Inter-hemispheric somatosensory coherence and parental stress in hypersensitivity at 8 months old: An electroencephalography study.

OBJECTIVE: Infant hypersensitivity affects daily challenges and parental stress. Although the crucial role of tactile sensation in infants' brain function has been highlighted, hypersensitive infants and their families lack support. Electroencephalography may be useful for understanding hypersensitivity traits. We investigated the relationship between infant perceptual hypersensitivity and parental stress, somatosensory-evoked potential (SEP), and magnitude-squared coherence (MSC) in the general population. METHODS: Infants aged 8 months (n = 63) were evaluated for hypersensitivity and parental stress using a questionnaire and for cortical activity using electroencephalography. Vibration stimuli were applied to the infant's left foot. SEP components that peaked around 150 ms (N2) and at 200 ms (P2) after stimulus onset were evaluated by amplitude and latency at the midline electrode (Cz) and MSC between the midline electrodes (C3-C4). RESULTS: Parental stress was associated with infant hypersensitivity. The latency of Cz was delayed, and C3-C4 delta MSC was high in infants with hypersensitivity. CONCLUSIONS: Increasing inter-hemispheric MSC synchrony in the stimulated condition in infants with hypersensitivity suggested atypical somatosensory cortical function. SIGNIFICANCE: These findings contribute to identifying, understanding the mechanisms of, and developing effective coping strategies for early-stage hypersensitivity.

Explainable Machine Learning Classification to Identify Vulnerable Groups Among Parenting Mothers: Web-Based Cross-Sectional Questionnaire Study.

BACKGROUND: One life event that requires extensive resilience and adaptation is parenting. However, resilience and perceived support in child-rearing vary, making the real-world situation unclear, even with postpartum checkups. OBJECTIVE: This study aimed to explore the psychosocial status of mothers during the child-rearing period from newborn to toddler, with a classifier based on data on the resilience and adaptation characteristics of mothers with newborns. METHODS: A web-based cross-sectional survey was conducted. Mothers with newborns aged approximately 1 month (newborn cohort) were analyzed to construct an explainable machine learning classifier to stratify parenting-related resilience and adaptation characteristics and identify vulnerable populations. Explainable k-means clustering was used because of its high explanatory power and applicability. The classifier was applied to mothers with infants aged 2 months to 1 year (infant cohort) and mothers with toddlers aged >1 year to 2 years (toddler cohort). Psychosocial status, including depressed mood assessed by the Edinburgh Postnatal Depression Scale (EPDS), bonding assessed by the Postpartum Bonding Questionnaire (PBQ), and sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI) between the classified groups, was compared. RESULTS: A total of 1559 participants completed the survey. They were split into 3 cohorts, comprising populations of various characteristics, including parenting difficulties and psychosocial measures. The classifier, which stratified participants into 5 groups, was generated from the self-reported scores of resilience and adaptation in the newborn cohort (n=310). The classifier identified that the group with the greatest difficulties in resilience and adaptation to a child's temperament and perceived support had higher incidences of problems with depressed mood (relative prevalence [RP] 5.87, 95% CI 2.77-12.45), bonding (RP 5.38, 95% CI 2.53-11.45), and sleep quality (RP 1.70, 95% CI 1.20-2.40) compared to the group with no difficulties in perceived support. In the infant cohort (n=619) and toddler cohort (n=461), the stratified group with the greatest difficulties had higher incidences of problems with depressed mood (RP 9.05, 95% CI 4.36-18.80 and RP 4.63, 95% CI 2.38-9.02, respectively), bonding (RP 1.63, 95% CI 1.29-2.06 and RP 3.19, 95% CI 2.03-5.01, respectively), and sleep quality (RP 8.09, 95% CI 4.62-16.37 and RP 1.72, 95% CI 1.23-2.42, respectively) compared to the group with no difficulties. CONCLUSIONS: The classifier, based on a combination of resilience and adaptation to the child's temperament and perceived support, was able identify psychosocial vulnerable groups in the newborn cohort, the start-up stage of childcare. Psychosocially vulnerable groups were also identified in qualitatively different infant and toddler cohorts, depending on their classifier. The vulnerable group identified in the infant cohort showed particularly high RP for depressed mood and poor sleep quality.

Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension.

Down syndrome (DS) is the most prevalent chromosomal disorder associated with a higher incidence of pulmonary arterial hypertension (PAH). The dysfunction of vascular endothelial cells (ECs) is known to cause pulmonary arterial remodeling in PAH, although the physiological characteristics of ECs harboring trisomy 21 (T21) are still unknown. In this study, we analyzed the human vascular ECs by utilizing the isogenic pairs of T21-induced pluripotent stem cells (iPSCs) and corrected disomy 21 (cDi21)-iPSCs. In T21-iPSC-derived ECs, apoptosis and mitochondrial reactive oxygen species (mROS) were significantly increased, and angiogenesis and oxygen consumption rate (OCR) were significantly impaired as compared with cDi21-iPSC-derived ECs. The RNA-sequencing identified that EGR1 on chromosome 5 was significantly upregulated in T21-ECs. Both EGR1 suppression by siRNA and pharmacological inhibitor could recover the apoptosis, mROS, angiogenesis, and OCR in T21-ECs. Alternately, the study also revealed that DYRK1A was responsible to increase EGR1 expression via PPARG suppression, and that chemical inhibition of DYRK1A could restore the apoptosis, mROS, angiogenesis, and OCR in T21-ECs. Finally, we demonstrated that EGR1 was significantly upregulated in the pulmonary arterial ECs from lung specimens of a patient with DS and PAH. In conclusion, DYRK1A/PPARG/EGR1 pathway could play a central role for the pulmonary EC functions and thus be associated with the pathogenesis of PAH in DS.

Prediction scores based on neonatal inflammatory markers for chorioamnionitis and funisitis in extremely low gestational age neonates.

AIM: The aim of the study was to examine the predictive value of inflammatory markers for chorioamnionitis and funisitis in extremely low gestational age neonates. METHODS: According to the Redline histopathological classification, extremely low gestational age neonates were classified into: (1) maternal inflammatory response ≤1 or ≥2, based on inflammatory findings of the placenta and (2) foetal inflammatory response ≤1 or ≥2, based on inflammatory findings of the umbilical cord. On admission and 12-36 h postnatally, procalcitonin and high-sensitivity C-reactive protein levels and white blood cell and neutrophil counts were compared. For both maternal and foetal inflammatory responses ≥2, the predictive value of each inflammatory marker was calculated. RESULTS: On admission, procalcitonin had the best predictive value for maternal and foetal inflammatory response ≥2. The maternal inflammatory response ≥2 prediction score includes procalcitonin level on admission, high-sensitivity C-reactive protein level and white blood cell count at 12-36 h postnatally. Foetal inflammatory response ≥2 prediction score includes procalcitonin level and white blood cell count on admission and 12-36 h postnatally. The sensitivities were 96.4% and 96.3%, respectively. CONCLUSION: Procalcitonin, high-sensitivity C-reactive protein levels and white blood cell count provide highly sensitive prediction scores for chorioamnionitis and funisitis in extremely low gestational age neonates.

An International Aircraft Transport of a Neonate From Georgia to Japan.

International air transport over long distances necessitates considerable effort. It is even more challenging when the patient is a neonate and has a congenital disease. We hereby report a case of an international aircraft transport of a neonate from Tbilisi, Georgia to Osaka, Japan. The patient was transported to Osaka University Hospital after being diagnosed with a double outlet right ventricle (DORV), requiring surgical intervention. This unique experience has raised four issues: 1) language issues for referral and consultation; 2) medical equipment and healthcare professionals required to accompany the transport for adequate care; 3) scheduling of the international flight; and 4) the administrative procedures such as birth certificate, passport, and healthcare insurance. In this report, we describe how the patient was successfully transported, received treatment, and discharged home.

Experimental method for haplotype phasing across the entire length of chromosome 21 in trisomy 21 cells using a chromosome elimination technique.

