Mechanisms and therapies for the neurobehavioral deficits from early Mn exposure

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Project Summary Studies in children/adolescents have linked developmental environmental manganese (Mn) exposure to inattention, impulsivity, hyperactivity, oppositional behaviors, and fine motor deficits, though these studies are limited by their cross-sectional designs and limited control of confounding that make it impossible to demonstrate that Mn causes these deficits. Our recent studies have shown that developmental Mn exposure causes lasting deficits in attention, impulse control, and fine motor function, providing the first causal evidence supporting the human studies. Our initial studies of the potential benefits of chronic oral methylphenidate (Ritalin) treatment revealed that the one dose studied alleviated the Mn-induced impulse control and fine motor dysfunctions, but impaired attentional performance in the Mn animals. We propose to build upon these findings to elucidate the neural mechanisms underlying the lasting attentional, impulse control, and fine motor dysfunction caused by developmental Mn exposure, and test potential therapeutic interventions (methylphenidate, guanfacine), in our established rodent model of childhood Mn exposure. Our testable hypotheses are 1) Oral MPH and/or guanfacine treatment will alleviate the lasting fine motor, attention and impulse control deficits caused by developmental Mn exposure; and 2) These lasting deficits caused by Mn exposure are due to changes levels of catecholaminergic system proteins in the pre-frontal cortex - striatal pathway. We will test these hypotheses via the following aims: Aim 1 will (i) Identify a clinically-relevant therapeutic regimen of MPH for the Mn deficits in attention, impulse control, and fine motor function by determining the dose-response relationship with MPH in male and female control vs Mn animals, and (ii) Determine involvement of DA D1, D2, and α2A adrenoreceptors in the Mn deficits and in the therapeutic efficacy of MPH, using administration of selective receptor antagonists during behavioral testing. Aim 2 will use PET neuroimaging and quantitative immunohistochemistry to further elucidate changes in catecholaminergic system proteins implicated in the attention/impulse control/fine motor Mn deficits, and the association of these measures with the attention/impulse control/fine motor outcomes. Aim 3 will test the hypotheses that guanfacine alleviates the attention/impulse control deficits produced by Mn. These studies will be the first to identify potentially efficacious therapies for the treatment/prevention of attentional and co-morbid fine motor deficits due to developmental Mn exposure, and to elucidate their neural mechanisms.