Distribution of calretinin-immunoreactive septal axons in the normal and deafferented medial habenula of adult rats.

To characterize the neural circuitry and plasticity of the septohabenular pathway, the present study analyzes the distribution of calretinin-immunoreactive fibers within the normal and deafferented medial habenula (MHb) at the light and ultrastructural levels. In the adult rat, a dense plexus of calretinin-positive fibers was found throughout the entire MHb neuropil; these immunoreactive terminals formed asymmetric synaptic contacts with unstained dendritic profiles. Calretinin-positive axons that innervate the MHb originated from neurons of the ipsilateral posterior septum, specifically those of the nucleus septofimbrialis and the nucleus triangularis. Unilateral deafferentation of the MHb resulted in the complete loss of calretinin-immunostained fibers within the ipsilateral MHb after 7 days; no reduction was apparent on the contralateral side. Four weeks after unilateral MHb deafferentation, new calretinin-immunoreactive fibers were found confined to the caudal regions of the MHb, these axons again formed asymmetrical contacts with unstained dendritic profiles. No calretinin-positive axons, however, were found within the MHb at 4 weeks following bilateral deafferentation, thus suggesting that the source of these new fibers within the long-term deafferented MHb arises from the contralateral septal neurons. Supporting this idea, injections of biotinylated dextran amine into the 4-week deafferented MHb resulted in retrogradely labeled somata observed in the contralateral posterior septum. These data reveal that septal projections to the MHb, which are normally ipsilateral, respond to a unilateral deafferentation by extending contralateral fibers that cross the midline at the habenular commissure and reinnervate the caudal regions of the nucleus.