Cell cultures prepared from oligodendrocytes directly obtained from adult rat brain are composed of mature cells that lose their cell processes and myelin membrane during their isolation and therefore represent a very useful model to investigate the factors that could stimulate their recovery. We have observed that mature oligodendrocytes isolated from adult animals remain as round cells that lack processes for the first 3-4 days in culture. At the end of this lag period, however, the majority of the adult oligodendrocytes show a remarkable recovery, rapidly growing complex and extensive cell processes. Interestingly, the end of this lag period is accompanied by a dramatic upregulation in the expression of thyroid hormone (T(3)) receptor (TR). The functional importance of this increase in TR levels is supported by the observation that the majority of the cells cultured in the presence of T(3) show significantly more extensive and complex process outgrowth than the control cells in cultures lacking this hormone. In addition, this reactivation of the adult cells was also preceded by an increased expression of glucocorticoid receptor (GR) and cyclic AMP-response element binding protein (CREB), two transcription factors that together with TR appear to play important roles in the control of neonatal oligodendrocyte development. Thus, it is possible to hypothesize that upregulation of these proteins may be part of the metabolic changes that occur during the lag period required for recovery of the adult oligodendrocytes. These observations raise the question of whether these transcription factors may play any significant role during remyelination after demyelinating lesions of adult CNS.