Identification of somatic mutations in postmortem human brains by whole genome sequencing and their implications for psychiatric disorders.

AIM: Somatic mutations in the human brain are hypothesized to contribute to the functional diversity of brain cells as well as the pathophysiology of neuropsychiatric diseases. However, there are still few reports on somatic mutations in non-neoplastic human brain tissues. This study attempted to unveil the landscape of somatic mutations in the human brain. METHODS: We explored the landscape of somatic mutations in human brain tissues derived from three individuals with no neuropsychiatric diseases by whole-genome deep sequencing at a depth of around 100. The candidate mutations underwent multi-layered filtering, and were validated by ultra-deep target amplicon sequencing at a depth of around 200 000. RESULTS: Thirty-one somatic mutations were identified in the human brain, demonstrating the utility of whole-genome sequencing of bulk brain tissue. The mutations were enriched in neuron-expressed genes, and two-thirds of the identified somatic single nucleotide variants in the brain tissues were cytosine-to-thymine transitions, half of which were in CpG dinucleotides. CONCLUSION: Our developed filtering and validation approaches will be useful to identify somatic mutations in the human brain. The vulnerability of neuron-expressed genes to mutational events suggests their potential relevance to neuropsychiatric diseases.

The usefulness of combined brain perfusion single-photon emission computed tomography, Dopamine-transporter single-photon emission computed tomography, and 123 I-metaiodobenzylguanidine myocardial scintigraphy for the diagnosis of dementia with Lewy bodies.

BACKGROUND: Current diagnostic criteria recommend neuroimaging as a diagnostic support tool for the clinical diagnosis of dementia with Lewy bodies (DLB). Because DLB causes characteristic impairments and disabilities, such as neuroleptic hypersensitivity, which may significantly increase morbidity and mortality, its prompt and correct diagnosis is very important. The aim of this study was to evaluate the extent to which diagnostic accuracy can be increased by using different combinations of brain perfusion single-photon emission computed tomography (bp-SPECT), 123 I-metaiodobenzylguanidine myocardial scintigraphy (MIBG scintigraphy), and DAT-SPECT. Taking finances and patient burden into consideration, we compared the tests to determine priority. METHODS: Thirty-four patients with probable DLB (75.0 ± 8.3 years old; 14 men, 20 women) underwent bp-SPECT, MIBG scintigraphy, and DAT-SPECT. RESULTS: Our comparison of three functional imaging techniques indicated that MIBG scintigraphy (79%) and Dopamine-transporter (DAT) SPECT (79%) had better sensitivity for characteristic abnormalities in DLB than bp-SPECT (53%). The combination of the three modalities could increase sensitivity for diagnosis of DLB to 100%. Additionally, the ratio of patients with rapid eye movement sleep behaviour disorder was significantly higher in the positive finding group on MIBG scintigraphy than in the negative finding group. CONCLUSIONS: In terms of stand-alone diagnostic means, priority should be placed on MIBG scintigraphy or DAT-SPECT for the diagnosis of DLB. However, our results suggest that the combination of bp-SPECT, MIBG scintigraphy, and DAT-SPECT increased the accuracy of the clinical diagnosis of DLB.

Neurons show distinctive DNA methylation profile and higher interindividual variations compared with non-neurons.

Epigenome information in mammalian brain cells reflects their developmental history, neuronal activity, and environmental exposures. Studying the epigenetic modifications present in neuronal cells is critical to a more complete understanding of the role of the genome in brain functions. We performed comprehensive DNA methylation analysis in neuronal and non-neuronal nuclei obtained from the human prefrontal cortex. Neuronal nuclei manifest qualitatively and quantitatively distinctive DNA methylation patterns, including relative global hypomethylation, differential enrichment of transcription-factor binding sites, and higher methylation of genes expressed in astrocytes. Non-neuronal nuclei showed indistinguishable DNA methylation patterns from bulk cortex and higher methylation of synaptic transmission-related genes compared with neuronal nuclei. We also found higher variation in DNA methylation in neuronal nuclei, suggesting that neuronal cells have more potential ability to change their epigenetic status in response to developmental and environmental conditions compared with non-neuronal cells in the central nervous system.

Stem cell therapy: a new approach to the treatment of refractory depression.

