When the cholinergic projection from the medial septum to the hippocampal formation is interrupted, peripheral sympathetic nerves, originating in the superior cervical ganglia, invade the hippocampal formation. Although, anatomically well delineated, the functional significance of this rearrangement has not been well defined. Recently, we have demonstrated that prevention of sympathetic ingrowth after medial septal lesions results in enhancement of learning of a spatial memory task. This strongly suggests that hippocampal sympathetic ingrowth is detrimental to learning/memory processes. The experiments outlined in this proposal are designed to further investigate this observation. All experiments will employ a modified version of the radial-eight arm maze task. Performance of this task appears not only to require many of the same behaviors as human learning and memory tasks, but also appears to be exquisitely sensitive to hippocampal and central cholinergic dysfunction. The first series of experiments will attempt to define the role of the superior cervical ganglia in normal learning and memory processes. The second series of experiments will attempt to determine if superior cervical ganglionectomy at the time of cholinergic denervation is protective for other types of learning behaviors. The third, fourth, and fifth series of experiments will examine possible mechanisms through which the protective effect of ganglionectomy are mediated. These experiments will attempt to define whether prevention of sympathetic ingrowth or lack of sympathetic nervous system activity at the time of cholinergic denervation is the critical factor. The role of the pineal gland as well as Alpha and Beta adrenergic receptors will also be addressed. The outcome of this research may have profound implications for patients with Alzheimer's Disease, a dementing illness, characterized by both cholinergic and hippocampal dysfunction. New and innovative therapeutic approaches to this disorder could be realized.
