Understanding underlying alteration in brain function is a prerequisite for the amelioration of age-related behavioral impairments and age-related neurodegenerative diseases which represent major problems for advanced societies. Research during the past decade has revealed that age-related morphological and physiological changes in neuron function can not be generalized to all neurons in the central nervous system but are brain region and cell type specific. In addition, recent studies have suggested that some neural functions successfully maintained with age may depend on the ability of neurons to preserve or repair their neural circuitry in response to naturally occurring cell loss, deafferentation or neurotransmitter deficits. Understanding these cellular mechanisms will provide a basis for the development of future therapeutic strategies aimed a amelioration of age-related neurodegenerative diseases. The proposed program project aims at contributing to such progress by providing information on age-related changes in basal ganglia function of the mammalian brain. Basal ganglia play a central role in motor function and are also involved in functions related to cognitive and emotional behavior. Disturbances in these behaviors are a clinical feature in some, but no all, elderly individuals and neuropathological changes in the basal ganglia are the hallmark of several neurodegenerative diseases, including Huntington's and Parkinson's disease. Emphasis is given to dopaminergic neurons whose degeneration is responsible for the majority of parkinsonian symptoms. The study of plasticity, neuronal death and age-related functional changes represent the main area of focus of the program project. Plasticity is a normal feature of a developing nervous system. While less frequent in the adult and aging nervous system, plasticity can occur in response to age- or disease-induced degenerative processes. The program project aims at establishing the extent of changes in plasticity of basal ganglia neurons induced by aging and injury. Neuronal atrophy an degeneration of selected neuronal populations accompanies aging and selective neuronal death is a key feature of neurodegenerative diseases. Several specific aims of the program project are directed at understanding molecular mechanisms playing a key role in determining the consequences of aging or of experimental injury to the brain. Attempts to prevent neuronal degeneration by the pharmacological use of protein growth factors or compounds altering transmitter functions is a central theme in the program project. Functional adaptations to aging have been partly characterized for dopaminergic but not other basal ganglia neurons.
A specific aim of this program project is to study the molecular basis of selected age-related functional changes in the dopaminergic system. An entire project aims at providing the first thorough description of age-related changes in electrophysiological behavior of basal ganglia neurons. Preliminary findings reported in this application suggest that aging does not generally produce neuronal atrophy or impair plasticity and functional adaptation of basal ganglia neurons. The possibility that basal ganglia undergo unique age-related changes retaining the ability for plasticity and functional adaptation represents a key hypothesis to be tested. The proposed experiments will help to understand the molecular basis of plasticity and adaptation.
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