Three-Dimensional Analysis of Mouse Habenula Subnuclei Reveals Reduced Volume and Gene Expression in the Lipopolysaccharide-mediated Depression Model

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脑部的僵核核团由内侧僵核（MHb）和外侧僵核（LHb）组成。许多研究都强调了LHb与抑郁的关系，而关注MHb的研究较少。近年来关注MHb的研究开始增多，MHb在形态与功能上都与脚间核（IPN）相关联。MHb-IPN通路在调节脑的高级功能（如认知、奖励、做决定）中起重要的作用。这表明MHb在抑郁发病机理中起着作用。本文主要就是研究MHb-IPN通路在抑郁中的作用。在慢性不可预知轻度应激压力模型（CUMS）暴露的大鼠中，MHb的代谢活性增加。暴露于CUMS的大鼠的MHb损伤逆转了类似快感缺乏的行为（糖水测试中），并显着下调了增加的IPN代谢活动。MHb中含有P物质（SP）的神经元可支配IPN，并且是IPN中SP的主要来源。暴露于CUMS的大鼠IPN组织中SP含量增加，MHb损伤逆转了这一变化。在体外实验中，放电速率记录显示SP灌注增加了IPN神经元的活性。本文的研究结果主要表明了MHb-IPN环路的极度活跃参与到了抑郁的快感缺失样行为中，而P物质介导了MHb对IPN神经元的作用。

The habenula (Hb) is small but important brain structure, anatomically and functionally links the forebrain with the midbrain to modulate various neuropsychiatric functions associated with drug addiction and emotion-associated dysfunctions. Several reports suggested that the dysfunction of Hb-related functions affected the Hb structurally and functionally. However, the technical limitation has awaited the solid conclusion of whether Hb change due to depression is likely to occur in certain subnuclei of the Hb. To probe this possibility, we developed 3-dimensional reconstruction methods for the high-resolution volumetric analysis of Hb and the mRNA levels at the given volume in normal or lipopolysaccharide (LPS)-mediated mouse model of depression. Notably, we discovered that the volume reduction was prominent in medial Hb but not in lateral Hb after LPS treatments. On the other hand, the RNA expression levels of known Hb regional markers such as Tac1 (dorsal part of medial Hb), ChAT (ventral part of medial Hb), and Tacr1 (medial and lateral Hb) were all decreased in all Hb subnuclei in LPS-injected mice. Accordingly, accurate volumetry with marker labeling was not feasible. Collectively, these established 3D analyses of mouse Hb successfully and precisely determine the volume-based changes of small brain structure, which should be applicable in a wider range of mouse models or pathological specimens.

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