Sego Chemutai, Gonçalves Luciano, Lima Leandro, Furigo Isadora C, Donato Jose, Metzger Martin
Department of Physiology & Biophysics, Institute of Biomedical Sciences, University of São Paulo, 05508-900, São Paulo, Brazil; Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, 05508-900, São Paulo, Brazil.
J Comp Neurol. 2014 May 1;522(7):1454-84. doi: 10.1002/cne.23533.
The lateral habenula (LHb) is an epithalamic structure differentiated in a medial (LHbM) and a lateral division (LHbL). Together with the rostromedial tegmental nucleus (RMTg), the LHb has been implicated in the processing of aversive stimuli and inhibitory control of monoamine nuclei. The inhibitory LHb influence on midbrain dopamine neurons has been shown to be mainly mediated by the RMTg, a mostly GABAergic nucleus that receives a dominant input from the LHbL. Interestingly, the RMTg also projects to the dorsal raphe nucleus (DR), which also receives direct LHb projections. To compare the organization and transmitter phenotype of LHb projections to the DR, direct and indirect via the RMTg, we first placed injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin into the LHb or the RMTg. We then confirmed our findings by retrograde tracing and investigated a possible GABAergic phenotype of DR-projecting RMTg neurons by combining retrograde tracing with in situ hybridization for GAD67. We found only moderate direct LHb projections to the DR, which mainly emerged from the LHbM and were predominantly directed to the serotonin-rich caudal DR. In contrast, RMTg projections to the DR were more robust, emerged from RMTg neurons enriched in GAD67 mRNA, and were focally directed to a distinctive DR subdivision immunohistochemically characterized as poor in serotonin and enriched in presumptive glutamatergic neurons. Thus, besides its well-acknowledged role as a GABAergic control center for the ventral tegmental area (VTA)-nigra complex, our findings indicate that the RMTg is also a major GABAergic relay between the LHb and the DR.
外侧缰核（LHb）是一个位于上丘脑的结构，可分为内侧（LHbM）和外侧部分（LHbL）。LHb与嘴内侧被盖核（RMTg）一起，参与了厌恶刺激的处理以及单胺能核团的抑制性控制。LHb对中脑多巴胺能神经元的抑制作用主要由RMTg介导，RMTg是一个主要为GABA能的核团，主要接受来自LHbL的输入。有趣的是，RMTg也投射到中缝背核（DR），而DR也直接接受LHb的投射。为了比较LHb直接投射到DR以及通过RMTg间接投射到DR的组织结构和递质表型，我们首先将顺行示踪剂菜豆凝集素注射到LHb或RMTg中。然后我们通过逆行示踪证实了我们的发现，并通过将逆行示踪与GAD67原位杂交相结合，研究了投射到DR的RMTg神经元可能的GABA能表型。我们发现LHb直接投射到DR的情况较少，主要来自LHbM，且主要指向富含5-羟色胺的尾侧DR。相比之下，RMTg投射到DR的情况更为显著，来自富含GAD67 mRNA的RMTg神经元，并集中指向一个独特的DR亚区，该亚区免疫组化特征为5-羟色胺含量低且富含假定的谷氨酸能神经元。因此，除了其作为腹侧被盖区（VTA）-黑质复合体的公认的GABA能控制中心的作用外，我们的研究结果表明，RMTg也是LHb和DR之间的主要GABA能中继站。
