Efferent Pathways of the Mouse Lateral Habenula

Abstract

The lateral habenula (LHb) is part of the habenula complex of the dorsal thalamus. Recent studies of the LHb have focused on its projections to the ventral tegmental area (VTA) and rostromedial tegmental nucleus (RMTg), which contain GABAergic neurons that mediate reward prediction error via inhibition of dopaminergic activity. However, older studies in the rat have also identified LHb outputs to the lateral and posterior hypothalamus, median raphe, dorsal raphe, and dorsal tegmentum. Although these studies have shown that the medial and lateral divisions of the LHb have somewhat distinct projections, the topographic specificity of LHb efferents is not completely understood, and the relative extent of these projections to brainstem targets is unknown. Here we have used anterograde tracing with adeno-associated virus mediated expression of green fluorescent protein, combined with serial two-photon tomography, to map the efferents of the LHb on a standard coordinate system for the entire mouse brain, and reconstruct the efferent pathways of the LHb in three dimensions. Using automated quantitation of fiber density, we show that in addition to the RMTg, the median raphe, caudal dorsal raphe, and pontine central gray are major recipients of LHb efferents. Using retrograde tract tracing with cholera toxin subunit B, we show that LHb neurons projecting to the hypothalamus, VTA, median raphe, and caudal dorsal raphe, and pontine central gray reside in characteristic, but sometimes overlapping regions of the LHb. Together these results provide the anatomical basis for systematic studies of LHb function in neural circuits and behavior in mice.

Review of the cytology and connections of the lateral habenula, an avatar of adaptive behaving

“…Quina et al (2015) used serial two-photon tomography combined with adeno-associated virus-mediated expression of green fluorescent protein to map LHb efferent connections in the mouse and produced data consistent with the classical tracing studies described above.…”

Determination of neurotensin projections to the ventral tegmental area in mice

“…However, given the paucity of Nts neurons in the VTA (Fig. 13), including the tail region that is thought to blend into the RMTg in mice (Bourdy and Barrot, 2012; Quina et al, 2015), it is unlikely that these local populations are a significant source of the Nts input to the VTA in mice. Additionally, FG can be taken up by damaged axons of passage near the injection site, which may lead to false-positive identification of afferents (Dado et al, 1990).…”

Control of behavioral flexibility by the lateral habenula

“…While no direct connection between the LHb and hippocampus is known to exist, they share a common afferent connection, the diagonal band of Broca, and the LHb indirectly projects to the hippocampus via the raphe nuclei (Lecourtier and Kelly 2007; Quina et al 2015). Additionally, the mPFC functionally connects the LHb and hippocampus via a hippocampus-mPFC-LHb projection that also likely contributes to memory related functions (Kim and Lee 2012; Mathis et al 2016).…”