 1-10, the rodent neonatal period. As adults, behavioral flexibility, attention, memory, and expression of the dopamine transporter in these rats was assessed. Rats exhibited changes in behavioral flexibility assessed in a spatial discrimination reversal procedure. Those rats exposed to the highest dose of methylmercury displayed subtly altered patterns of perseveration compared to control animals. During acquisition of the attention/memory procedure, rats exposed to this dose also had slower acquisition, and achieved lower overall accuracy during training, compared to controls despite neither attention nor memory being affected once the task was acquired. Finally, dopamine transporter expression in the striatum, prefrontal cortex, and hippocampus was unchanged in these adult rats. The results of this study replicate the trend of findings seen with exposure during gestation or during adolescence.

Adolescence as a sensitive period for neurotoxicity: Lifespan developmental effects of methylmercury.

Neurotoxicity resulting from the environmental contaminant, methylmercury (MeHg), is a source of concern for many human populations that rely heavily on the consumption of fish and rice as stable ingredients in the diet. The developmental period of exposure is important both to the qualitative effects of MeHg and to the dose required to produce those effects. MeHg exposure during the sensitive prenatal period causes deleterious and long-lasting changes in neurodevelopment at particularly low doses. The effects include a wide host of cognitive and behavioral outcomes expressed in adulthood and sometimes not until aging. However, neurotoxic outcomes of MeHg when exposure occurs during adolescence are only recently revealing impacts on human populations and animal models. This review examines the current body of work and showcases the sensitivity of adolescence, a period that straddles early development and adulthood, to MeHg neurotoxicity and the implications such toxicity has in our understanding of MeHg's effects in human populations and animal models.

Selective dopaminergic effects on attention and memory in male mice exposed to Methylmercury during adolescence.

Gestational exposure to methylmercury disrupts dopamine-mediated behavior and produces heightened sensitivity to monoamine agonists later in life. This has been reported and replicated following both pre- and post-natal exposure. Impacts of methylmercury when exposure occurs during the sensitive period of adolescence, a key period of dopaminergic development, remain underexplored. There have been variable results thus far in studies investigating links between adolescent exposure to methylmercury and alterations in executive function and altered sensitivity to monoamine agonists. The current study was designed to investigate adolescent exposure by exposing male mice to 0, 0.3, or 3 ppm methylmercury during adolescence and training them in a hybrid task to assess two executive functions, attention and memory, in adulthood. Behavior in these animals was probed with a range of doses of the dopamine agonist, d-amphetamine, and the norepinephrine agonist, desipramine. Attention and memory in these mice were sensitive to disruption by d-amphetamine and interacted with methylmercury exposure. Choice latencies were also longer in the MeHg-exposed mice. Desipramine did not affect behavior in these animals nor did it interact with methylmercury. It is concluded that methylmercury-related inhibition of behavior observed in this study were differentially sensitive to acute disruption in dopamine, but not norepinephrine, neurotransmission.

Baseline-dependency: How genotype and signaled delays influence amphetamine's effects on delay discounting.

