UC Santa Cruz

Studies in children have reported associations between elevated manganese (Mn) exposure and ADHD-related symptoms of inattention, impulsivity/hyperactivity, and psychomotor impairment. Rodent model studies have recapitulated these ADHD-like impairments and found that these deficits are associated with hypofunctioning of the catecholaminergic system in the prefrontal cortex and striatum - brain regions that in part mediate attention, impulse control, emotion regulation, and sensorimotor function – but the mechanism by which Mn causes these lasting alterations is not well understood. While therapies such as methylphenidate (Ritalin) have proven to be effective in lessening symptoms for some children diagnosed with ADHD, there are no established treatments available for children exhibiting ADHD-like symptoms that may be linked to elevated Mn exposure during development. Ideally, rather than rely on medications to treat the ADHD-like symptoms associated with elevated Mn exposure, it would be preferred to have intervention options that might protect against the neurotoxic effects of Mn. One potential nutritional intervention to protect against Mn-induced deficits is maternal choline supplementation (MCS), which has been shown to provide cognitive benefits to typically developing children and animal models and lessen cognitive and molecular dysfunction caused by various environmental and genetic insults. Given this, my dissertation focuses on further elucidating the lasting effects of Mn on cognition and neuronal function, and investigates whether MCS is an effective intervention to protect against Mn-induced deficits. In Chapter 1, I present a review of Mn, including a broad overview of its properties and human usage, its role in physiological systems, as well as toxicity of elevated exposure. This chapter also provides an overview of choline, including sources, biological function, and the cognitive and neurological benefits of choline supplementation. This information will provide context for the gap in knowledge addressed in this research; namely, whether MCS is effective in protecting against Mn-induced cognitive and molecular alterations. In Chapter 2, I demonstrate that developmental Mn exposure produces a constellation of deficits consistent with ADHD symptomology in a rat model of childhood environmental Mn exposure, including dysfunction in attention, reactivity to errors and reward omission, and deficits in learning and sensorimotor function. I also show that MCS offered some protection against the adverse Mn effects, including lessening Mn-induced attentional dysfunction and partially normalizing behavioral reactivity, but provided no protection against Mn-induced learning or sensorimotor dysfunction. In Chapter 3, I show that developmental Mn exposure causes lasting molecular alterations in the prefrontal cortex. Using tissues from behaviorally tested animals from Chapter 2, we found that Mn-induced changes include alterations in expression of a variety of genes, such as those related to neuronal function and inflammation, as well as changes in DNA methylation, all of which may underlie the ADHD-like behavioral phenotype described in Chapter 2. I also demonstrate that MCS is effective in protecting against some, but not all, of these Mn-induced alterations in gene expression and DNA methylation. Finally, in Chapter 4, I summarize the findings from both data chapters, and discuss how these findings contribute to the fields of both Mn and MCS research. Altogether, the findings presented here provide further compelling evidence that developmental Mn exposure causes ADHD-like symptoms in a rat model of childhood Mn exposure, supporting the epidemiological evidence that elevated Mn exposure is a risk factor for ADHD. These findings also add to the wealth of literature demonstrating that MCS is neuroprotective for offspring and improves offspring cognitive functioning. These data provide additional support for efforts to increase choline intake during pregnancy and lactation, particularly for women at risk of environmental exposure to Mn.