In order to fully understand the pathophysiological basis of brain disorders it is necessary to develop animal models that can recapitulate neurochemical and pathological alterations found in human diseases. Molecular genetic approaches have made possible for scientists to understand many aspects of brain disorders by controlling gene expression in mice. However, developing countries have scarce resources and technical expertise to routinely generate genetically modified mice to investigate brain dysfunction. As a consequence, we lack key resources to validate novel therapeutic strategies, and to define molecular aspects of neurodegenerative and psychiatric diseases. In this proposal, by extending a collaboration with the Duke University Medical Center, we plan to create the means to generate distinct genetically modified mice in Brazil, to probe the role of the cholinergic system in brain function and behavior. Neurons secreting acetylcholine in the brain participate in several mechanisms of plasticity and can control distinct behaviors. Moreover, central cholinergic dysfunction is a hallmark of certain brain diseases, such as Alzheimer's disease, in which cholinergic hypofunction may be related to cognitive and neuropsychiatric behaviors. Our long term goal is to understand how acetylcholine controls behavior in mice and how that can be used to understand cholinergic related behavioral and cognitive dysfunction in humans with brain disorders. To achieve this goal, mouse lines will be created to mimic cholinergic dysfunction using the Cre/loxP to target the key component necessary for acetylcholine secretion, the vesicular acetylcholine transporter. A second long term goal is to define strategies that can lead to increased cholinergic function, by generating a new transgenic line to validate presynaptic mechanisms that increase acetylcholine synthesis and secretion. These mouse lines will be fully characterized at the neurochemical and behavioral levels to provide a complete understanding of cholinergic control of brain functions related to Alzheimer's disease, aging and drugs of abuse. It is expected that this proposal will evolve to a full collaborative effort to develop novel animal model systems and investigate pathophysiological changes that will help in the understanding and treatment of several brain disorders, including Alzheimer's disease. ? ? ?
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