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Abstract：
The habenulo-interpeduncular system (HIPS) is now recognized as a critical circuit modulating aversion, reward, and social behavior. There is evidence that dysfunction of this circuit leads to psychiatric disorders. Because psychiatric diseases may originate in developmental abnormalities, it is crucial to investigate the developmental mechanisms controlling the formation of the HIPS. Thus far, this issue has been the focus of limited studies. Here, we explored the developmental processes underlying the formation of the medial habenula (MHb) and its unique output, the interpeduncular nucleus (IPN), in mice independently of their gender. We report that the Otx2 homeobox gene is essential for the proper development of both structures. We show that MHb and IPN neurons require Otx2 at different developmental stages and, in both cases, Otx2 deletion leads to disruption of HIPS subcircuits. Finally, we show that Otx2+ neurons tend to be preferentially interconnected. This study reveals that synaptically connected components of the HIPS, despite radically different developmental strategies, share high sensitivity to Otx2 expression.SIGNIFICANCE STATEMENT Brain reward circuits are highly complex and still poorly understood. In particular, it is important to understand how these circuits form as many psychiatric diseases may arise from their abnormal development. This work shows that Otx2, a critical evolutionary conserved gene implicated in brain development and a predisposing factor for psychiatric diseases, is required for the formation of the habenulo-interpeduncular system (HIPS), an important component of the reward circuit. Otx2 deletion affects multiple processes such as proliferation and migration of HIPS neurons. Furthermore, neurons expressing Otx2 are preferentially interconnected. Therefore, Otx2 expression may represent a code that specifies the connectivity of functional subunits of the HIPS. Importantly, the Otx2 conditional knock-out animals used in this study might represent a new genetic model of psychiatric diseases.
摘要：
habenulo-peducular系统（HIPS）现在被认为是一种关键的电路调制厌恶，奖励,和社会行为。有证据表明该回路的功能障碍会导致精神疾病。因为精神疾病可能起源于发育异常，研究控制HIPS形成的发育机制至关重要。到目前为止,这个问题一直是有限研究的焦点。这里,我们探索了内囊（MHb）形成的基础发育过程及其独特的输出，椎间核（IPN），在小鼠中独立于其性别。我们报告说，Otx2同源盒基因对于两种结构的正确发育至关重要。我们表明MHb和IPN神经元在不同的发育阶段需要Otx2，在这两种情况下，Otx2删除导致HIPS子电路中断。最后,我们表明Otx2+神经元倾向于优先互连。这项研究揭示了HIPS的突触连接成分，尽管发展战略截然不同，共享Otx2表达式的高灵敏度。重要声明大脑奖励回路非常复杂，仍然知之甚少。特别是,重要的是要了解这些回路是如何形成的，因为许多精神疾病可能是由它们的异常发展引起的。这项工作表明，Otx2是与大脑发育有关的关键进化保守基因，也是精神疾病的诱发因素，是形成habenulo-peducular系统（HIPS）所必需的，奖励电路的重要组成部分。Otx2缺失影响HIPS神经元的增殖和迁移等多个过程。此外，表达Otx2的神经元优先互连。因此,Otx2表达式可以表示指定HIPS的功能子单元的连接性的代码。重要的是,本研究中使用的Otx2条件性敲除动物可能代表了一种新的精神疾病遗传模型。