Modern sequencing technologies produce a single consensus sequence without distinguishing between homologous chromosomes. Haplotype phasing solves this limitation by identifying alleles on the maternal and paternal chromosomes. This information is critical for understanding gene expression models in genetic disease research. Furthermore, the haplotype phasing of three homologous chromosomes in trisomy cells is more complicated than that in disomy cells. In this study, we attempted the accurate and complete haplotype phasing of chromosome 21 in trisomy 21 cells. To separate homologs, we established three corrected disomy cell lines (ΔPaternal chromosome, ΔMaternal chromosome 1, and ΔMaternal chromosome 2) from trisomy 21 induced pluripotent stem cells by eliminating one chromosome 21 utilizing the Cre-loxP system. These cells were then whole-genome sequenced by a next-generation sequencer. By simply comparing the base information of the whole-genome sequence data at the same position between each corrected disomy cell line, we determined the base on the eliminated chromosome and performed phasing. We phased 51,596 single nucleotide polymorphisms (SNPs) on chromosome 21, randomly selected seven SNPs spanning the entire length of the chromosome, and confirmed that there was no contradiction by direct sequencing.

A human isogenic iPSC-derived cell line panel identifies major regulators of aberrant astrocyte proliferation in Down syndrome.

Astrocytes exert adverse effects on the brains of individuals with Down syndrome (DS). Although a neurogenic-to-gliogenic shift in the fate-specification step has been reported, the mechanisms and key regulators underlying the accelerated proliferation of astrocyte precursor cells (APCs) in DS remain elusive. Here, we established a human isogenic cell line panel based on DS-specific induced pluripotent stem cells, the XIST-mediated transcriptional silencing system in trisomic chromosome 21, and genome/chromosome-editing technologies to eliminate phenotypic fluctuations caused by genetic variation. The transcriptional responses of genes observed upon XIST induction and/or downregulation are not uniform, and only a small subset of genes show a characteristic expression pattern, which is consistent with the proliferative phenotypes of DS APCs. Comparative analysis and experimental verification using gene modification reveal dose-dependent proliferation-promoting activity of DYRK1A and PIGP on DS APCs. Our collection of human isogenic cell lines provides a comprehensive set of cellular models for further DS investigations.

Successful neurosurgical separation of conjoined spinal cords in pygopagus twins: illustrative cases.

BACKGROUND: Conjoined twins represent a rare congenital malformation. Pygopagus twins are fused at the sacrum and perineum, with union of the spine. The authors report a successful separation of a unique case of pygopagus twins sharing a U-shaped spinal cord, which the authors identified through aberrant nerves by intraoperative physiological spinal root examination. OBSERVATIONS: The 6-month-old male pygopagus conjoined twins, who were diagnosed in the prenatal period, underwent separation. They had a single dural sac containing a U-shaped continuous spinal cord; their filum terminale appeared completely fused and the anatomical border of the spinal cord was not distinguishable. A triggered electromyogram (tEMG) was used on each nerve root to determine which belonged to one twin versus the other, to detect nerve cross, and to identify functional midline cleavage. Finally, the twins were separated after spinal division. Both twins recovered uneventfully with no lower limb neurological deficits or walking impairment for 16 months. LESSONS: Pygopagus twins with a conjoined spinal cord are very rare, but a good long-term functional prognosis can be expected with successful separation. Intraoperative tEMG is useful in spinal separation surgery for twins with a conjoined spinal cord.

Prenatal clinical manifestations in individuals with COL4A1/2 variants.

BACKGROUND: Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. METHODS: We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. RESULTS: Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. CONCLUSIONS: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregates.

