Analysis of search strategies for evaluating low-dose heavy metal mixture induced cognitive deficits in rats: An early sensitive toxicological approach

Abstract Heavy metals such as lead (Pb), cadmium (Cd), and mercury (Hg) are representative neurotoxicological contaminants that can evoke cognitive dysfunctions. Low levels of these contaminants can be detected simultaneously in the human blood. In our previous study, behavioral performances were markedly impaired by exposure to these heavy metal mixtures (MM) at low levels. However, the aspects of cognitive functions involved are not well understood. Here, we further analyzed search strategies using a new algorithm named Morris water maze-unbiased strategy classification (MUST-C). Rat pups were co-exposed to low doses of Pb, Cd, and Hg during the embryonic and lactation stage. MM exposure at low doses, similar to those found in the general population, impaired search strategies even though their latency and path length were not affected in the Morris water maze task. MM-exposed rats preferred to use more directionless repetition strategies and less target orientation strategies than did vehicle-exposed animals in a dose-dependent manner. In addition, thionine staining and electron microscopy further revealed that MM exposure induced dose-dependent search strategy related place cell injures in the hippocampal CA1 and CA3 regions. These results demonstrate that the use of suboptimal search strategies underlies the early cognitive deficits in rats exposed to low doses of MM. The current study determined that search strategy analysis might be a novel sensitive assessment method for evaluating in the neurobehavioral toxicity.