Handa Takehisa, Sugiyama Taku, Islam Tanvir, Johansen Joshua P, Yanagawa Yuchio, McHugh Thomas J, Okamoto Hitoshi
Laboratory for Neural Circuit Dynamics of Decision Making, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
Laboratory of Molecular Neuroscience, Medical Research Institute, Institute of Science Tokyo (formerly Tokyo Medical and Dental University), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Mol Psychiatry. 2025 Mar 26. doi: 10.1038/s41380-025-02964-8.
The medial habenula (MHb) and its projection target, the interpeduncular nucleus (IPN), are highly conserved throughout vertebrate evolution. The MHb-IPN pathway connects the limbic system to the brainstem, consisting of subpathways that project in a topographically organized manner, and has been implicated in the regulation of fear and anxiety. Previous studies have revealed subregion-specific functions of the cholinergic ventral MHb and a substance P (SP)-positive (SP) subpart of the dorsal MHb (dMHb). In contrast, the dMHb also contains another subpart, a SP-negative subpart known as the 'superior part of MHb (MHbS)'. Although the MHbS has been characterized from various aspects, e.g. distinct c-Fos responses to stressful events and electrophysiological properties compared to other subregions, many of its physiological functions remain to be investigated. Here we found that dopamine receptor D3 (DRD3)-Cre mice enable the labeling of the IPN subregion that receives the MHbS projection. The Cre-expressing somata within the lateral subnucleus of the IPN (LIPN) were concentrated in its most lateral area, which we refer to as the 'lateral subregion of the LIPN (lLIPN)'. This region is characterized by the absence of SP axons, in contrast to the medial subregion of the LIPN (mLIPN) innervated by the SP axons from the dorsal MHb. Chemogenetic activation and genetically induced synaptic silencing of the DRD3-Cre cells reduced and enhanced anxiety-like behavior, respectively. Moreover, c-Fos expression was increased in the lLIPN under an anxiogenic environment. These findings suggest that the MHbS-lLIPN pathway is activated under anxiogenic environments to counteract anxiety.
内侧缰核（MHb）及其投射靶点脚间核（IPN）在整个脊椎动物进化过程中高度保守。MHb-IPN通路将边缘系统与脑干相连，由以拓扑学方式组织投射的子通路组成，并与恐惧和焦虑的调节有关。先前的研究已经揭示了胆碱能腹侧MHb以及背侧MHb（dMHb）中物质P（SP）阳性（SP）亚部分的亚区域特异性功能。相比之下，dMHb还包含另一个亚部分，即称为“MHb上部（MHbS）”的SP阴性亚部分。尽管已经从各个方面对MHbS进行了表征，例如与其他亚区域相比，对压力事件有不同的c-Fos反应和电生理特性，但其许多生理功能仍有待研究。在这里，我们发现多巴胺受体D3（DRD3）-Cre小鼠能够标记接受MHbS投射的IPN亚区域。IPN外侧亚核（LIPN）内表达Cre的胞体集中在其最外侧区域，我们将其称为“LIPN外侧亚区域（lLIPN）”。与由来自背侧MHb的SP轴突支配的LIPN内侧亚区域（mLIPN）相反，该区域的特征是没有SP轴突。对DRD3-Cre细胞进行化学遗传激活和基因诱导的突触沉默分别减少和增强了焦虑样行为。此外，在致焦虑环境下，lLIPN中的c-Fos表达增加。这些发现表明，在致焦虑环境下，MHbS-lLIPN通路被激活以对抗焦虑。
