Serotonergic regulation of hippocampal rhythmical activity

Abstract The dorsal (DR) and median raphe (MR) nuclei are major serotonin-containing nuclei of the brainstem with extensive projections to the forebrain. With a few exceptions, DR and MR give rise to separate, nonoverlapping, projections to the forebrain. The MR is a midline/paramidline system with fibers mainly distributing to medial parts of the hypothalamus and thalamus, the medial basal forebrain, the septum, and the hippocampus. By contrast, DR is a “lateral” system distributing to the substantia nigra, the lateral hypothalamus, amygdala, lateral basal forebrain, and cortex. The DR and MR essentially only send common projections to the midline and intralaminar thalamus. These differential projections undoubtedly reflect functional differences of the two systems. Recent examinations of inputs and outputs of serotonergic DR and MR cells, using viral-based techniques, has largely confirmed, but also extended, previous descriptions of DR/MR systems using conventional tracers. Serotonergic DR/MR fibers distribute heavily, and largely selectively, to “limbic-related” sites of the forebrain. This is exemplified by the distribution of serotonin (5-HT) fibers to the thalamus and cortex; that is, pronounced 5-HT (SERT+) fiber labeling in the anterior, midline, and intralaminar nuclei of thalamus compared to sparse labeling of principal thalamic nuclei, and dense 5-HT labeling of limbic cortices as opposed to sensorimotor cortices. Serotonergic MR fibers strongly target the hippocampus (HF) and weakly the neocortex, whereas the 5-HT DR fibers distribute heavily to the neocortex and minimally to the HF. Serotonergic MR fibers to the HF serve a prominent role in the modulation of the hippocampal theta rhythm, as this is the only input to the HF that serves to desynchronize the hippocampal EEG—or block the theta rhythm. In an analogous manner, serotonin acting at various 5-HT-receptor sites in the HF also strongly suppresses gamma oscillations and ripple activity in the hippocampus. In effect, the serotonergic MR system serves to suppress the three major oscillations of the hippocampus (theta, gamma, ripples)—and as a corollary, inhibition of the MR triggers each of these rhythms. The dual serotonergic MR actions on hippocampal oscillations has opposite effects on learning and memory; that is, the suppression of hippocampal oscillations severely disrupts memory, whereas releasing rhythmical activity (via inhibition of MR) enhances memory. It has been suggested that median raphe nucleus is an important part of a system of connections that blocks or temporarily suspends memory in the hippocampus and by so doing may direct the hippocampus to essentially disregard insignificant environmental events.