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The Effects of Lead (Pb+2) on Learning and Memory Processes and Gene Expression
EPA Grant Number: U916009Title: The Effects of Lead (Pb+2) on Learning and Memory Processes and Gene Expression
Investigators: Vazquez, Adrinel
Institution: University of Puerto Rico, Central Administration
EPA Project Officer: Graham, Karen
Project Period: January 1, 2001 through January 1, 2003
Project Amount: $77,339
RFA: GRO (formerly MAI ) Graduate Fellowships (2001)
Research Category: Academic Fellowships , Fellowship - Environmental Science , Ecological Indicators/Assessment/Restoration
Description:
Objective:The objective of this research project is to study the effects of lead (Pb+2) on spatial learning and memory using a hippocampal-dependent discrimination task. The neurobehavioral toxicity of Pb+2 has been associated to its interference with normal calcium (Ca+2) signaling in neurons. The long-term storage of information in the brain, known as long-term memory (LTM), depends on a variety of intracellular-signaling cascades utilizing Ca+2 and cyclic adenosine monophosphate as second messengers. In particular, Ca+2/phospholipid-dependent protein kinase C (PKC) activity has been proposed to be necessary for the transition from short-term memory to LTM.
Approach:Adult rats received microinfusions of either Na+ or Pb+2 acetate in the CA1 hippocampal subregion prior to each one of four training sessions. A retention test was given 7 days later to examine LTM. Results suggest that intrahippocampal Pb+2 did not affect learning of the task, but significantly impaired retention. The effect is dependent on dose. The effects of Pb+2 selectively impaired reference memory measured in the retention test, but had no effect on general performance because it did not affect the latency to complete the task during the test. No evidence of gliosis was observed, suggesting that our Pb+2 acetate infusions did not cause major pathologic abnormalities in the hippocampus. In addition, we examined the effects of Pb+2 on the induction of hippocampal Ca+2/phospholipid-dependent PKC activity during acquisition training. The results showed that Pb+2 interfered with the learning-induced activation of Ca+2/phospholipid-dependent PKC on day 3 of acquisition of the task. The effect was not observed on a pretrained group. Overall, our results indicate that Pb+2 causes cognitive impairments in adult rats, and that such effects might be subserved by interference with Ca+2- related signaling mechanisms required for normal LTM. Because LTM requires changes in gene expression and new protein synthesis, we propose that the Pb+2 treatment also blocks learning-related gene expression in the brain. Preliminary data using the microarray technology showed that Pb+2 interferes with the mRNA expression of membrane receptors, intracellular signaling and cell adhesion molecules, transcription factors, and Ca+2- dependent molecules.
Supplemental Keywords:fellowship, lead, Pb, calcium, Ca, learning, spatial learning, learning processes, memory processes, long-term memory, LTM, protein kinase C, PKC, hippocampus, hippocampal-dependent, gene expression, neurons, protein synthesis, signaling, intracellular signaling, cognitive impairments. , Scientific Discipline, Health, PHYSICAL ASPECTS, Risk Assessments, Health Risk Assessment, Physical Processes, Environmental Chemistry, developmental neurotoxicology, effects on long term memory, lead, cognitive impairments, human health risk, genetic analysis, exposure