The neurobiological role of the gonadal steroid hormones (estrogens and androgens) and of the binding protein, alpha-fetoprotein (AFP), in the neurogenesis, differentiation and development of the steroid receptor-containing regions of the developing mouse central nervous system (CNS) will be investigated in a tissue culture system. Long-term organotypic cultures of various regions of the fetal and neonatal CNS will be studied morphologically in living and stained preparations using Nissl, Golgi-Cox and neuro-fibrillary stains; 3H-steroid-, thymidine- and 125I-autoradiography and immunocytochemistry. Findings will be correlated with biochemical measures of receptor functionality during development as determined by studies of by steroidal effects on glucose uptake; protein biosynthesis; steroid metabolism; receptor content and of hormonal specificity. The developmental importance of AFP will be investigated by studies concerned with: the ontogeny and natural history of intraneuronal AFP; the cellular effects and cytological responses to AFP; AFP modulation of ligand uptake, and with the mode of uptake of AFP and its ultrastructural distribution. The delineation of the organizational roles of the gonadal hormones and of AFP on the developing brain is fundamental to an understanding of the genesis of sexually differentiated behavioral and neuroendocrine functions and of CNS development in general. Since evidence from in vivo studies implicates gonadal hormones in the normal organization of several brain regions and demonstrates the widespread intraneuronal distribution of AFP, the proposed studies offer a new and unique approach to an understanding of the developmental aspects of the neural regulation of reproductive function and behaviors and the cellular mechanisms by which interactions between the developing CNS, the gonadal steroids and AFP any induce, regulate or modify the basic developmental processes. This has significance for an understanding of neural plasticity and of the origins of a wide variety of developmental abnormalities in the human which are of considerable clinical, socio-cultural and educational importance. These include certain types of reproductive infertility, the postulated sexually dimorphic disorders of cognition, and of psychosexual differentiation.
