Anterior and posterior parts of the rat ventral tegmental area and the rostromedial tegmental nucleus receive topographically distinct afferents from the lateral habenular complex

Abstract

That activation of the reward system involves increased activity of dopaminergic (DA) neurons in the ventral tegmental area (VTA) is widely accepted. In contrast, the lateral habenular complex (LHb), which is known as the center of the anti-reward system, directly and indirectly inhibits DA neurons in the VTA. The VTA, however, is not a homogenous entity. Instead, it displays major functional differences between its anterior (aVTA) and posterior (pVTA) regions. It is not precisely known, whether habenular input to the aVTA, pVTA, and the newly recognized rostromedial tegmental nucleus (RMTg) are similarly or differently organized. Consequently, the present investigation addressed the connections between LHb and aVTA, pVTA, and RMTg using retrograde and anterograde tracing techniques in the rat. Our experiments disclosed strictly reciprocal and conspicuously focal interconnections between LHbM (LHbMPc/LHbMC) and PN, as well as between RLi and LHbLO. In addition, we found that LHb inputs to the aVTA are dorsoventrally ordered. Dorsal parts of the aVTA receive afferents from LHbL and LHbM, whereas ventral parts of the aVTA are preferentially targeted by the LHbM. LHb afferents to the pVTA are distinct from those to the RMTg, given that the RMTg is primarily innervated from the LHbL, whereas pVTA receives afferents from LHbM and LHbL. These data indicate the existence of two separate pathways from the LHb to the VTA, a direct and an indirect one, which may subserve distinct biological functions.

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

“…Activation of this pathway is aversive and regulated by mesocortical dopamine receptors (Lammel et al, 2012). Petzel et al (2017) have made the related observation that more LHb neurons project to the VTA than RMTg, consistent with abundant direct LHb effects on VTA DA and local GABAergic neurons. However, the size of the terminal arbors (Omelchenko et al, 2009) and the physiological potency (Ji and Shepard, 2007) of direct LHb-VTA/SNc inhibitory projections are reported to be subordinate to those of the RMTg-VTA/SNc connection (Ji and Shepard, 2007; Jhou et al, 2009a;b; Balcita-Pedicino et al, 2011; Hong et al, 2011).…”

“…8 in Gonçalves et al, 2012 and Figs. 4–7 and 9 in Petzel et al, 2017). Indeed, there is a moderately strong projection from the medial LHb to the ipsilateral and contralateral RMTg (Jhou et al, 2009b).…”

“…The notion that LHb outputs to the RMTg are topographically organized has been challenged by the argument that LHbM and LHbL project, respectively, to the VTA and RMTg relatively exclusively (Gonçalves et al, 2012; Petzel et al, 2017). While there is clearly a tendency along these lines, were the connectivity to be as selective as advocated by these investigators, injection of retrograde tracer into the VTA should produce robust labeling in LHbM and none in LHbL, which is contrary not only to our results (Jhou et al, 2009b), but also theirs (see Fig.…”

“…[2] RMTg outputs are not limited only to midbrain DA-expressing cell groups, but rather comprise, in addition, dense descending projections to the serotoninergic raphe nuclei and other parts of the mesopontine reticular formation, such as the cholinergic MEA and laterodorsal tegmental nuclei (Jhou et al, 2009b; Gonçalves et al, 2012; Lavezzi et al, 2012; Zahm, 2016), as well as modest ascending projections to the parafascicular thalamic nucleus, entopeduncular nucleus, LH, thalamic midline and intralaminar cell groups, LPO, diagonal band complex, VP, dorsal hippocampus and frontal cortex. Among these structures is a significant proportion to which the LHb also projects, and which, like the VTA/SNc (Petzel et al, 2017), thus get major excitatory input directly from the LHb in combination with an LHb inhibitory influence relayed indirectly via the RMTg. Some of these structures include the raphe nuclei, mesopontine tegmentum, parafascicular nucleus, LH, LPO, VP and diagonal band nuclei.…”

Connections of the laterodorsal tegmental nucleus with the habenular‐interpeduncular‐raphe system

“…Moreover, in line with previous findings (Cornwall et al, ), we found that LHbM also receives, albeit more modest, projections back from LDTg. Notably, the LHbMPc/LHbMC complex of the LHbM has already been described as the primary, but not exclusive (Petzel, Bernard, Poller, & Veh, ), habenular source and also target of reciprocal direct connections with state‐setting neuromodulatory nuclei such as the DR/MnR (Bernard & Veh, ; Lima et al, ; Sego et al, ; Zhang et al, ), and VTA (Goncalves et al, ; Gruber et al, ; Li, Takada, Shinonaga, & Mizuno, ). In all, our findings provide further evidence that LHbMPc/LHbMC are subnuclei with a fairly distinct connectional profile (Zahm & Root, 2017), which can be characterized by their abundant reciprocal connections with major monoaminergic nuclei and the cholinergic LDTg.…”