RATIONALE: Delay discounting, in which an animal chooses between a small, immediate or large, delayed reinforcer, is an experimental model of impulsivity. In previous studies, d-amphetamine has both increased and decreased preference for larger-delayed reinforcers depending on experimental conditions. OBJECTIVE: Identify genotype X environment interactions responsible for these disparate findings in a single study and assess the hypothesis that baseline-dependence unifies d-amphetamine's effects. METHODS: Delay discounting by BALB/c and C57Bl/6 mice was evaluated using a choice procedure in which six delays to a larger reinforcer were presented in a single session. Components were presented both with and without stimuli that uniquely signaled reinforcer delays. d-Amphetamine's (0.1-1.7 mg/kg) effects on delay and magnitude sensitivity were assessed when specific stimuli did or did not uniquely signal the delay to a larger reinforcer. d-Amphetamine's effects were determined using a model-comparison approach. RESULTS: During baseline, magnitude and delay sensitivity were identical across signal conditions for BALB/c mice and generally greater than the C57Bl/6 mice. For C57Bl/6 mice, magnitude and delay sensitivity were higher during the signaled than the unsignaled component. Amphetamine decreased delay sensitivity during both components for BALB/c mice, but this effect was attenuated by delay-specific stimuli. For C57Bl/6 mice, amphetamine decreased their high magnitude and delay sensitivity when delays were signaled and, conversely, increased the low magnitude and delay sensitivity when delays were unsignaled. CONCLUSIONS: BALB/c mice showed high delay and magnitude sensitivity regardless of signal conditions. C57Bl/6's magnitude and delay sensitivity depended on signaling. d-Amphetamine usually decreased high baseline delay- and magnitude sensitivity and increased low sensitivities, a baseline-dependence that occurred regardless of whether delay sensitivity was driven by biological (genotype) or environmental (signaling) variables. The C57Bl/6 mouse may be a good model of environmentally-induced impulsivity while BALB/c mice could model impulsivity with a strong genetic contribution.

The Relevance of Operant Behavior in Conceptualizing the Psychological Well-Being of Captive Animals.

The term "psychological well-being" is used in reference to husbandry with animals in human care settings such as research, agriculture, and zoos. This article seeks to clarify and conceptualize the term based upon two approaches that draw from several bodies of literature: the experimental analysis of behavior, experimental psychology, animal welfare and husbandry, farm animal behavior, zoo husbandry, and ethology. One approach focuses on the presence of problem behavior such as stereotypies, depressive-like behavior, and aggression, and emphasizes the conditions under which aberrant behavior in animals under human care occurs. The second approach examines what might be considered wellness by emphasizing opportunities to engage with its environment, or the absence of such opportunities, even if problematic behavior is not exhibited. Here, access to an interactive environment is relatively limited so opportunities for operant (voluntary) behavior could be considered. Designing for operant behavior provides opportunities for variability in both behavior and outcomes. Operant behavior also provides control over the environment, a characteristic that has been a core assumption of well-being. The importance of interactions with one's environment is especially evident in observations that animals prefer opportunities to work for items necessary for sustenance, such as food, over having them delivered freely. These considerations raise the importance of operant behavior to psychological well-being, especially as benefits to animals under human care.

Methylmercury, attention, and memory: baseline-dependent effects of adult d-amphetamine and marginal effects of adolescent methylmercury.

Methylmercury (MeHg) is an environmental neurotoxicant known to disrupt behavior related to dopamine neurotransmission in experimental models. Such disruptions are sensitive to dopamine agonists when administered acutely after exposure to MeHg has ended or when administered concurrently with MeHg exposure. Sustained attention and short-term remembering, components of attention-deficit/hyperactivity disorder (ADHD), are partially mediated by dopamine neurotransmission. In order to observe MeHg-related alterations in sustained attention and short-term memory, as well as determine sensitivity of MeHg exposed animals to dopamine agonists commonly used in the treatment of ADHD symptoms, rats were exposed to 0, 0.5, or 5 ppm MeHg throughout adolescence and trained in a hybrid sustained attention/short term memory visual signal detection task in adulthood. Behavior was then probed with acute i.p. injections of the dopamine agonist, d-amphetamine, which improves impaired attention and inhibits short-term memory in clinical syndromes like ADHD. Acute d-amphetamine dose-dependently decreased short-term memory as well as sustained attention. While MeHg alone did not impair accuracy or memory, it did interact with d-amphetamine to produce baseline-dependent inhibition of behavior. These findings further show that changes in behavior following low-level exposure to MeHg during adolescence are augmented by dopamine agonists. Observed impairments in memory following acute d-amphetamine are consistent with previous findings.

Adolescent methylmercury exposure alters short-term remembering, but not sustained attention, in male Long-Evans rats.