Individuals with Down syndrome (DS) commonly show unique pathological phenotypes throughout their life span. Besides the specific effects of dosage-sensitive genes on chromosome 21, recent studies have demonstrated that the gain of a chromosome exerts an adverse impact on cell physiology, regardless of the karyotype. Although dysregulated transcription and perturbed protein homeostasis are observed in common in human fibroblasts with trisomy 21, 18, and 13, whether and how this aneuploidy-associated stress acts on other cell lineages and affects the pathophysiology are unknown. Here, we investigated cellular stress responses in human trisomy 21 and 13 neurons differentiated from patient-derived induced pluripotent stem cells. Neurons of both trisomies showed increased vulnerability to apoptotic cell death, accompanied by dysregulated protein homeostasis and upregulation of the endoplasmic reticulum stress pathway. In addition, misfolded protein aggregates, comprising various types of neurodegenerative disease-related proteins, were abnormally accumulated in trisomic neurons. Intriguingly, treatment with sodium 4-phenylbutyrate, a chemical chaperone, successfully decreased the formation of protein aggregates and prevented the progression of cell apoptosis in trisomic neurons. These results suggest that aneuploidy-associated stress might be a therapeutic target for the neurodegenerative phenotypes in DS.

Successful management of fetal hemolytic disease due to strong anti-Rh17 with plasma exchange and intrauterine transfusion in a woman with the D-- phenotype.

The rare blood phenotype D-- is characterized by the absence of RhCcEe antigens. Women with this blood type who have experienced previous pregnancies may produce anti-Rh17 antibodies, which may cause severe fetal hemolytic anemia or fetal death in subsequent pregnancies. We report successful management of a pregnancy associated with fetal hemolytic disease owing to high titers of anti-Rh17 (1:4096) in a woman with a history of a pregnancy with fetal hydrops and intrauterine fetal death. During her second pregnancy, she received two sets of plasma exchange (PE) per week from weeks 12 till 20. Intrauterine transfusions (IUTs) were performed at 26, 27, 29, and 31 weeks. A male infant was born at 32 weeks and 4 days by normal vaginal delivery, with a birth weight of 1916 g (+ 0.16 SD). He received an exchange transfusion on day 0, immunoglobulin (intravenous immunoglobulin: 1 g/kg) on days 0 and 1, and photo therapy from days 0 to 6. He showed normal development without neurological abnormality and was discharged from the hospital on day 36. We successfully prevented complications caused by the presence of anti-Rh17 antibodies in the mother during pregnancy. The IUT and maternal PE may have promoted this favorable outcome.

Elimination of protein aggregates prevents premature senescence in human trisomy 21 fibroblasts.

Chromosome abnormalities induces profound alterations in gene expression, leading to various disease phenotypes. Recent studies on yeast and mammalian cells have demonstrated that aneuploidy exerts detrimental effects on organismal growth and development, regardless of the karyotype, suggesting that aneuploidy-associated stress plays an important role in disease pathogenesis. However, whether and how this effect alters cellular homeostasis and long-term features of human disease are not fully understood. Here, we aimed to investigate cellular stress responses in human trisomy syndromes, using fibroblasts and induced pluripotent stem cells (iPSCs). Dermal fibroblasts derived from patients with trisomy 21, 18 and 13 showed a severe impairment of cell proliferation and enhanced premature senescence. These phenomena were accompanied by perturbation of protein homeostasis, leading to the accumulation of protein aggregates. We found that treatment with sodium 4-phenylbutyrate (4-PBA), a chemical chaperone, decreased the protein aggregates in trisomy fibroblasts. Notably, 4-PBA treatment successfully prevented the progression of premature senescence in secondary fibroblasts derived from trisomy 21 iPSCs. Our study reveals aneuploidy-associated stress as a potential therapeutic target for human trisomies, including Down syndrome.

Genetic correction of induced pluripotent stem cells mediated by transcription activator-like effector nucleases targeting ALPL recovers enzyme activity and calcification in vitro.

