Over the past several decades studies of the neurohypophysis have provided abundant information regarding the function of magnocellular neurons producing vasopressin and oxytocin and the physiological stimuli that regulate release of these hormones from the posterior pituitary. Much is also known about the consequences of loss of neurohypophyseal function, and the production of diabetes insipidus by damage to the pituitary and/or hypothalamo-neurohypophyseal tracts is a well-known complication of both head trauma and neurosurgical procedures. However, the factors which determine when trauma to magnocellular neurons or tracts to the neural lobe results in diabetes insipidus are less well understood. These studies propose to develop a new method for producing a selective neurolobectomy via controlled compression of the pituitary stalk using a unique triangular-shaped blunt knife. Use of this model to cause a reproducible degree of trauma to the pituitary stalk will allow accurate quantification of the effects of such lesions on survival of hypothalamic vasopressin and oxytocin neurons. This in turn will allow studies of the influence of various physiological factors on magnocellular survival and function following stalk compression, and specifically the effects of changes in ambient plasma osmolality as a determinant of the metabolic activity of magnocellular neurons. This model will also be used to assess the response of surviving magnocellular neurons with regard to their capacity for enhanced vasopressin and oxytocin synthesis, to ascertain whether this constitutes an adaptive mechanism allowing long-term recovery from diabetes insipidus induced by the initial lesion. By combining neuroanatomical, physiological, and molecular biological methodologies to address these questions, this project will constitute a broad multi-disciplinary training experience for the PSA applicant in addition to providing important new information in an area of interest both scientifically as well as clinically.
