Specific connections of the interpeduncular subnuclei reveal distinct components of the habenulopeduncular pathway

Abstract

The habenulopeduncular pathway consists of the medial habenula (MHb), its output tract, the fasciculus retroflexus, and its principal target, the interpeduncular nucleus (IP). Several IP subnuclei have been described, but their specific projections and relationship to habenula inputs are not well understood. Here we have used viral, transgenic, and conventional anterograde and retrograde tract-tracing methods to better define the relationship between the dorsal and ventral MHb, the IP, and the secondary efferent targets of this system. Although prior studies have reported that the IP has ascending projections to ventral forebrain structures, we find that these projections originate almost entirely in the apical subnucleus, which may be more appropriately described as part of the median raphe system. The laterodorsal tegmental nucleus receives inhibitory inputs from the contralateral dorsolateral IP, and mainly excitatory inputs from the ipsilateral rostrolateral IP subnucleus. The midline central gray of the pons and nucleus incertus receive input from the rostral IP, which contains a mix of inhibitory and excitatory neurons, and the dorsomedial IP, which is exclusively inhibitory. The lateral central gray of the pons receives bilateral input from the lateral IP, which in turn receives bilateral input from the dorsal MHb. Taken together with prior studies of IP projections to the raphe, these results form an emerging map of the habenulopeduncular system that has significant implications for the proposed function of the IP in a variety of behaviors, including models of mood disorders and behavioral responses to nicotine.

Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

“…Recent work characterized the downstream targets of the MHb-IPN pathway and show that serotonergic raphe nuclei receive dense innervation from vMHbinnervated IPN neurons (Quina et al 2017). The MHb also densely expresses the 5-HT3A, -4, -5A and -5B receptors, suggesting that it receives serotonergic inputs, potentially from the same raphe-serotonergic population receiving innervation from the IPN (Filip et al 2004;Ichikawa et al 2005;Wagner et al 2014).…”

“…The dMHb and vMHb send strong projections to distinct subnuclei within the predominantly GABAergic interpeduncular nucleus (IPN), which, in turn, regulates serotonergic signaling from the raphe nuclei (Han et al 2017;Quina et al 2017). In contrast, the lateral habenula negatively regulates dopamine signaling primarily through projections to GABAergic interneurons within the rostral medial tegmental gray (Ji & Shepard 2007;Stamatakis & Stuber 2012).…”

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

“…IP is composed of several subnuclei (Lenn & Hamill, ) that receive dense topographically organized inputs from MHb via the fasciculus retroflexus (Contestabile et al, ; Qin & Luo, ; Quina, Wang, Ng, & Turner, ). Interestingly, the MHb‐IP axis (Agetsuma et al, ; Koppensteiner, Melani, & Ninan, ; Molas, DeGroot, Zhao‐Shea, & Tapper, ; Yamaguchi, Danjo, Pastan, Hikida, & Nakanishi, ; Zhang et al, ) and some of its major downstream targets, such as the LDTg and MnR (Lima et al, ; Quina, Harris, Zeng, & Turner, ), have now also been identified as regulators of fear and anxiety‐like behaviors (Amo et al, ; Andrade, Zangrossi Jr., & Graeff, 2013; Borges et al, ; Teissier et al, ; Wolfman et al, ; Yang et al, ).…”

Conexôes aferentes e eferentes do núcleo interpeduncular com enfoque especial para os circuitos entre a habênula, o núcleo interpeduncular e os núcleos da rafe.

“…As massivas entradas da MHb percorrem o fascículo retroflexo (fr) e terminam de uma maneira bastante peculiar no IP (HERKENHAM; SUTHERLAND, 1982;KIM;2009). A intrigante topografia e assinatura neuroquímica dessas entradas tem sido descritas detalhadamente em ratos (CONTESTABILE et al, 1987) e camundongos (QIN; LUO, 2009;HSU et al, 2013;GARDON et al 2014;QUINA et al, 2017). Assim, os axônios que originam da parte dorsal da MHb (MHbD) usam glutamato e substância P como neurotransmissor e inervam seletivamente o IPL e o teto dorsal do IP, enquanto os axônios oriundos da parte ventral da MHb (MHbV) co-liberam glutamato e acetilcolina nos restantes subnúcleos do IP (REN et al, 2011;FRAHM et al, 2015).…”

“…Ademais, a maioria dos axônios oriundos da MHb atravessa o IP várias vezes num plano horizontal antes de terminar ipsilateralmente (HERKENHAM; NAUTA, 1979;KIM, 2009). Com relação a sua própria neuroquímica, o IP contém essencialmente neurônios GABAérgicos, além de uma minoria de neurônios glutamatérgicos (QUINA et al, 2017). Outros estudos pioneiros usando técnicas de imunoistoquímica e rastreamento neural (CONTESTABILE; FLUMERFELT, 1981;GROENEWEGEN et al, 1986;SHIBATA;SUZUKI;MATSUSHITA, 1986) Em relação as suas funções, o IP foi contextualizado como um dos principais alvos do sistema de condução diencefálica dorsal (DDC; SUTHERLAND, 1982).…”