Hippocampal Noradrenaline Regulates Spatial Working Memory in the Rat

Degeneration of noradrenergic neurons in the locus coeruleus and loss of fiber terminals in the neocortical and hippocampal target regions represent prominent and early features of Alzheimer’s disease, however, whether these events are causally linked to cognitive decline in Alzheimer’s disease is still unclear. In the present study, the noradrenergic contribution to the regulation of hippocampus-dependent spatial learning and memory was investigated. Postnatal day 4 rats underwent selective immunolesioning of hippocampal noradrenergic afferents and, 4 days later, the bilateral intrahippocampal implantation of locus coeruleus noradrenergic neuroblasts. Starting from 4 weeks and up to about 9 months postsurgery, sensory-motor and spatial navigation abilities were evaluated, followed by postmortem tissue analyses. All animals in the Control, Lesion, and Lesion+Transplant groups exhibited normal sensory-motor function and were equally efficient in the reference memory version of the water maze task, whereas working memory abilities were seen consistently impaired in the Lesion-only rats. Notably, the noradrenergic reinnervation promoted by the grafted progenitors reinstated a fairly normal working memory performance, suggesting a primary role for coeruleo-hippocampal noradrenergic inputs in the maintenance of specific aspects of cognition.