Hypophosphatasia (HPP) is an inheritable disease affecting both skeletal systems and extra-skeletal organs due to mutations of the gene ALPL, which encodes tissue-nonspecific alkaline phosphatase. Recently, an enzyme replacement therapy using asfotase alfa was developed to ameliorate the complications of HPP. However, it requires frequent injections and is expensive to maintain. As an alternative, cell and gene therapy using human induced pluripotent stem cells (iPSCs) after precise correction of the mutation is feasible due to advances in genome-editing technology. In the study, we examined the alkaline phosphatase (ALP) activity and calcification in vitro of two childhood HPP patient-derived iPSCs after the correction of the c.1559delT mutation, which is the most frequent mutation in Japanese patients with HPP, using transcription activator-like effector nucleases (TALENs). The gene correction targeting vector was designed for site-directed mutagenesis using TALEN. After selection with antibiotics, some clones with the selection cassette were obtained. Gene correction was confirmed by Sanger sequencing. The mutation was corrected in one allele of ALPL in homozygous patients and compound heterozygous patients. The correction of ALPL did not result in an increase in ALP when the selection cassette remained. Conversely, iPSCs exhibited ALP activity after the elimination of the cassette using Cre/LoxP. The quantitative analysis showed the half ALP activity in corrected iPSCs of that of control iPSCs, corresponding to heterozygous correction of the mutation. In addition, osteoblasts differentiated from the corrected iPSCs exhibited high ALP activity and some calcification in vitro. Moreover, the osteoblast-like phenotype was confirmed by increased expression of osteoblast-specific genes such as COL1A1 and osteocalcin. These results suggest that gene correction in iPSCs may be a candidate treatment for HPP patients.

A Pair of Maternal Chromosomes Derived from Meiotic Nondisjunction in Trisomy 21 Affects Nuclear Architecture and Transcriptional Regulation.

Eukaryotic genomes are organised into complex higher-order structures within the nucleus, and the three-dimensional arrangement of chromosomes is functionally important for global gene regulation. The existence of supernumerary chromosome 21 in Down syndrome may perturb the nuclear architecture at different levels, which is normally optimised to maintain the physiological balance of gene expression. However, it has not been clearly elucidated whether and how aberrant configuration of chromosomes affects gene activities. To investigate the effects of trisomy 21 on nuclear organisation and gene expression, we performed three-dimensional fluorescent imaging analysis of chromosome-edited human induced pluripotent stem cells (iPSCs), which enabled identification of the parental origin of the three copies of chromosome 21. We found that two copies of maternal chromosomes resulting from meiotic nondisjunction had a higher tendency to form an adjacent pair and were located relatively distant from the nuclear membrane, suggesting the conserved interaction between these homologous chromosomes. Transcriptional profiling of parental-origin-specific corrected disomy 21 iPSC lines indicated upregulated expression of the maternal alleles for a group of genes, which was accompanied by a fluctuating expression pattern. These results suggest the unique effects of a pair of maternal chromosomes in trisomy 21, which may contribute to the pathological phenotype.

Systematic Cellular Disease Models Reveal Synergistic Interaction of Trisomy 21 and GATA1 Mutations in Hematopoietic Abnormalities.

Chromosomal aneuploidy and specific gene mutations are recognized early hallmarks of many oncogenic processes. However, the net effect of these abnormalities has generally not been explored. We focused on transient myeloproliferative disorder (TMD) in Down syndrome, which is characteristically associated with somatic mutations in GATA1. To better understand functional interplay between trisomy 21 and GATA1 mutations in hematopoiesis, we constructed cellular disease models using human induced pluripotent stem cells (iPSCs) and genome-editing technologies. Comparative analysis of these engineered iPSCs demonstrated that trisomy 21 perturbed hematopoietic development through the enhanced production of early hematopoietic progenitors and the upregulation of mutated GATA1, resulting in the accelerated production of aberrantly differentiated cells. These effects were mediated by dosage alterations of RUNX1, ETS2, and ERG, which are located in a critical 4-Mb region of chromosome 21. Our study provides insight into the genetic synergy that contributes to multi-step leukemogenesis.

Successful induction of sclerostin in human-derived fibroblasts by 4 transcription factors and its regulation by parathyroid hormone, hypoxia, and prostaglandin E2.

