The habenula (Hb) is a phylogenetically old epithalamic structure differentiated into two nuclear complexes, the medial (MHb) and lateral habenula (LHb). After decades of search for a great unifying function, interest in the Hb resurged when it was demonstrated that LHb plays a major role in the encoding of aversive stimuli ranging from noxious stimuli to the loss of predicted rewards. Consistent with a role as an anti-reward center, aberrant LHb activity has now been identified as a key factor in the pathogenesis of major depressive disorder. Moreover, both MHb and LHb emerged as new players in the reward circuitry by primarily mediating the aversive properties of distinct drugs of abuse. Anatomically, the Hb serves as a bridge that links basal forebrain structures with monoaminergic nuclei in the mid-and hindbrain. So far, research on Hb has focused on the role of the LHb in regulating midbrain dopamine release. However, LHb/MHb are also interconnected with the dorsal (DR) and median (MnR) raphe nucleus. Hence, it is conceivable that some of the habenular functions are at least partly mediated by the complex network that links MHb/LHb with pontomesencephalic monoaminergic nuclei. Here, we summarize research about the topography and transmitter phenotype of the reciprocal connections 66 | METZGER ET al. 1 | INTRODUCTION Major depressive disorder (MDD) is a multifaceted disorder (Belmaker & Agam, 2008; Pizzagalli, 2014) that affected about 322 million people worldwide in 2017 (World Health Organization/WHO, 2017). MDD is characterized by low mood, lack of motivation, feelings of despair, and anhedonia-a reduced ability to experience pleasure (Willner, Scheel-Kruger, & Belzung, 2013). Importantly, MDD is highly comorbid with anxiety and addictive disorders (Swendsen et al., 2010), and it has been postulated that these disorders are closely related, as they are all characterized in part by disarrangements in the reward circuitry (Eshel & Roiser, 2010; Russo & Nestler, 2013). A relative new player in the pathogenesis of MDD, as well as in the reward circuitry, is the habenula (Hb), which interestingly now is considered not only to be involved in aversive mood states such as MDD and anxiety (

The laterodorsal tegmental nucleus (LDTg) is a hindbrain cholinergic cell group thought to be involved in mechanisms of arousal and the control of midbrain dopamine cells. Nowadays, there is increasing evidence that LDTg is also engaged in mechanisms of anxiety/fear and promotion of emotional arousal under adverse conditions. Interestingly, LDTg appears to be connected with other regulators of aversive motivational states, including the lateral habenula (LHb), medial habenula (MHb), interpeduncular nucleus (IP), and median raphe nucleus (MnR). However, the circuitry between these structures has hitherto not been systematically investigated. Here, we placed injections of retrograde or anterograde tracers into LDTg, LHb, IP, and MnR.We also examined the transmitter phenotype of LDTg afferents to IP by combining retrograde tracing with immunofluorescence and in situ hybridization techniques.We found LHb inputs to LDTg mainly emerging from the medial division of the LHb (LHbM), which also receives axonal input from LDTg. The bidirectional connections between IP and LDTg displayed a lateralized organization, with LDTg inputs to IP being predominantly GABAergic or cholinergic and mainly directed to the contralateral IP. Moreover, we disclosed reciprocal LDTg connections with structures involved Abbreviations: 3V, third ventricle; 4V, fourth ventricle; 4n, trochlear nerve; A13, A13 dopamine cell group; ac, anterior commissure; AcbRP, nucleus accumbens, rostral pole; AD, anterodorsal thalamic nucleus; AID, agranular insular cortex, dorsal part; AIV, agranular insular cortex, ventral part; AM, anteromedial thalamic nucleus; BAC, bed nucleus of the anterior commissure; BST, bed nucleus of the stria terminalis; Cg1, cingulate cortex 1in the modulation of hippocampal theta rhythm including MnR, nucleus incertus, and supramammillary nucleus. Our findings indicate that the habenula is linked with LDTg either by direct reciprocal projections from/to LHbM or indirectly via the MHb-IP axis, supporting a functional role of LDTg in the regulation of aversive behaviors, and further characterizing LHb as a master controller of ascending brainstem state-setting modulatory projection systems.

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Anatomical and functional evidence suggests that the PFC is fairly unique among all cortical regions, as it not only receives input from, but also robustly projects back to mesopontine monoaminergic and cholinergic cell groups. Thus the PFC is in a position to exert a powerful top-down control over several state setting modulatory transmitter systems that are critically involved in the domains of arousal, motivation, reward/aversion, working memory, mood regulation, and stress processing. Regarding this scenario, the origin of cortical afferents to the ventral tegmental area (VTA), laterodorsal tegmental nucleus (LDTg), and median raphe nucleus (MnR) was here compared, by using the retrograde tracer cholera toxin subunit b (CTb). CTb injections into VTA, LDTg, or MnR produced retrograde labeling in the cortical mantle, which was mostly confined to medial, orbital, and lateral PFC subdivisions, along with rostral and mid-cingulate areas. Remarkably, in all of the three groups, retrograde labeling was densest in layer V pyramidal neurons of the infralimbic, prelimbic, medial orbital and frontal polar cortex. Moreover, a conspicuous lambda-shaped region around the apex of the rostral pole of the nucleus accumbens stood consistently out as heavily labeled. At almost all rostrocaudal levels through the PFC analyzed, retrograde labeling was strongest following injections into MnR and weakest following injections into VTA. Altogether, our findings reveal a broadly similar set of prefrontal afferents to VTA, LDTg, and MnR, further supporting an eminent functional role of the PFC as a controller of all major state setting mesopontine modulatory transmitter systems.

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