DESCRIPTION (provided by applicant): Dysfunction of the noradrenergic system and profound neuronal loss in the locus coeruleus (LC) of the brain is a common element of both aging and neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Although the deficiency in the central noradrenergic system has been recognized to play a critical role in the development and progression of aging, PD, and AD, the cause and mechanisms underlying the LC neuronal disturbance in these states are poorly understood. Phox2a and Phox2b are two homeodomain transcription factors. Exclusively expressed in noradrenergic neurons, these factors are determinants of the development of noradrenergic neurons. Our preliminary study demonstrated that the expression of Phox2a and Phox2b in the LC shows an age-associated reduction in rats, a process coincidently accompanied by the decreased expression of dopamine p-hydroxylase (DBH) and norepinephrine transporter (NET). As both DBH and NET are characteristic of the noradrenergic system, our preliminary data, together with other findings in the literature, indicated that there is a possible functional relevance between Phox2a/2b genes and the mature noradrenergic system. We hypothesize that Phox2a/2b genes play an important maintenance role for function of LC neurons in mature brains. This proposal will utilize the techniques of gene transfer and small interfering RNA (siRNA) to accomplish two specific aims: (1) To determine whether over-expression of Phox2a and Phox2b in the LC areas will boost the expression of DBH and NET per se and in terminal areas in adult rats; (2) To examine whether decreased expression, knock down, of endogenous Phox2a/2b genes in the LC will reduce the expression of DBH and NET in the LC and its terminal areas. Furthermore, the effect of these manipulations of the LC on the neuroplasticity in two terminal areas, the olfactory bulb and hippocampal dentate gyrus, will be investigated. This proposed work will provide new insights into causal interaction between Phox2 genes and the dysfunction of LC neurons in both aging and degenerative diseases. This information may greatly facilitate the development of meaningful, testable therapeutic intervention for aging, PD, and AD.