Dissociable pathways facilitate theta and non‐theta states in the median raphe—Septohippocampal circuit

Hippocampal theta rhythms in vivo are modulated by a synchronizing projection from the medial septum (MS) and a desynchronizing input from the median raphe nucleus (MRn) of the brainstem. Inactivation of the MS suppresses theta rhythms while inactivation of the median raphe produces persistent theta. However, different pathways arise from within the MS and the median raphe and therefore different brain states could be facilitated by different forms of median raphe or septohippocampal inputs. Here, we found in urethane anesthetized rats that suppression of outputs from the MRn with procaine leads to persistent hippocampal theta as previously reported. The discharge properties of hippocampal theta-related cells recorded during both spontaneously occurring theta and MRn 8-OH-DPAT-induced theta did not differ significantly. This persistent theta was abolished by inactivation of the MS with either procaine or atropine sulfate. Selective inactivation of serotonergic median raphe outputs with the 5-HT-1A agonist (8-OH-DPAT) induced theta that was also abolished by medial septal inactivation using procaine. Thus, persistent theta following complete median raphe inactivation or selective serotonergic inactivation arises from a median raphe to MS pathway. However, 8-OH-DPAT infusions into the median raphe together with atropine infusions in the MS did not abolish theta activity. These data suggest that the non-serotonergic (possibly glutamatergic) median raphe projections to the MS can facilitate the generation of hippocampal theta in the absence of medial septal cholinergic tone. These results demonstrate that dissociable neuronal pathways in the median raphe-MS-hippocampal circuit promote different brain states (theta or non-theta) and a median raphe non-serotonergic (likely glutamatergic) system may serve a separate function from the ascending serotonergic raphe projection in the regulation of hippocampal network activity.