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Recent clinical neuroimaging studies have revealed a possible relationship between morphological brain changes and the manifestation of psychiatric disorders such as depression, schizophrenia, and alcoholism. Although its biological mechanism is still unclear, the emerging evidence suggests that the alteration of neurogenesis is the key factor for the morphological brain changes of these psychiatric disorders. In our previous work, we analyzed the mechanism of neural network disruption by ethanol using cultured cells, and found a suppressive effect of ethanol on neural stem cell (NSC) differentiation. While, we also demonstrated that antidepressants, mood stabilizers and atypical antipsychotics stimulate NSC differentiation which was inhibited by ethanol. In the present work, we have demonstrated that the usefulness of intravenous transplantation of NSCs to fetal alcohol spectrum disorder (FASD) model rat for the purpose of reconstructing the impaired neural network and investigating the possibility of regenerative therapy for patients with neurobehavioral deficits of FASD. We have shown the potential migration of transplanted NSCs into the brain by visualizing a fluorescent cell marker and radioisotope, as well as the possible recovery of behavioral abnormalities observed in FASD model rats, such as memory/cognitive function, and social interaction. We further assessed the characteristics of transplanted cells in the brain and found that the GABAergic interneurons were increased in amygdale, DG, cingulated cortex areas in the model rat. In the amygdala and cingulate Cortex of model rats, number of parvalbumin positive cells was reduced and the NSC transplantation recovered these disturbances. Moreover, in the amygdala and cingulate cortex, intravenous NSC transplantation appears to regenerate expression of post-synaptic density protein 95 (PSD95) in FASD model rats. These results indicate that intravenous NSC transplantation has the potential to become a therapeutic intervention for FASD patients.

Ethanol exposure during gestation can have devastating consequences on the developing organism. Children who have a history of prenatally exposure to ethanol may show morphological and functional alterations, referred to as fetal alcohol spectrum disorders (FASD). Fetal alcohol syndrome (FAS), which is characterized by pre- and postnatal growth deficiency, specific cranial/facial features, and dysfunction of central nervous system, is the most severe end of FASD. FAS or FASD children are known to suffer from disturbance of sleep and/or food intake behaviors. These neuropsychiatric symptoms may be due to impairment of the system regulating circadian rhythms. Recently, animal studies revealed that ethanol exposure during brain development can cause alterations in the circadian rhythm and its regulating system. We examined the effects of pre- or postnatal exposure to ethanol on the circadian rhythm in adulthood by measuring deep body temperature and wheel running activity in rats. After a phase delay in the light/dark cycle, ethanol-exposed rats took longer than control rats to resynchronize to the new light/dark cycle. These results suggest that both pre- and postnatal ethanol exposure impair the development of the circadian clock response to light cue. Because abnormal development of the circadian clock system might contribute to the neuropsychiatric symptoms seen in FASD, it is believed that normalizing the disturbed rhythm improves the symptoms. However, the mechanisms of dysfunction and potential interventions for disturbance of circadian clock system still remain to be elucidated. Further investigations are required to fully understand long-term effects of ethanol on the development of circadian rhythms.

This is the first report of an adult patients with the fetal alcohol syndrome (FAS) in Japan, who was treated for psychiatric disorders. The case was a 35 years-old woman who had many neuropsychiatric symptoms. She had been treated for 15 years at the Kurihama Alcoholism Center, for mental retardation, schizophrenic symptoms, attention deficit hyperactivity disorder, learning disorder, trichotillomania, bipolar disorder, and impulsive behavior. She had low body weight at birth, mental retardation and a small facial malformation, which were diagnosed as FAS. At first admission, she was not diagnosed as FAS because her parent denied that her mother drank during pregnancy. Recently, her family admitted her mother's heavy drinking during pregnancy, and we diagnosed her as having FAS. She showed many pathological symptoms of the central nervous system such as very lower scores for performance IQ than for verbal IQ in the WAIS-R and enlargement of the lateral ventricle on MRI. Recently many reports have mentioned that prenatal alcohol exposure brings about severe damage of the central nervous system. Therefore, one author proposes that such disorders are referred to as fetal alcohol spectrum disorders (FASD). This patient showed many symptoms of FASD, and was difficult to treat because of these symptoms.