Gadd45b is a neural activity-induced immediate early gene in mature hippocampal neurons that promotes epigenetic DNA demethylation and adult neurogenesis. Mice lacking Gadd45b show deficits in neural progenitor proliferation and dendritic growth of newborn neurons in the adult hippocampus. Mechanistically, Gadd45b is required for activity-induced DNA demethylation of specific promoters and expression of genes critical for adult neurogenesis, including brain-derived neurotrophic factor (Bdnf) and fibroblast growth factor (Fgf-1). Thus, Gadd45b links neuronal circuit activity to epigenetic DNA modification and expression of secreted factors in mature neurons for extrinsic modulation of neurogenesis in the adult brain. Adult neurogenesis represents a prominent form of structural plasticity through continuous generation of new neurons in the mature mammalian brain. It is modulated by a plethora of external stimuli, including synchronized activation of mature dentate neurons by electro-convulsive treatment (ECT), which causes sustained up-regulation of hippocampal neurogenesis without any detectable cell damage. Epigenetic mechanisms potentially provide a basis for such long-lasting modulation. We examined the expression profiles of known epigenetic regulators in response to ECT, including those involved in chromatin modification. One gene strongly induced by ECT was Gadd45b, a member of the Gadd45 family previously implicated in DNA repair, adaptive immune response, and DNA 5-methylcytosine excision in cultured cells. We first characterized Gadd45b induction by neuronal activity in the adult hippocampus. Analysis of microdissected dentate gyrus tissue showed robust, transient induction of Gadd45b expression by a single ECT. In situ analysis revealed induction largely in NeuN⁺ mature dentate granule cells. Spatial exploration of a novel environment, a behavioral paradigm that activates immediate early genes (IEGs), also led to significant induction of Gadd45b, but not Gadd45a or Gadd45g. Most Gadd45b-positive cells also expressed Arc, a classic activity-induced IEG. Thus, physiological stimulation is sufficient to induce Gadd45b expression in dentate granule cells. Experiments with pharmacological manipulations of primary hippocampal neurons further suggested that Gadd45b induction by activity requires the N-methyl-D-aspartate receptor (NMDAR), Ca²⁺, and calcium/calmodulin-dependent protein kinase signaling. In vivo injection of the NMDAR antagonist CPP abolished ECT-induced Gadd45b and Arc expression in the adult dentate gyrus. Together, these results suggest that Gadd45b shares the same induction pathway as classic activity-induced IEGs. We next assessed whether Gadd45b induction is required for neural activity-dependent adult neurogenesis. Adult Gadd45b knockout (KOGadd45b is a neural activity-induced immediate early gene in mature hippocampal neurons that promotes epigenetic DNA demethylation and adult neurogenesis. Mice lacking Gadd45b show deficits in neural progenitor proliferation and dendritic growth of newborn neurons in the adult hippocampus. Mechanistically, Gadd45b is required for activity-induced DNA demethylation of specific promoters and expression of genes critical for adult neurogenesis, including brain-derived neurotrophic factor (Bdnf) and fibroblast growth factor (Fgf-1). Thus, Gadd45b links neuronal circuit activity to epigenetic DNA modification and expression of secreted factors in mature neurons for extrinsic modulation of neurogenesis in the adult brain. Adult neurogenesis represents a prominent form of structural plasticity through continuous generation of new neurons in the mature mammalian brain. It is modulated by a plethora of external stimuli, including synchronized activation of mature dentate neurons by electro-convulsive treatment (ECT), which causes sustained up-regulation of hippocampal neurogenesis without any detectable cell damage. Epigenetic mechanisms potentially provide a basis for such long-lasting modulation. We examined the expression profiles of known epigenetic regulators in response to ECT, including those involved in chromatin modification. One gene strongly induced by ECT was Gadd45b, a member of the Gadd45 family previously implicated in DNA repair, adaptive immune response, and DNA 5-methylcytosine excision in cultured cells. We first characterized Gadd45b induction by neuronal activity in the adult hippocampus. Analysis of microdissected dentate gyrus tissue showed robust, transient induction of Gadd45b expression by a single ECT. In situ analysis revealed induction largely in NeuN⁺ mature dentate granule cells. Spatial exploration of a novel environment, a behavioral paradigm that activates immediate early genes (IEGs), also led to significant induction of Gadd45b, but not Gadd45a or Gadd45g. Most Gadd45b-positive cells also expressed Arc, a classic activity-induced IEG. Thus, physiological stimulation is sufficient to induce Gadd45b expression in dentate granule cells. Experiments with pharmacological manipulations of primary hippocampal neurons further suggested that Gadd45b induction by activity requires the N-methyl-D-aspartate receptor (NMDAR), Ca²⁺, and calcium/calmodulin-dependent protein kinase signaling. In vivo injection of the NMDAR antagonist CPP abolished ECT-induced Gadd45b and Arc expression in the adult dentate gyrus. Together, these results suggest that Gadd45b shares the same induction pathway as classic activity-induced IEGs. We next assessed whether Gadd45b induction is required for neural activity-dependent adult neurogenesis. Adult Gadd45b knockout (KO