Learning and behavior problems among US children appear to be rising steadily, however the etiology for these behavioral changes is unknown. Exposure to low-levels of various neurotoxins has been suggested as a potential factor in these changes. For example, low levels of lead are known to be associated with learning deficits and social behavior problems. One issue with animal models for the effects of various neurotoxins is that they are limited to investigating only one factor even though human exposures occur together with many other environmental factors. For example, it is known that there is a differential exposure to heavy metals in low social economic status households. Therefore, we will investigate the effects of lead and manganese (since manganese is known to potentiate the increase in the amount of lead that accumulates in the brain) in combination with stressors (isolation, overcrowding, or limited resources with maternal depression) to mimic human conditions.
The first aim i s to determine which stressor has the greatest impact on heavy metal exposure by measuring physiological parameters during the period of administration as well as investigating the long-term effects of this combination on neurotransmitters and long-term potenitation induction.
The second aim i s to investigate the dose-dependency of lead or manganese in combination with stress on the learning ability and social aspects of the animals. We will be using a novel approach to investigating learning and memory in these animals by using a combination of learning tests that test different types of learning. This is relevant to how humans would have to learn as well.
This aim will provide a foundation to model low level exposure and to understand the functional changes that occur.
The third aim i s to combine lead, manganese and stress and assess the impact of this more relevant combination to human exposures on learning and memory and social behavior. The last aim is designed to investigate the developmental changes that occur related to the three combination exposure by using MRI as well as looking at the nuerophysiological response when the animals are adults. These studies will provide much needed data on the low-level effects of neurotoxins in combination with environmentally relevant stressors. Potential mechanisms will be explored by investigating neurotransmitter and neuroendocrine systems and the glutamate receptor complex.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015689-04
Application #
7632166
Study Section
Special Emphasis Panel (ZES1-LKB-A (C1))
Program Officer
Kirshner, Annette G
Project Start
2006-09-18
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2009
Total Cost
$356,843
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Sprowles, Jenna L N; Amos-Kroohs, Robyn M; Braun, Amanda A et al. (2018) Developmental manganese, lead, and barren cage exposure have adverse long-term neurocognitive, behavioral and monoamine effects in Sprague-Dawley rats. Neurotoxicol Teratol 67:50-64
Amos-Kroohs, Robyn M; Davenport, Laurie L; Atanasova, Nina et al. (2017) Developmental manganese neurotoxicity in rats: Cognitive deficits in allocentric and egocentric learning and memory. Neurotoxicol Teratol 59:16-26
Amos-Kroohs, Robyn M; Graham, Devon L; Grace, Curtis E et al. (2016) Developmental stress and lead (Pb): Effects of maternal separation and/or Pb on corticosterone, monoamines, and blood Pb in rats. Neurotoxicology 54:22-33
Braun, Amanda A; Amos-Kroohs, Robyn M; Gutierrez, Arnold et al. (2016) 6-Hydroxydopamine-Induced Dopamine Reductions in the Nucleus Accumbens, but not the Medial Prefrontal Cortex, Impair Cincinnati Water Maze Egocentric and Morris Water Maze Allocentric Navigation in Male Sprague-Dawley Rats. Neurotox Res 30:199-212
Amos-Kroohs, Robyn M; Davenport, Laurie L; Gutierrez, Arnold et al. (2016) Developmental manganese exposure in combination with developmental stress and iron deficiency: Effects on behavior and monoamines. Neurotoxicol Teratol 56:55-67
Braun, Amanda A; Amos-Kroohs, Robyn M; Gutierrez, Arnold et al. (2015) Dopamine depletion in either the dorsomedial or dorsolateral striatum impairs egocentric Cincinnati water maze performance while sparing allocentric Morris water maze learning. Neurobiol Learn Mem 118:55-63
Vorhees, Charles V; Graham, Devon L; Braun, Amanda A et al. (2015) Prenatal immune challenge in rats: effects of polyinosinic-polycytidylic acid on spatial learning, prepulse inhibition, conditioned fear, and responses to MK-801 and amphetamine. Neurotoxicol Teratol 47:54-65
Amos-Kroohs, Robyn M; Bloor, Colin P; Qureshi, Momina A et al. (2015) Effects of developmental exposure to manganese and/or low iron diet: Changes to metal transporters, sucrose preference, elevated zero-maze, open-field, and locomotion in response to fenfluramine, amphetamine, and MK-801. Toxicol Rep 2:1046-1056
Vorhees, Charles V; Williams, Michael T (2014) Assessing spatial learning and memory in rodents. ILAR J 55:310-32
Vorhees, Charles V; Graham, Devon L; Amos-Kroohs, Robyn M et al. (2014) Effects of developmental manganese, stress, and the combination of both on monoamines, growth, and corticosterone. Toxicol Rep 1:1046-1061

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