To better understand the relationship of repeated exposure to adversity during early development as a risk factor for refractory depression, we exposed pregnant female rats to ethanol and the resulting pups to corticosterone during adolescence. A stressful forced swim test was then used to induce depression-like behavior. The adolescent rat brains were examined for the possible therapeutic benefit of a combination of sertraline, an antidepressant, and neural stem cells (NSCs) complexed with atelocollagen in relation to the level of GABAergic interneuron and synaptic protein density in different brain regions. The combined exposures of prenatal and adolescent stress resulted in a reduction in parvalbumin (PV)-positive phenotype of GABAergic interneurons and reduced postsynaptic density protein 95 (PSD-95) levels in the anterior cingulate cortex, amygdala, and hippocampus. Treatments with sertraline and NSCs reversed the reductions in PV-positive cells and PSD-95 levels. Furthermore, the combined treatment of sertraline and NSCs resulted in reduced depressive-like behaviors. These experiments underscore a potentially important role for synaptic remodeling and GABAergic interneuron genesis in the treatment of refractory depression and highlight the therapeutic potential of stem cell and pharmacological combination treatments for refractory depression.

Plasticity-related gene 1 is important for survival of neurons derived from rat neural stem cells.

Plasticity-related gene 1 (Prg1) is a membrane-associated lipid phosphate phosphatase. In this study, we first investigated the role of Prg1 in the survival of neurons derived from rat neural stem cells (NSCs) using small interfering RNA (siRNA). Prg1 knock-down decreased the cell number. Interestingly, Prg1 knock-down increased genomic DNA fragmentation, suggesting the possible induction of apoptosis. Exogenously expressed Prg1 rescued the cells from death and restored the loss of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) activity induced with Prg1 siRNA. However, exogenously expressed mutated-Prg1 (the 253rd amino acid, histidine253, had been changed to alanine) did not rescue the cell death or restore the MTT activity. Histidine253 of Prg1 has been reported to be important for lipid phosphate phosphatase activity. These results suggest that Prg1 is important for survival of neurons through its dephosphorylation activity.

Effects of atelocollagen on neural stem cell function and its migrating capacity into brain in psychiatric disease model.

Stem cell therapy is well proposed as a potential method for the improvement of neurodegenerative damage in the brain. Among several different procedures to reach the cells into the injured lesion, the intravenous (IV) injection has benefit as a minimally invasive approach. However, for the brain disease, prompt development of the effective treatment way of cellular biodistribution of stem cells into the brain after IV injection is needed. Atelocollagen has been used as an adjunctive material in a gene, drug and cell delivery system because of its extremely low antigenicity and bioabsorbability to protect these transplants from intrabody environment. However, there is little work about the direct effect of atelocollagen on stem cells, we examined the functional change of survival, proliferation, migration and differentiation of cultured neural stem cells (NSCs) induced by atelocollagen in vitro. By 72-h treatment 0.01-0.05% atelocollagen showed no significant effects on survival, proliferation and migration of NSCs, while 0.03-0.05% atelocollagen induced significant reduction of neuronal differentiation and increase of astrocytic differentiation. Furthermore, IV treated NSCs complexed with atelocollagen (0.02%) could effectively migrate into the brain rather than NSC treated alone using chronic alcohol binge model rat. These experiments suggested that high dose of atelocollagen exerts direct influence on NSC function but under 0.03% of atelocollagen induces beneficial effect on regenerative approach of IV administration of NSCs for CNS disease.

Reduced sociability in a prenatal immune activation model: Modulation by a chronic blonanserin treatment through the amygdala-hippocampal axis.

The environmental disturbances in a critical neurodevelopmental period exert organizational effects on brain intrinsic plasticity including excitatory and inhibitory (E/I) neurotransmission those can cause the onset of psychiatric illness. We previously reported that treatment of neural precursor cells with N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 induced reduction of GABAergic interneuron differentiation, and these changes recovered by atypical antipsychotic blonanserin treatment in vitro. However, it remains unclear how this treatment affects neural circuit changes in hippocampus and amygdala, which might contribute to the prevention of onset process of schizophrenia. To elucidate the pathogenic/preventive mechanisms underlying prenatal environmental adversity-induced schizophrenia in more detail, we administered poly (I:C) followed by antipsychotics and examined alterations in social/cognitive behaviors, GABA/glutamate-related gene expressions with cell density and E/I ratio, and brain-derived neurotrophic factor (Bdnf) transcript levels, particularly in limbic areas. Treatment with antipsychotic blonanserin ameliorated impaired social/cognitive behaviors and increased parvalbumin (PV)-positive (+) cell density and its mRNA levels as well as Bdnf with long 3'UTR mRNA levels, particularly in the dorsal hippocampus, in rats exposed to maternal immune activation (MIA). Low dose of blonanserin and haloperidol altered GABA and glutamate-related mRNA levels, the E/I ratio, and Bdnf long 3'UTR mRNA levels in the ventral hippocampus and amygdala, but did not attenuate behavioral impairments. These results strongly implicate changes in PV expression, PV(+) GABAergic interneuron density, and Bdnf long 3'UTR expression levels, particularly in the dorsal hippocampus, in the pathophysiology and treatment responses of MIA-induced schizophrenia and highlight the therapeutic potential of blonanserin for developmental stress-related schizophrenia.

