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

Abstract

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.

The low-frequency blood oxygenation level-dependent functional connectivity signature of the hippocampal–prefrontal network in the rat brain

“…Anatomically, the rat hippocampal region projects via the septal-preoptic pathway to the lateral habenula, a region that is involved in negative and positive reward responses (Geisler and Trimble, 2008;Hikosaka, 2010). Additionally, prefrontal and insula regions project via both the mediodorsal thalamus and the ventral striatopallidal system to the lateral habenula (Geisler and Trimble, 2008;Kim and Lee, 2012) corroborating the functional connectivity that we observed with respect to several seeds in the hippocampal-prefrontal network (Supplemental Material available from the authors) indicating adjacent mediodorsal thalamic and lateral habenular regions. Indeed, using an anatomically defined habenula seed yielded a correlation map (not shown) that overlapped considerably with the predominant hippocampal-prefrontal pattern observed in the present study, including coupling with the mPFC, cingulate cortex, posterior hippocampus as well as septal and medial midbrain regions (ventral tegmental area).…”

Electrical Stimulation of the Insular Region Attenuates Nicotine-Taking and Nicotine-Seeking Behaviors

“…It is through these two pathways that the insula is posited to be involved in both nicotine-taking and -seeking behaviors. However, it should be noted that recent evidence suggests the lateral habenula may also be involved in conveying information from the anterior insular cortex to midbrain monoaminergic centers (Kim and Lee, 2012).…”

Excitatory Transmission to the Lateral Habenula Is Critical for Encoding and Retrieval of Spatial Memory

“…The learning and memory deficits induced by CNQX strongly suggest that excitatory glutamatergic transmission to the LHb participates in encoding and retrieval of spatial information. One possible origin of glutamatergic inputs to the LHb is the prefrontal cortex, which sends projections to the LHb (Kim and Lee, 2012). Therefore, the hippocampocortical system, whose participation in memory processes has been clearly demonstrated (Winocur et al, 2010), could transmit relevant information to the LHb through the prefrontal cortex.…”

“…The second strategy enabled a more precise investigation of the role of glutamatergic inputs to the LHb, which have gained interest recently. They arise from the basal ganglia (Shabel et al, 2012), the ventral tegmental area (Hnasko et al, 2012), and potentially from the prefrontal cortex given the likely glutamatergic projections from several prefrontal regions to the LHb (Kim and Lee, 2012). Complementary experiments controlled for potential drug-induced behavioral alterations, which could have biased WM performance.…”