CHOLINERGIC MANIPULATIONS IN THE MEDIAL SEPTAL AREA - AGE-RELATED EFFECTS ON WORKING-MEMORY AND HIPPOCAMPAL ELECTROPHYSIOLOGY

Aged rats have impairments in several types of cognitive functions, in cluding spatial working memory (WM), that are dependent upon the septo hippocampal cholinergic system. The present series of experiments was designed to assess the effectiveness of pharmacological manipulations of the medial septal area (MSA) in order to influence the physiology o f the septohippocampal pathway and, therefore, the brain functions in which this pathway participates. Aged (22MO) and young (4MO) Fischer-3 44 rats received microinfusions into the MSA with either saline, the m uscarinic agonist, oxotremorine (OXO), or the muscarinic antagonist, s copolamine (SCOP). Working memory was tested in a T-maze spatial alter nation task, prior to infusion, immediately after infusion, and 90 min after infusion. Hippocampal theta activity and the population excitat ory postsynaptic potential (pEPSP) of the dentate gyrus to perforant p ath stimulation were recorded immediately following behavioral testing at each of the three time periods. In 22MO rats, intraseptal OXO (0.5 mu g, 2 mu g, 5 mu g) produced a dose-dependent improvement in choice accuracy, a shift of the hippocampal theta peak to a lower frequency and a higher peak power, and an increase in the initial slope of pEPSP . OXO, 0.1 mu g, did not have an effect on behavior or hippocampal phy siology and OXO, 10 mu g, produced an impairment in performance. In 4M O rats, OXO did not affect choice accuracy, nor the pEPSP slope, but a ltered hippocampal theta peak frequency and power similarly as in 22MO . The lowest behaviorally effective dose, 0.5 mu g OXO, did not influe nce WM performance when infused into the lateral ventricles (intracere broventricularly) of either 22MO or 4MO rats. SCOP (2 mu g, 5 mu g, 15 mu g) decreased choice accuracy in a dose-dependent fashion in both 2 2MO and 4MO rats. However, in 22MO rats, the behavioral dose-response curve for scopolamine was shifted towards greater sensitivity. SCOP pr oduced a shift of the hippocampal theta to a higher frequency and a lo wer peak power, and a decrease in the initial slope of pEPSP. In 4MO r ats, SCOP altered hippocampal theta similarly to 22MO, but did not aff ect the pEPSP slope. These results indicate that (1) cholinergic recep tors in the MSA are a useful target for drugs to improve WM in aging r ats, (2) age-related changes in the activity of the septohippocampal p athway may increase its sensitivity to drugs which alter its activity, and (3) alterations in hippocampal physiology may contribute differen tly to changes in WM in young and in old rats.