Aging is associated with selective reductions in the number of neurons and neuronal connections in the brain. These changes are potentially important determinants of the widespread alterations in physiological function that accompany aging. The objective of this proposal is to identify specific neuronal changes that are associated with and may contribute to reproductive failure in the female, one of the earliest and most striking aspects of the mammalian aging process. Neuroendocrine failure to produce a preovulatory surge of luteinizing hormone (LH) occurs during midlife in laboratory rodents. This functional loss can be delayed by long-term ovariectomy, implicating chronic exposure to ovarian secretions as an etiologic factor. This aging change provides an opportunity to examine the vases for age-related dysfunction unencumbered by the potentially confounding effects of diseases of aging, and to determine whether these changes can be modulated by an intervention that delays functional decline. The preoptic area (POA) plays a major role in the preovulatory surge of LH in rodents. Pharmacologic and biochemical studies indicate that the noradrenergic and opiatergic systems interact in the regulation of the LH surge and appear to play a role in its age-related decline. However, the neurocytoarchitectural substrates for noradrenergic-opiatergic-LHRH interactions and age-related changes are unknown. This proposal has three main objectives using the C57BL/6J mouse: 1] to determine the effect of aging on a) the number and distribution of noradrenergic and opiatergic neuronal elements impinging on LHRH neurons; and on b) the relationship between noradrenergic and opiatergic elements in the POA; 2] to determine by pharmacological approaches, the effect of aging on noradrenergic and opiatergic influence on the estradiol induced LH surge; and 3]. to determine whether long-term ovariectomy attenuates the age-related changes that are identified. Neuroanatomical studies will involve ultrastructural colocalization of neuronal elements of the noradrenergic and opiatergic systems using immunocytochemistry, radioimmunocytochemistry, and autoradiography. These complementary neuroanatomical and pharmacological studies will clarify the role of the noradrenergic and opiatergic systems in the diminished E2-induced LH surge during aging.
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