Sclerostin, coded by SOST, is a secretory protein that is specifically expressed in osteocytes and suppresses osteogenesis by inhibiting WNT signaling. The regulatory mechanism underlying SOST expression remains unclear mainly due to the absence of an adequate human cell model. Thus, we herein attempted to establish a cell model of human dermal fibroblasts in order to investigate the functions of sclerostin. We selected 20 candidate transcription factors (TFs) that induce SOST expression by analyzing gene expression patterns in the human sarcoma cell line, SaOS-2, between differentiation and maintenance cultures using microarrays. An effective set of TFs to induce SOST expression was sought by their viral transduction into fibroblasts, and a combination of four TFs: ATF3, KLF4, PAX4, and SP7, was identified as the most effective inducer of SOST expression. Quantitative PCR demonstrated that the expression levels of SOST in fibroblasts treated with the 4 TFs were 199- and 1439-fold higher than those of the control after 1-week and 4-week cultures, respectively. The level of sclerostin in the conditioned medium, as determined by ELISA, was 21.2pmol/l 4weeks after the transduction of the 4 TFs. Interestingly, the production of Dickkopf1 (DKK1), another secreted inhibitor of WNT signaling, was also increased by transduction of these 4 TFs. Parathyroid hormone (PTH) significantly suppressed the induced SOST by 38% and sclerostin by 82% that of the vehicle. Hypoxia increased the induced SOST by 62% that of normoxia. Furthermore, prostaglandin E2 (PGE2) increased SOST expression levels to 16-fold those of the vehicle. In conclusion, the efficient induction of SOST expression and sclerostin production was achieved in human dermal fibroblasts by the transduction of ATF3, KLF4, PAX4, and SP7, and the induced SOST and sclerostin were regulated by PTH, hypoxia, and PGE2. This model may contribute to elucidating the regulatory mechanisms underlying SOST expression and advancing drug development for metabolic bone diseases.

Secreted frizzled-related protein 3 regulates activity-dependent adult hippocampal neurogenesis.

Adult neurogenesis, the process of generating mature neurons from adult neural stem cells, proceeds concurrently with ongoing neuronal circuit activity and is modulated by various physiological and pathological stimuli. The niche mechanism underlying the activity-dependent regulation of the sequential steps of adult neurogenesis remains largely unknown. Here, we report that neuronal activity decreases the expression of secreted frizzled-related protein 3 (sFRP3), a naturally secreted Wnt inhibitor highly expressed by adult dentate gyrus granule neurons. Sfrp3 deletion activates quiescent radial neural stem cells and promotes newborn neuron maturation, dendritic growth, and dendritic spine formation in the adult mouse hippocampus. Furthermore, sfrp3 reduction is essential for activity-induced adult neural progenitor proliferation and the acceleration of new neuron development. Our study identifies sFRP3 as an inhibitory niche factor from local mature dentate granule neurons that regulates multiple phases of adult hippocampal neurogenesis and suggests an interesting activity-dependent mechanism governing adult neurogenesis via the acute release of tonic inhibition.

Chordin-induced lineage plasticity of adult SVZ neuroblasts after demyelination.

The mechanisms that regulate the developmental potential of adult neural progenitor populations under physiological and pathological conditions remain poorly defined. Glutamic acid decarboxylase 65 (GAD65)- and Doublecortin (Dcx)-expressing cells constitute major progenitor populations in the adult mouse subventricular zone (SVZ). Under normal physiological conditions, SVZ-derived GAD65-positive and Dcx-positive cells expressed the transcription factor Pax6 and migrated along the rostral migratory stream to the olfactory bulb to generate interneurons. After lysolecithin-induced demyelination of corpus callosum, however, these cells altered their molecular and cellular properties and migratory path. Demyelination upregulated chordin in the SVZ, which redirected GAD65-positive and Dcx-positive progenitors from neuronal to glial fates, generating new oligodendrocytes in the corpus callosum. Our findings suggest that the lineage plasticity of SVZ progenitor cells could be a potential therapeutic strategy for diseased or injured brain.

Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis.

The mammalian brain exhibits diverse types of neural plasticity, including activity-dependent neurogenesis in the adult hippocampus. How transient activation of mature neurons leads to long-lasting modulation of adult neurogenesis is unknown. Here we identify Gadd45b as a neural activity-induced immediate early gene in mature hippocampal neurons. Mice with Gadd45b deletion exhibit specific deficits in neural activity-induced proliferation of neural progenitors 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 corresponding genes critical for adult neurogenesis, including brain-derived neurotrophic factor and fibroblast growth factor. 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.