Methylmercury is an environmental neurotoxicant found in fish that produces behavioral deficits following early developmental exposure. The impact of adolescent exposure to this developmental neurotoxicant is only recently being explored in animal models. Here, short-term memory and sustained attention were examined using a rodent model of adolescent methylmercury exposure. Rats were exposed to 0, 0.5, or 5 ppm methylmercury throughout the adolescent period and tested on a two-choice visual signal detection task in adulthood. Methylmercury improved short-term remembering in this procedure but the dose-effect curve was nonmonotonic, as has been reported previously: effects on memory were observed in animals exposed to 0.5 ppm methylmercury, but not 5 ppm. Methylmercury did not significantly alter sustained attention, which is in contrast to effects following gestational exposure in human populations. The results may suggest that attention is not involved with previously reported effects of methylmercury during adolescence, but certain procedural issues remain unresolved.

Behavioral effects of chronic WIN 55,212-2 administration during adolescence and adulthood in mice.

Marijuana, a psychoactive drug that activates cannabinoid-1 (CB1) receptors in the brain, is the most prevalently abused illicit drug among American adolescents and young adults. However, the long-term consequences of adolescent exposure to cannabinoids on the brain and behavior remain poorly understood. In both humans and nonhumans, adolescence is characterized by the maturation of the endocannabinoid neurotransmitter system in the prefrontal cortex and striatum-brain regions that underlie choice and decision making and are densely packed with CB1 receptors. In the current study, the effects of chronic WIN 55,212-2 (a CB1 agonist) exposure during adolescence on reversal learning and delay discounting were compared with those of adult-onset exposure using mice. Mice were administered 3.0 mg/kg/day WIN 55,212-2 or vehicle for 21 days beginning in adolescence (postnatal days 28-49) or adulthood (postnatal days 90-111). For the reversal-learning task, there was no difference in errors or omissions to criterion following a reversal in adolescent-exposed mice but adult-exposed mice showed a delay in beginning the reversal, suggesting that adolescents, but not adults, are resilient to this drug. Adult mice given WIN 55,212-2 in adolescence displayed greater impulsivity in the form of preference for smaller-sooner reinforcers over larger-delayed ones in the delay-discounting procedure, but this was seen to a lesser extent with adult-onset exposure. These data underscore the importance of variables related to the timing and duration of exposure as well as the specific and persistent behavioral endpoints affected by chronic cannabinoid administration. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

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

Gestational exposure to methylmercury (MeHg), an environmental neurotoxicant, and adolescent administration of d-amphetamine (d-AMP) disrupt dopamine neurotransmission and alter voluntary behavior in adult rodents. We determined the impact of adolescent exposure to MeHg and d-AMP on monoamine neurotransmission in mice by assessing sensitivity to acute d-AMP, desipramine, and clomipramine, drugs that target dopamine, norepinephrine, and serotonin reuptake, respectively. Male C57Bl/6n mice were given 0 (control) or 3 ppm MeHg via drinking water from postnatal day 21 to 60 (murine adolescence). Within each group, mice were given once-daily injections of d-AMP or saline (i.p.) from postnatal day 28 to 42. This exposure regimen produced four treatment groups (n = 10-12/group): control, d-AMP, MeHg, and d-AMP + MeHg. As adults, the mice lever pressed under fixed-ratio schedules of reinforcement (FR 1, 5, 15, 30, 60, and 120). Acute i.p. injections of d-AMP (.3-1.7 mg/kg), desipramine (5.6-30 mg/kg), and clomipramine (5.6-30 mg/kg) were administered in adulthood after a stable behavioral baseline was established. Adolescent MeHg exposure increased saturation rate and minimum response time, an effect that was mitigated by chronic administration of d-AMP in adolescence. In unexposed mice, the three monoamine reuptake inhibitors had separable behavioral effects. Adolescent d-AMP increased sensitivity to acute d-AMP, desipramine, and clomipramine. Adolescent MeHg exposure alone did not alter drug sensitivity. Combined adolescent d-AMP + MeHg exposure enhanced sensitivity to acute d-AMP's and desipramine's effects on minimum response time. Adolescence is a vulnerable developmental period during which exposure to chemicals can have lasting effects on monoamine function and behavior.

