The neural crest is a unique structure in vertebrates. Wnt1-cre and Wnt1-GAL4 double transgenic (dTg) mice have been used in a variety of studies concerning neural crest cell lineages in which the Cre/loxP or GAL4/UAS system is applied. Here, we show psychiatric disorder-related behavioral abnormalities and histologic alterations in a neural crest-derived brain region in dTg mice. The dTg mice exhibited increased locomotor activity, decreased social interaction, impaired short-term spatial memory and nesting behavior, and hypersensitivity to sound. The choline acetyltransferase- and vesicular glutamate transporter 2-immunoreactive habenulointerpeduncular fiber tracts that project from the medial habenular nucleus of the epithalamus to the interpeduncular nucleus of the midbrain tegmentum appeared irregular in the dTg mice. Also, the inferior colliculus (IC) in the dTg mice is dilated in appearance. Either of the medial habenula nucleus, the interpeduncular nucleus and IC was confirmed to be derived from the neural crest. The findings of the present study suggest that neural crest-derived cells have pathogenic roles in the development of psychiatric disorders and that the dTg mouse could be a useful animal model for studying the pathophysiology of mental illness such as autism and schizophrenia. Scientists that use the dTg mice as a cre-transgenic deleter line should be cautious in its possible toxicity, especially if behavioral analyses are to be performed.