Cholinergic, dopaminergic, and glutamatergic systems are among the most vulnerable circuits in aging and neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Recently, genes coding for subtypes of muscarinic, cholinergic, dopaminergic, and glutamatergic receptors have been cloned, and, based on identified sequences, antibodies have been generated that can be used for immunocytochemical studies. Thus, we will localize, at the light/electron microscopic levels, the distributions of these receptor subtypes in circuits critical for cognition/memory and motor control. This information is essential for the design of new pharmacological strategies that target specific receptors. Neurotrophins are trophic peptides that promote the survival/differentiation of specific neuronal populations expressing receptors for these factors. The neurotrophins, a family including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3), bind to specific receptors (i.e., the p75 NGF receptor and products of trk proto-oncogenes). Thus, circuits (i.e., factors and their receptors) exist within the central nervous system (CNS). Recently, it has been suggested that neurotrophic factors may be useful in the treatment of neurological diseases. We will demonstrate the distributions of neurotrophins and their receptors and will then delineate these circuits using retrograde transport of injected-labeled neurotrophins in the CNS. These studies, which complement investigations outlined in Projects 2 and 4, will define neuronal systems potentially responsive to these neurotrophic factors.
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