A spectrum of diseases, both psychiatric and neurological in nature, involve long term progressive changes that may well begin in the earliest phases of brain development. The symptoms of schizophrenia, Tourette's syndrome, Parkinson's disease and Huntington's chorea, may emerge from defects in the anatomical organization of the basal ganglia that result in disordered neurochemical function. The underlying neuropathology appears to involve the striatum (caudate and putamen), a key structure of the basal ganglia- that is characterized by a dense dopaminergic innervation and a compartmentalized distribution of intrinsic neurons. Studies described here will focus on the development of the anatomical organization of this structure, attempting to dissociate those aspects that are intrinsically specified by the striatal neurons, as opposed to those directed by the ingrowth of dopaminergic afferents that occurs very early in life.
The aim of the present proposal is to provide an anatomical basis for understanding how interference with the proper development of this key structure may lead to disordered functioning later in life. As a foundation for studying the behavioral consequences of pathological development, it is necessary to understand the factors involved in guiding the normal development of the striatum. The specific experiments involve a temporal and spatial analysis of the development of several cell types found within the striatum, defined immunocytochemically on the basis of their neurotransmitter phenotype. Experimental manipulations will be made it order to perturb the normal development of the distinctive striatal compartmentalization now known to exist. The effects of early removal of dopamine input on striatal development and organization will be assessed both in vivo and in transplanted striatal tissue. Other rats will be treated in utero with an antimitotic agent timed so as to kill a select population of striatal neurons, and the resultant consequences on the development of other cells and afferents to the striatum assessed. These studies are expected to reveal ways in which genetic defects or neurotoxic insults produce alterations in anatomical development of the striatum that result in long-lasting abnormalities in basal ganglia organization and function.
