This FIRST Award is aimed at advancing our understanding of the responses of the developing mammalian brain to selective regional damage of dopamine (DA) systems. Brain injury early in development can produce severe disturbances in behavioral and cognitive capacities as seen in cerebral palsy, and may result in subtle neuropsychiatric sequelae, possibly including some forms of schizophrenia. It is important to understand how the developing mammalian brain responds to injury, and how the early environment may affect this adaptation. An effective model of selective lesioning is removal of DA with the neurotoxin 6-hydroxydopamine (60HDA). In adult rats, such lesions induce akinesia and potentially fatal aphagia and adipsia. Neonatally lesioned rats eat, drink and grow at nearly normal rates but display hyperactivity and learning deficits after profound DA depletion before 20 days of age. Depletion of DA is associated with increased serotonin (5HT) and DA D-l receptors in the forebrain of neonatal rats, but not adults, presumably by secondary adaptation of immature neurons that may include """"""""sprouting"""""""" of neuronal processes. A major aim of this award is to understand the role of these processes in recovery and adaptation to lesioning of DA systems, using behavioral, neuropharmacological, and tissue culture techniques. In recent years there has also been an astonishing convergence of studies which have revitalized interest in the prefrontal cortex (PFCTX), and demonstrated the potential importance of this substrate in the pathophysiology of schizophrenia. The proposed studies will add to this important emerging area by focusing on the developmental neuropharmacology of the PFCTX and its connections. Specifically, my studies will determine the time course for the emergence of PFCTX inhibitory control of DA systems innervating the striatum and nucleus accumbens, the age at which DA input to PFCTX becomes specifically activated by certain forms of environmental stress, and the effects of such early stress on the development of the slowly maturing PFCTX. Finally, the consequences of early deafferentation of the PFCTX and the early loss of intrinsic cell bodies will be studied using regional neurotoxic injections. Effects of such lesions on DA turnover, monoamine and metabolite levels, and behavior will be determined. These studies will help bridge the gap between understanding the normal function and development of the PFCTX and the possible pathophysiological impairments that might ensue from damage to different components of this system during development and maturation.
