Abnormalities of the dopamine (DA) neuron system are present in several types of dementia and in normal aging. The two most common degenerative disorders of the elderly, Parkinson's disease (PD) and Alzheimer's disease AD), both have abnormalities of this system, capable of producing clinical symptoms. Dysfunction of the DA system has been implicated in causing a variety of clinical symptoms including the well known motor abnormalities in PD, but also a variety of cognitive, memory, affective, and behavioral symptoms. Neuropathological findings in the substantia nigra suggest that these neurons are differentially lost depending on location, pigmentation, and projection area. Recent studies in rodents and primates demonstrate that the DA system is very widely distributed in the cerebral cortex, as well as in the hippocampus and amygdala, providing a neuroanatomical substrate for influencing diverse cerebral functions. Animal models of DA dysfunction reveal that DA neurons are also differentially vulnerable to neurotoxins and are capable of recovery and compensation under different conditions. The initial objectives of this proposal are to study the differential vulnerability and mechanisms of DA recovery and compensation in two animal models of DA dysfunction. Both the mesostriatal and mesolimbocortical systems will be addressed to determine if these systems are differentially affected and relate these systems to higher cerebral functions relevant to man. Initial mouse studies will be done to determine whether subsets or regions of DA neurons are differentially sensitive to the neurotoxin MPTP. Recovery or compensation of DA indices will be examined over time in this model and in the rat 6-OHDA model to determine possible mechanisms for this compensation. Subsequent studies will address factors that may impede or augment forms of recovery and compensation. Brains from lesioned and control animals will be analyzed using a variety of techniques including in situ hybridization histochemistry for the tyrosine hydroxylase (TH), cholecystokinin (CCK), and neurotensin (NT) genes, and neuron counts in the substantia nigra (SN)/ventral tegmental area (VTA), and DA levels, density of the DA uptake complex, tyrosine hydroxylase activity and protein levels in projection areas of the striatum, hippocampus, and cerebral cortex. Results of these studies will serve to guide future studies in human postmortem brains, and may provide information for the design of interventions in man. Brains from patients with AD will be divided into groups of patients with and without extrapyramidal symptoms, while PD brains will be divided into groups with and without dementia. Other clinical factors to be considered in the analysis will include age, age of onset, duration of disease, and clinical severity. The methods employed in the rodent studies will be used, along with additional techniques of counting neuromelanin positive neurons and the use of multiple probes for the variable human TH message, to examine similar issues of differential DA neuronal vulnerability in these different patient groups. Projection areas will be examined to determined if particular area are deficient in DA markers which might correlate with clinical symptomatology. Results of this aim will provide information about the pathophysiology of these disorders, and might suggest rational interventions.
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