Dual-hit hypothesis of aging-related DA dysfunction

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DESCRIPTION (provided by applicant): It is well known that the aged brain undergoes a series of subtle but progressive alterations that eventually lead to altered neuronal function and, ultimately, altered behavior of the individual. Together with the well-described age related decline in cognitive performance, it has also been found that motor function undergoes a steady and progressive decline in most aged humans. The midbrain dopaminergic neurons, which are important for regulation of motor activity, appear to be especially vulnerable to age-related factors, leading to a specific increase in neurodegenerative disorders afflicting these neurons, such as Parkinson's disease (PD) with age. This program project grant is focused on understanding why midbrain dopamine neurons are selectively vulnerable to environmental and endogenous agents, leading to lost function and structure during aging. We will work along an overall "dual-hit" hypothesis, proposing that it is a combined endogenous inability to cope with oxidative stress and external factors making it worse that leads to a selective degeneration of these neurons in some individuals but not others during aging. Every project is devoted to the understanding of age-related deterioration in the function and morphology of the midbrain dopaminergic system, with a focus on motor impairment following specific intrinsic and extrinsic damaging events. To this end, all primary projects in the program (Project 0001-0005) will provide a distinct level of analysis of three specific determinants of motor impairment, namely: growth factor reduction (intrinsic, genetic alteration), endotoxin exposure (prenatal extrinsic factor, LPS), and methamphetamine exposure (extrinsic factor to young adult mice). The Animal Core will provide all subjects to guarantee consistency between each project, and thereby facilitate the capacity to unite discoveries emerging from different research approaches into a coherent understanding of the neurobiological basis of factors that might affect the impact of aging in this transmitter system. The subjects will be examined at many levels of analysis, including cellular (Projects 0001 - 0004), tissue culture (Project 0005) and behavioral (Project 0001 and 2). Project 0003 will integrate the different treatments (GDNF/BDNF partial deletion, LPS treatment, and methamphetamine) from the perspective of neuroinflammation, and Project 0004 will examine the same three factors from the perspective of in-depth analysis of neurotransmission itself. Finally, Project 0005 will examine intrinsic versus extrinsic determinants of the alterations observed by isolating the brain regions (substantia nigra and striatum) in slice cultures or transplants. This thematic integration around an animal model (GDNF/BDNF knockouts) with external factors will focus multiple dimensions of research activity on a single problem (age-related decreased motor function) with the goal of providing a relatively complete description of the neurological basis of age-related dopamine neuron cell dysfunction leading to motor impairment.