HIPPOCAMPAL THETA-ACTIVITY FOLLOWING SELECTIVE LESION OF THE SEPTAL CHOLINERGIC SYSTEM

The characteristic electroencephalographic patterns within the hippoca mpus are theta and sharp waves. Septal neurons are believed to play an essential role in the rhythm generation of the theta pattern. The pre sent study examined the physiological consequences of complete and sel ective damage of septohippocampal cholinergic neurons on hippocampal t heta activity in rats. A selective immunotoxin against nerve growth fa ctor receptor bearing cholinergic neurons (192 immunoglobulin G-sapori n), [Wiley R. G. et al. (1991) Brain Res, 562, 149-153] was infused in to the medial septal area (0.11-0.42 mu g). Hippocampal electrical act ivity was monitored during trained wheel running, drinking and the par adoxical phase of sleep, as well as following cholinomimetic treatment . A moderate dose of toxin (0.21 mu g) eliminated the septohippocampal cholinergic projection, as evidenced by a near total absence of choli ne acetyltransferase-immunoreactive neurons in the medial septum and t he vertical limb of the diagonal band, and by the absence of acetylcho linesterase-positive fibers in the dorsal hippocampus. In the same rat s, parvalbumin immunoreactivity, a reliable marker for septohippocampa l GABAergic neurons, [Freund T. F. (1989) Brain Res. 478, 375-381], re mained unaltered. In addition, retrograde transport of the tracer fluo rogold demonstrated that the parvalbumin cell population preserved its axonal projection to the hippocampus. Following toxin treatment, the power of hippocampal theta, but not its frequency, decreased in a dose -dependent manner. Reduction of theta power occurred between three and seven days after the toxin treatment and remained unaltered thereafte r up to eight weeks. A dose which eliminated al septohippocampal choli nergic neurons (0.21 mu g) left a small but significant theta peak in the power spectra during wheel running, paradoxical phase of sleep and intraseptal infusion of carbachol (5 mu g). Peripheral administration of physostigmine (1 mg/kg) induced only slow (1.5-2.0 Hz) rhythmic wa ves. No changes were observed in the gamma (50-100 Hz) band. These fin dings indicate that the integrity of the septohippocampal GABAergic pr ojection is sufficient to maintain some hippocampal theta activity. We hypothesize that cholinergic neurons serve to increase the population phase-locking of septal cells and thereby regulate the magnitude of h ippocampal theta.