Evidence from clinical observations and experimental investigations indicates that few enduring functional impairments are produced by subtotal damage to monoaminergic neurons, despite considerable evidence for their involvement in a wide variety of physiological and behavioral processes. We have proposed that this apparent paradox results from the capacity for """"""""synaptic homeostasis"""""""" that exists in these systems and that leads to compensatory events occurring after partial injury. We propose to use a multidisciplinary approach to describe at the cellular level the initial deficits, recovery of function and residual deficits produced by subtotal destruction of such a monoaminergic system and then to explore the biological bases of those phenomena. Our work will focus on the dopaminergic projection of the nigrostriatal bundle. Where appropriate, other monoaminergic systems will be used for these studies, including the sympathoadrenal system and the noradrenergic locus coeruleus-hippocampus projection. First, we will examine the impact of subtotal injury on monoaminergic function as determined by biochemical, physiological, electrophysilogical, and behavioral measurements. Second, we will attempt to determine the biological bases of the sparing of function that occurs after moderate lesions and the recovery of function that occurs after larger lesions. Third, we will test the ability of certain treatments to extend recovery of striatal function. Fourth, we will examine several other states which may be related to lesion induced-hypoinnervation, including development and chronic neuroleptic treatment. Finally, we will examine the influence of the age at which brain injury is sustained on the behavioral and biological consequences. These results should provide insights into the neurobiology of monoaminergic systems under normal conditions and after damage, as well as provide information of relevance to the detection and treatment of subclinical brain damage in disorders involving abnormalities of monoamine-containing systems.
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