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

Debora Bueno, Leandro B Lima, Rudieri Souza, Luciano Gonçalves, Fernanda Leite, Stefani Souza, Isadora C Furigo, Jose Donato, Martin Metzger

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17 Citations (Scopus)


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 in 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.

Original languageEnglish
Pages (from-to)3046-3072
Number of pages27
JournalThe Journal of comparative neurology
Issue number18
Early online date14 Jun 2019
Publication statusPublished - 15 Dec 2019
Externally publishedYes

Bibliographical note

© 2019 Wiley Periodicals, Inc.


  • anxiety
  • arousal
  • aversion
  • median raphe nucleus
  • nucleus incertus
  • prefrontal cortex
  • RRID: AB_2313636
  • RRID: AB_726860
  • RRID: AB_2315137
  • RRID: AB_2315136
  • RRID: AB_572263
  • RRID: AB_11214092
  • RRID: AB_2187832
  • RRID: AB_572268


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