Impaired spatial learning ln aged rats is associated with loss of p75-positive neurons in the basal forebrain

We investigated age-related changes in the number and size of neurons posit ive for the p75 neurotrophin receptor in the cholinergic basal forebrain of female Dark Agouti rats. Since the integrity of these neurons is known to be closely associated with performance in tests of spatial learning ability , we also investigated the incidence of age-related spatial learning impair ments, using the Barnes maze. Spatial learning impairments occurred with in creasing frequency with age. No rats showed impairment at six months, but 5 0% were impaired at 14 months and 71% at 26 months. There was no correlatio n between age and decreased number of p75-positive neurons in the rostral b asal forebrain, which consists of the medial septum and vertical limb of th e diagonal band of Broca. In the caudal basal forebrain, which consists of the horizontal limb and the nucleus of Meynert, there was a 13% reduction i n the number of p75-positive neurons at 17 months compared to six months, a nd a 30% reduction at 26 months. There was a strong correlation between the presence of spatial learning impairment and a reduction in the number of p 75-positive neurons. This correlation was most evident in the rostral basal forebrain, but was also present in the caudal basal forebrain. In the rost ral basal forebrain, all learning impaired rats had fewer p75-positive neur ons than the average number in unimpaired rats. A close correspondence betw een the presence of p75 and choline acetyltransferase was evident in basal forebrain neurons of learning-impaired and unimpaired rats. Gross pathologi cal changes to the morphology of p75-positive neurons were relatively frequ ent in learning-impaired rats. These changes consisted of hypertrophy, appe arance of vacuoles, and marginalisation of the cytoplasm. The results indicate the susceptibility of p75-positive neurons to degenera tive changes with aging, and show that the loss of these neurons in the bas al forebrain was strongly correlated with impairment in spatial learning. ( C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.