Topography of descending projections from anterior insular and medial prefrontal regions to the lateral habenula of the epithalamus in the rat.

The epithalamic lateral nucleus of the habenula (LHb) plays a key role in regulating firing of dopamine and serotonin neurons in the midbrain and is thereby involved in various cognitive and affective behaviors. It is not yet clear, however, from where the LHb receives cognitive and affective information relevant to its regulation of the midbrain monoaminergic systems. The prefrontal cortex would be among the ideal sources. Here, using anterograde and retrograde tracer injections in the rat brain, we characterized the topography of the corticohabenular projections. Following injections of cholera toxin subunit B into the LHb, retrogradely labeled neurons were produced in the anterior insular, cingulate, prelimbic and infralimbic cortices. Consistent with this retrograde tracing, injections of biotinylated dextran amine (BDA) into these cortical regions labeled robust terminals in the LHb. Our quantification of the BDA-impregnated varicosities revealed that projections from the anterior insula terminated mainly in the intersection regions of the lateral and ventral two-thirds of the LHb, while projections from the cingulate cortex terminated mainly in the lateral two-thirds of the LHb. By comparison, BDA-labeled terminals originating from the medial prefrontal regions were contained mainly in the medial plus ventral one-third of LHb. Based on these data, we hypothesize that LHb provides a link for conveying cognitive and affective information from prefrontal and insular regions to the midbrain monoaminergic centers.