The long-term objective is to elucidate the functional relationship between the brain and its extracellular fluids - interstitial fluid (ISF) and cerebrospinal fluid (CSF). Completed work has confirmed classical concepts of a network of channels with brain, analogous to lymphatics, for drainage of ISF. The significance of this system for clearing polar compounds from brain has been emphasized. Proposed experiments would continue to examine ISF flow in normal nervous tissue and to evaluate the functional significance of this flow, both with respect to its role in brain volume regulation and its relation to immune function. Studies of ISF flow in normal nervous tissue would (i) complete ongoing investigations of the pathways and dynamics of ISF flow from different regions of brain into CSF and deep cervical lymph in the rabbit and (ii) examine the role of perivascular spaces in the cortical subarachnoid space in the drainage of brain ISF. Studies of the volume regulatory function of bulk flow would (i) quantify the contribution of bulk flow of extracellular fluid between brain and CSF to tissue volume regulation under defined experimental conditions, (ii) measure the driving force and (iii) outline the pathways for flow under the same conditions, and (iv) examine the role vasopressin in brain volume regulation. To evaluate the significance of ISF-CSF drainage pathways for humoral immune function, antigen would be microinjected into brain or CSF and the kinetics of appearance of antigen-specific antibodies and antibody forming cells followed in central and systemic fluids and tissues, respectively. The same protein, human serum albumin, is used to measure flow of ISF and as antigen, facilitating the analysis of results in terms of brain- immune system interactions. Techniques include: intracerebral microinjection; perfusion of cerebral ventricles and subarachnoid space; collection of deep cervical lymph; quantitative autoradiography; measurement of ISF pressure, volume and tortuosity using micropipettes. Results would have wide applicability to CNS pathologies including autoimmune disorders, multiple sclerosis, CNS tumors and conditions characterized by excess brain fluids (edema, hydrocephalus, spinal cord injury).