The etiology of age-related neurodegeneration is largely unknown to date, but multiple findings suggest that specific events (such as mutations and/or injury) during early development may give rise to life-long, masked deficiencies in especially vulnerable neuronal populations, such as the dopaminergic system of the midbrain substantia nigra. This deficiency may not be symptomatic during childhood and early adulthood, since the monoamine systems are extremely adaptive to change. However, when protection mechanisms fail during the natural aging process, the added sensitivity of a sub-optimal system may then give rise to deficient functioning, leading to oxidative stress, phenotypic loss, and, finally, cell death. Dopaminergic neurons are dependent upon neurotrophic factors for their development and continued neuroplasticity throughout life. In particular, glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF), have both been shown to have powerful effects on these neurons, both in the developing nervous system and in the adult individual. Both GDNF and BDNF are unregulated in the striarum following a selective dopamine lesion, and this growth factor response is diminished during aging, suggesting that a loss of growth factor stimulation may be one of the factors leading to age-related neurodegenerative processes. We propose to utilize animals heterozygous to a GDNF (GDNF+/-) and BDNF (BDNF+/-) null mutation to study age-related alterations in motor behavior, dopamine morphology, and dopamine neurotransmission (Aim 1). In addition, we propose to utilize prenatal exposure to the endo toxin lipopolysaccharide (LPS) as a model for prenatal reduction in dopamine neurons, to determine if this reduction also gives rise to altered DA function later in life (Aim #2), and, finally, we propose to combine this prenatal exposure to endotoxins with a partial loss of the two growth factors in GDNF+/- or BDNF+/- mice (Aim #3). These studies are aimed to determine if these two triggers of DA dysfunction have synergistic or additive effects on overall dopamine function during aging. The overall goal of Project 0001 is to determine if a combination of fewer dopamine neurons (LPS treatment) and a life-long reduction in growth factors (BDNF+/- or GDNF+/-) is especially deleterious to dopamine neurons during aging. Project 0001 will provide brain tissues to Project 0003 and 0004, for studies of neuroinflammation and neurotransmission, respectively, and to Project 0005 for detection of subpopulations of nigral DA neurons. All animals will be generated by the Animal Core.
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