An Information Theoretic Approach to Model Selection: A Tutorial with Monte Carlo Confirmation.

A reliance on null hypothesis significance testing (NHST) and misinterpretations of its results are thought to contribute to the replication crisis while impeding the development of a cumulative science. One solution is a data-analytic approach called Information-Theoretic (I-T) Model Selection, which builds upon Maximum Likelihood estimates. In the I-T approach, the scientist examines a set of candidate models and determines for each one the probability that it is the closer to the truth than all others in the set. Although the theoretical development is subtle, the implementation of I-T analysis is straightforward. Models are sorted according to the probability that they are the best in light of the data collected. It encourages the examination of multiple models, something investigators desire and that NHST discourages. This article is structured to address two objectives. The first is to illustrate the application of I-T data analysis to data from a virtual experiment. A noisy delay-discounting data set is generated and seven quantitative models are examined. In the illustration, it is demonstrated that it is not necessary to know the "truth" is to identify the one that is closest to it and that the most likely models conform to the model that generated the data. Second, we examine claims made by advocates of the I-T approach using Monte Carlo simulations in which 10,000 different data sets are generated and analyzed. The simulations showed that 1) the probabilities associated with each model returned by the single virtual experiment approximated those that resulted from the simulations, 2) models that were deemed close to the truth produced the most precise parameter estimates, and 3) adding a single replicate sharpens the ability to identify the most probable model.

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

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.

Heavy Metal Neurotoxicants Induce ALS-Linked TDP-43 Pathology.

Heavy metals, such as lead, mercury, and selenium, have been epidemiologically linked with a risk of ALS, but a molecular mechanism proving the connection has not been shown. A screen of putative developmental neurotoxins demonstrated that heavy metals (lead, mercury, and tin) trigger accumulation of TDP-43 into nuclear granules with concomitant loss of diffuse nuclear TDP-43. Lead (Pb) and methyl mercury (MeHg) disrupt the homeostasis of TDP-43 in neurons, resulting in increased levels of transcript and increased splicing activity of TDP-43. TDP-43 homeostasis is tightly regulated, and positively or negatively altering its splicing-suppressive activity has been shown to be deleterious to neurons. These changes are associated with the liquid-liquid phase separation of TDP-43 into nuclear bodies. We show that lead directly facilitates phase separation of TDP-43 in a dose-dependent manner in vitro, possibly explaining the means by which lead treatment results in neuronal nuclear granules. Metal toxicants also triggered the accumulation of insoluble TDP-43 in cultured cells and in the cortices of exposed mice. These results provide novel evidence of a direct mechanistic link between heavy metals, which are a commonly cited environmental risk of ALS, and molecular changes in TDP-43, the primary pathological protein accumulating in ALS.

Variable behavior and repeated learning in two mouse strains: Developmental and genetic contributions.

Behavioral inflexibility is often assessed using reversal learning tasks, which require a relatively low degree of response variability. No studies have assessed sensitivity to reinforcement contingencies that specifically select highly variable response patterns in mice, let alone in models of neurodevelopmental disorders involving limited response variation. Operant variability and incremental repeated acquisition (IRA) were used to assess unique aspects of behavioral variability of two mouse strains: BALB/c, a model of some deficits in ASD, and C57Bl/6. On the operant variability task, BALB/c mice responded more repetitively during adolescence than C57Bl/6 mice when reinforcement did not require variability but responded more variably when reinforcement required variability. During IRA testing in adulthood, both strains acquired an unchanging, performance sequence equally well. Strain differences emerged, however, after novel learning sequences began alternating with the performance sequence: BALB/c mice substantially outperformed C57Bl/6 mice. Using litter-mate controls, it was found that adolescent experience with variability did not affect either learning or performance on the IRA task in adulthood. These findings constrain the use of BALB/c mice as a model of ASD, but once again reveal this strain is highly sensitive to reinforcement contingencies and they are fast and robust learners.

