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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.

Developmental Requirement of Homeoprotein Otx2 for Specific Habenulo-Interpeduncular Subcircuits