Differential projections from the lateral habenula to the rostromedial tegmental nucleus and ventral tegmental area in the rat

Abstract

The mesopontine rostromedial tegmental nucleus (RMTg) is a mostly γ-aminobutyric acid (GABA)ergic structure believed to be a node for signaling aversive events to dopamine (DA) neurons in the ventral tegmental area (VTA). The RMTg receives glutamatergic inputs from the lateral habenula (LHb) and sends substantial GABAergic projections to the VTA, which also receives direct projections from the LHb. To further specify the topography of LHb projections to the RMTg and VTA, small focal injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin were aimed at different subdivisions of the LHb. The subnuclear origin of LHb inputs to the VTA and RMTg was then confirmed by injections of the retrograde tracer cholera toxin subunit b into the VTA or RMTg. Furthermore, we compared the topographic position of retrogradely labeled neurons in the RMTg resulting from VTA injections with that of anterogradely labeled axons emerging from the LHb. As revealed by anterograde and retrograde tracing, LHb projections were organized in a strikingly topographic manner, with inputs to the RMTg mostly arising from the lateral division of the LHb (LHbL), whereas inputs to the VTA mainly emerged from the medial division of the LHb (LHbM). In the RMTg, profusely branched LHb axons were found in close register with VTA projecting neurons and were frequently apposed to the latter. Overall, our findings demonstrate that LHb inputs to the RMTg and VTA arise from different divisions of the LHb and provide direct evidence for a disynaptic pathway that links the LHbL to the VTA via the RMTg.

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

“…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. 8 in Gonçalves et al, 2012 and Figs. 4–7 and 9 in Petzel et al, 2017).…”

“…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.…”

The antero-posterior heterogeneity of the ventral tegmental area

“…For example, the tVTA inputs from the dorsal raphe and the locus coeruleus are non-aminergic and those from the lateral hypothalamus are mostly non-orexinergic (Kaufling et al, 2009), and the VTA and tVTA inputs from the lateral habenula preferentially arise from its medial and lateral subdivisions respectively (Goncalves et al, 2012). Presently, the most studied input to the tVTA remains the lateral habenula (Herkenham and Nauta, 1979;Jhou et al, 2009aJhou et al, , 2013Brinschwitz et al, 2010;Balcita-Pedicino et al, 2011;Hong et al, 2011;Goncalves et al, 2012;Lammel et al, 2012;Stamatakis and Stuber, 2012;Stamatakis et al, 2013). The output from the tVTA targets relatively few forebrain regions.…”

Reward processing by the lateral habenula in normal and depressive behaviors

“…2). The lateral part of LHb (LHb-l) receives inputs mainly from the basal ganglia through the border region of the globus pallidus (GPb) 47 and sends outputs mainly to the DA system (SNc and VTA) through RMTg 48 . In contrast, the medial part of LHb (LHb-m) receives inputs from the limbic areas (e.g., diagonal band of Broca) 47 and sends outputs mainly to the 5HT system (dorsal and median raphe nuclei, DRN and MRN) 11, 48, 49 .…”

“…The lateral part of LHb (LHb-l) receives inputs mainly from the basal ganglia through the border region of the globus pallidus (GPb) 47 and sends outputs mainly to the DA system (SNc and VTA) through RMTg 48 . In contrast, the medial part of LHb (LHb-m) receives inputs from the limbic areas (e.g., diagonal band of Broca) 47 and sends outputs mainly to the 5HT system (dorsal and median raphe nuclei, DRN and MRN) 11, 48, 49 . Manipulations of LHb outputs (electrical stimulation, lesion, inactivation) induce changes in 5HT release in the 5HT nuclei and their target brain areas 50, 51, 52 which may lead to changes in behavior and possibly emotion 53, 54 .…”