Effects of adolescent exposure to methylmercury and d-amphetamine on reversal learning and an extradimensional shift in male mice.

Adolescence is associated with the continued maturation of dopamine neurotransmission and is implicated in the etiology of many psychiatric illnesses. Adolescent exposure to neurotoxicants that distort dopamine neurotransmission, such as methylmercury (MeHg), may modify the effects of chronic d-amphetamine (d-AMP) administration on reversal learning and attentional-set shifting. Male C57Bl/6n mice were randomly assigned to two MeHg-exposure groups (0 ppm and 3 ppm) and two d-AMP-exposure groups (saline and 1 mg/kg/day), producing four treatment groups (n = 10-12/group): control, MeHg, d-AMP, and MeHg + d-AMP. MeHg exposure (via drinking water) spanned postnatal days 21-59 (the murine adolescent period), and once daily intraperitoneal injections of d-AMP or saline spanned postnatal days 28-42. As adults, mice were trained on a spatial-discrimination-reversal (SDR) task in which the spatial location of a lever press predicted reinforcement. Following 2 SDRs, a visual-discrimination task (extradimensional shift) was instated in which the presence of a stimulus light above a lever predicted reinforcement. Responding was modeled using a logistic function, which estimated the rate (slope) of a behavioral transition and trials required to complete half a transition (half-max). MeHg, d-AMP, and MeHg + d-AMP exposure increased estimates of half-max on the second reversal. MeHg exposure increased half-max and decreased the slope term following the extradimensional shift, but these effects did not occur following MeHg + d-AMP exposure. MeHg + d-AMP exposure produced more perseverative errors and omissions following a reversal. Adolescent exposure to MeHg can modify the behavioral effects of chronic d-AMP administration. (PsycINFO Database Record

Are positive and negative reinforcement "different"? Insights from a free-operant differential outcomes effect.

Although theoretical discussions typically assume that positive and negative reinforcement differ, the literature contains little unambiguous evidence that they produce differential behavioral effects. To test whether the two types of consequences control behavior differently, we pitted money-gain positive reinforcement and money-loss-avoidance negative reinforcement, scheduled through identically programmed variable-cycle schedules, against each other in concurrent schedules. Contingencies of response-produced feedback, normally different in positive and negative reinforcement, were made symmetrical. Steeper matching slopes were produced compared to a baseline consisting of all positive reinforcement. This free-operant differential outcomes effect supports the notion that that stimulus-presentation positive reinforcement and stimulus-elimination negative reinforcement are functionally "different." However, a control experiment showed that the feedback asymmetry of more traditional positive and negative reinforcement schedules also is sufficient to create a "difference" when the type of consequence is held constant. We offer these findings as a small step in meeting the very large challenge of moving negative reinforcement theory beyond decades of relative quiescence.

Adolescent methylmercury exposure affects choice and delay discounting in mice.

The developing fetus is vulnerable to low-level exposure to methylmercury (MeHg), an environmental neurotoxicant, but the consequences of exposure during the adolescent period remain virtually unknown. The current experiments were designed to assess the effects of low-level MeHg exposure during adolescence on delay discounting, preference for small, immediate reinforcers over large, delayed ones, using a mouse model. Thirty-six male C57BL/6n mice were exposed to 0, 0.3, or 3.0ppm mercury (as MeHg) via drinking water from postnatal day 21 through 59, encompassing the murine adolescent period. As adults, mice lever pressed for a 0.01-cc droplet of milk solution delivered immediately or four 0.01-cc droplets delivered after a delay. Delays ranged from 1.26 to 70.79s, and all were presented within a session. A model based on the Generalized Matching Law indicated that sensitivity to reinforcer magnitude was lower for MeHg-exposed mice relative to controls, indicating that responding in MeHg-exposed mice was relatively indifferent to the larger reinforcer. Sensitivity to reinforcer delay was reduced (delay discounting was decreased) in the 0.3-ppm group, but not in the 3.0-ppm group, compared to controls. Adolescence is a developmental period during which the brain and behavior may be vulnerable to MeHg exposure. As with gestational MeHg exposure, the effects are reflected in the impact of reinforcing stimuli.

