2002 — 2006 |
Williams, Michael T |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Developmental Interactions of Methamphetamine and Stress @ Children's Hospital Med Ctr (Cincinnati)
DESCRIPTION: (Provided by Applicant) My immediate goals are to establish myself as an independent researcher, to gain an understanding for the interaction of methamphetamine (MA) and the hypothalamic-pituitary-adrenal (HPA) axis during development, and to increase my experience in methods related to learning and memory. For my long-term goals, I see myself in an academic position that allows for interaction among a variety of fields and interests with the possibility of collaborative work. I would like to be in a position to be promoted to a tenure track position and to gain tenure. My research pursuits will continue to be in the areas of drugs of abuse, development, learning and memory, neurotrophic factors, gene expression, and hormones. I feel that concurrent investigation of these areas will provide possible mechanisms for the development of cognitive deficits following drug exposure. Since very little research has incorporated all of these areas in a focused manner, this research will enable me to have a strong influence in developmental problems associated with early drug exposure, especially MA. MA use has reached epidemic proportions in a very short period of time. Very few data exist for the effects of MA during development in humans, therefore of particular concern is that women of childbearing age are among the growing number of users/abusers. Research in Dr. Charles V. Vorhees' laboratory, the mentor for the proposed application, has demonstrated that rats exposed to MA during a period of hippocampal development that correlates with third trimester human development, show cognitive impairments as adults, without apparent alterations to neurotransmitters or neurotoxicity during drug administration. Recently we have demonstrated that MA administration on P11-20 causes elevated corticosterone (CORT) and ACTH levels. The proposed studies will investigate the interaction of MA and the hormones of the HPA axis to determine if the elevation in these hormones mediates the cognitive deficits. Several converging lines of research will be used to determine these effects. Investigations will include assessing the dose-dependent response of the HPA axis to MA, the critical period of hormone release, the effect early MA exposure has on the development of the HPA axis and release of these hormones following exposure to an environmental challenge (either forced swim in a novel environment, or a novel environment alone). Further, experiments investigating the effect of CORT on cell proliferation, development, and receptors has been proposed. Investigation of gene expression changes will be undertaken. The use of different strains of rats prone to hyper- or hyposecretion of HPA axis hormones will be used, as will animals that are exposed to MA without the concurrent increase in CORT.
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0.939 |
2006 — 2010 |
Williams, Michael T |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Effect of Lead, Manganese and Stress During Development @ Cincinnati Childrens Hosp Med Ctr
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 is 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 is 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 is 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.
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0.939 |
2021 |
Vorhees, Charles V [⬀] Williams, Michael T |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gene-Pesticide Interactions and Adhd @ Cincinnati Childrens Hosp Med Ctr
Attention Deficit Hyperactivity Disorder (ADHD) is the most prevalent neurodevelopmental psychiatric disorder (9.4% prevalence in children; 4.4% in adults) and is polygenic. A novel gene associated with ADHD is Latrophilin-3 found in striatum, hippocampus, cerebellum, prefrontal cortex (PFC), and amygdala. In humans, there are 21 variants of LPHN3 associated with ADHD. Some pesticides may interact with ADHD genetic risk factors to trigger or exacerbate the symptoms. We found that the common pyrethroid, deltamethrin (DLM), administered prior to weaning in rats causes long-term behavioral, neurochemical, and electrophysiological effects. We developed the first KO rats of Lphn3. Lphn3 KO rats are hyperactive, hyper-reactive to startle stimuli, and cognitively impaired. This PAR-19-386 ?Environmental Risks for Psychiatric Disorders: Biological Basis of Pathophysiology? seeks models that will elucidate Gene x Environment interactions related to neuropsychiatric disorders, such as ADHD. We hypothesize that Lphn3-/- and Lphn3+/- rats will interact with DLM (Type II pyrethroid) or permethrin (PRM, Type I pyrethroid) to exacerbate an ADHD-like phenotype. Specific Aim 1: Determine the effects of DLM in Lphn3-/-, Lphn3+/-, and wildtype (WT) rats on activity, reactivity, learning and memory (L&M), dopamine (DA) and NMDA markers, and apoptosis. Aim-1a: Compare WT rats with Lphn3-/- and Lphn3+/- rats administered 0, 0.5, or 2.0 mg/kg DLM from P3-20 for changes in activity, acoustic and tactile startle (including prepulse inhibition (PPI)) egocentric, allocentric, and working L&M, and for changes in DA and NMDA-R markers in various brain regions, including markers for programmed cell death. Aim-1b, neurochemical outcomes in rats not behaviorally tested. Specific Aim 2: Determine the effects of PRM in Lphn3-/-, Lphn3+/- rats vs. WT rats on the outcomes used in Aim-1. Aim-2a: Same as Aim-1a with PRM. Aim-2b: Same as Aim-1b with PRM. Specific Aim 3: Determine the effects of DLM in adult Lphn3- /-, Lphn3+/- rats vs. WT rats. Aim-3a: same outcomes as in Aim-1a. Adults with ADHD are an understudied and a population susceptible for higher exposure to pyrethroids from occupational exposure, making Aims 3 and 4 important. Aim-3b: Same as Aim-1b in adult rats. Specific Aim 4: Determine the effects of PRM in adult Lphn3-/-, Lphn3+/- rats vs. WT rats. Aim-4a: Same outcomes used in Aim-1a. Aim-4b: Same as Aim-1b in adult rats not behaviorally tested. Impact: ADHD interferes with normal development, costs billions to treat and manage, yet we know little about environmental contributions to those with ADHD. Insecticides are suspected in ADHD but such interactions between gene and environment are not established. Lphn3-/- and Lphn3+/- rats represent a novel approach to probing the effects of exposure to pyrethroids using a known ADHD genetic susceptibility. The model will shed new light on how a gene known to be associated with ADHD affects the behavioral and biochemical effects of prototypical pyrethroids. Interaction data can be used for risk assessment and help provide safeguards against pyrethroid exposure for those with ADHD.
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0.939 |