Nestler E J, Kelz M B, Chen J
Laboratory of Molecular Psychiatry and Center for Genes and Behavior Yale University School of Medicine and Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06508, USA.
Brain Res. 1999 Jul 17;835(1):10-7. doi: 10.1016/s0006-8993(98)01191-3.
DeltaFosB, a member of the Fos family of transcription factors, is derived from the fosB gene via alternative splicing. Just as c-Fos and many other Fos family members are induced rapidly and transiently in specific brain regions in response to many types of acute perturbations, novel isoforms of DeltaFosB accumulate in a region-specific manner in brain uniquely in response to many types of chronic perturbations, including repeated administration of drugs of abuse or of antidepressant or antipsychotic treatments. Importantly, once induced, these DeltaFosB isoforms persist in brain for relatively long periods due to their extraordinary stability. Mice lacking the fosB gene show abnormal biochemical and behavioral responses to chronic administration of drugs of abuse or antidepressant treatments, consistent with an important role for DeltaFosB in mediating long-term adaptations in the brain. More definitive evidence to support this hypothesis has recently been provided by inducible transgenic mice, wherein biochemical and behavioral changes, which mimic the chronic drug-treated state, are seen upon overexpression of DeltaFosB in specific brain regions. This evolving work supports the view that DeltaFosB functions as a type of 'molecular switch' that gradually converts acute responses into relatively stable adaptations that underlie long-term neural and behavioral plasticity to repeated stimuli.
DeltaFosB是转录因子Fos家族的成员之一，它通过可变剪接从fosB基因衍生而来。正如c-Fos和许多其他Fos家族成员在特定脑区对多种类型的急性扰动迅速且短暂地被诱导一样，DeltaFosB的新型异构体仅在对多种类型的慢性扰动（包括反复给予滥用药物、抗抑郁药或抗精神病药治疗）作出反应时，以区域特异性方式在脑中积累。重要的是，一旦被诱导，这些DeltaFosB异构体由于其非凡的稳定性而在脑中持续相对较长的时间。缺乏fosB基因的小鼠对长期给予滥用药物或抗抑郁药治疗表现出异常的生化和行为反应，这与DeltaFosB在介导大脑长期适应性方面的重要作用一致。最近，可诱导转基因小鼠提供了更确凿的证据来支持这一假设，在这些小鼠中，当DeltaFosB在特定脑区过表达时，会出现模拟长期药物治疗状态的生化和行为变化。这项不断发展的研究支持了这样一种观点，即DeltaFosB作为一种“分子开关”发挥作用，逐渐将急性反应转化为相对稳定的适应性变化，这些变化构成了对重复刺激的长期神经和行为可塑性的基础。