Aging, motor function, and sensitivity to calcium channel blockers: An investigation using chronic methylmercury exposure.

Methylmercury (MeHg) neurotoxicity is thought to be mediated, in part, by dysregulation of calcium (Ca(2+)) homeostasis, a mechanism that may also slowly and progressively degrade neuronal function during normal aging. Longitudinal studies of MeHg exposure provide a powerful approach to studying neural and behavioral mechanisms by which both MeHg toxicity and aging affect motor function. Wheel-running and rotarod performance were assessed in two age groups of BALB/c mice chronically exposed to 0 or 1.2mg/kg/day MeHg and 0 or 20mg/kg/day nimodipine, a 1,4-dihyrdopyridine L-type calcium channel blocker (CCB), for approximately 8.5 months. Adults began exposure on postnatal day (PND) 72 and retired breeders on PND 296. A log-survivor bout analysis partitioned wheel-running into bouts that identified motor (within-bout rates) and motivational (bout-initiation rates) influences. Retired breeders ran farther, because of a higher bout-initiation rates, but performed more poorly on the rotarod than younger adults, a difference unaffected by nimodipine. MeHg produced relatively age-independent deficits in wheel-running and rotarod performance, whereas nimodipine afforded greater protection to adult mice than to retired breeders. Rotarod performance and within-bout response rate were more sensitive to and more reliable predictors of MeHg toxicity than bout-initiation rate, which was least affected by MeHg exposure. Thus the motivation to run was unimpaired as the ability to do so declined. While chronic MeHg exposure produced functionally similar behavior deficits between age groups, the age-dependent neuroprotection by nimodipine supports the notion that underlying neurobiological systems mediated by Ca(2+) signaling, are differentially affected in older adults.

A bout analysis reveals age-related methylmercury neurotoxicity and nimodipine neuroprotection.

Age-related deficits in motor and cognitive functioning may be driven by perturbations in calcium (Ca(2+)) homeostasis in nerve terminals, mechanisms that are also thought to mediate the neurotoxicity of methylmercury (MeHg). Calcium-channel blockers (CCBs) protect against MeHg toxicity in adult mice, but little is known about their efficacy in other age groups. Two age groups of BALB/c mice were exposed to 0 or 1.2mg/kg/day MeHg and 0 or 20mg/kg/day of the CCB nimodipine for approximately 8.5 months. Adults began exposure on postnatal day (PND) 72 and the retired breeders on PND 296. High-rate operant behavior was maintained under a percentile schedule, which helped to decouple response rate from reinforcer rate. Responding was analyzed using a log-survivor bout analysis approach that partitioned behavior into high-rate bouts separated by pauses. MeHg-induced mortality did not depend on age but nimodipine neuroprotection was age-dependent, with poorer protection occurring in older mice. Within-bout response rate (a marker of sensorimotor function) was more sensitive to MeHg toxicity than bout-initiation rate (a marker of motivation). Within-bout rate declined almost 2 months prior to overt signs of toxicity for the MeHg-only retired breeders but not adults, suggesting greater delay to toxicity in younger animals. Motor-based decrements also appeared in relatively healthy adult MeHg+NIM animals. Aging appeared to alter the processes underlying Ca(2+) homeostasis thereby diminishing protection by nimodipine, even in mice that have not reached senescence. The study of MeHg exposure presents an experimental model by which to study potential mechanisms of aging.