Identification of epigenetically active L1 promoters in the human brain and their relationship with psychiatric disorders.

Long interspersed nuclear element-1 (LINE-1, L1) affects the transcriptome landscape in multiple ways. Promoter activity within its 5'UTR plays a critical role in regulating diverse L1 activities. However, the epigenetic status of L1 promoters in adult brain cells and their relationship with psychiatric disorders remain poorly understood. Here, we examined DNA methylation and hydroxymethylation of the full-length L1s in neurons and nonneurons and identified "epigenetically active" L1s. Notably, some of epigenetically active L1s were retrotransposition competent, which even had chimeric transcripts from the antisense promoters at their 5'UTRs. We also identified differentially methylated L1s in the prefrontal cortices of patients with psychiatric disorders. In nonneurons of bipolar disorder patients, one L1 was significantly hypomethylated and showed an inverse correlation with the expression level of the overlapping gene NREP. Finally, we observed that altered DNA methylation levels of L1 in patients with psychiatric disorders were not affected by the surrounding genomic regions but originated from the L1 sequences. These results suggested that altered epigenetic regulation of the L1 5'UTR in the brain was involved in the pathophysiology of psychiatric disorders.

Rhotekin modulates differentiation of cultured neural stem cells to neurons.

Rhotekin is a downstream signal of Rho and is expressed in the central nervous system. However, the physiological role of rhotekin in the development of neural stem cells (NSCs) into neurons is unknown. In this study, we knocked down the expression of rhotekin protein with small interfering RNA (siRNA) in the NSCs and in neural differentiated cells and measured cell proliferation, differentiation, neurite length, and survival. By using immunocytochemistry and Western blot, the production of rhotekin was observed in NSCs and neuronal cells. Furthermore, rhotekin production was increased in accordance with neural differentiation. Rhotekin knock-down reduced 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) activity and increased the cell death 72 hr after transfection in neurons. On the other hand, in NSCs, rhotekin knock-down increased MTT activity and the number of 5-bromo-2'-deoxyuridine (BrdU)-positive cells. In the present study, we demonstrated that rhotekin is required for maintenance and survival of neurons and positively regulates differentiation and neurite outgrowth. Moreover, we found that rhotekin is produced in NSCs and that the role of rhotekin is to regulate cell proliferation negatively. In conclusion, these results suggest that rhotekin is one of the key molecules in the differentiation of NSCs into neurons.

Antipsychotic induced alteration of growth and proteome of rat neural stem cells.

Neural stem cells (NSCs) play a crucial role in the development and maturation of the central nervous system and therefore have the potential to target by therapeutic agents for a wide variety of diseases including neurodegenerative and neuropsychiatric illnesses. It has been suggested that antipsychotic drugs have significant effects on NSC activities. However, the molecular mechanisms underlying antipsychotic-induced changes of NSC activities, particularly growth and protein expression, are largely unknown. NSCs were treated with either haloperidol (HD; 3 µM), risperidone (RS; 3 µM) or vehicle (DMSO) for 96 h. Protein expression profiles were studied through a proteomics approach. RS promoted and HD inhibited the growth of NSCs. Proteomics analysis revealed that 15 protein spots identified as 12 unique proteins in HD-, and 20 protein spots identified as 14 proteins in RS-treated groups, were differentially expressed relative to control. When these identified proteins were compared between the two drug-treated groups, 2 proteins overlapped leaving 10 HD-specific and 12 RS-specific proteins. Further comparison of the overlapped altered proteins of 96 h treatment with the neuroleptics-induced overlapped proteins at 24 h time interval (Kashem et al. [40] in Neurochem Int 55:558-565, 2009) suggested that overlapping altered proteins expression at 24 h was decreased (17 proteins i.e. 53 % of total expressed proteins) with the increase of time (96 h) (2 proteins; 8 % of total expressed proteins). This result indicated that at early stage both drugs showed common mode of action but the action was opposite to each other while administration was prolonged. The opposite morphological pattern of cellular growth at 96 h has been associated with dominant expression of oxidative stress and apoptosis cascades in HD, and activation of growth regulating metabolic pathways in RS treated cells. These results may explain RS induced repairing of neural damage caused by a wide variety of neural diseases including schizophrenia.

Heat stress activates ER stress signals which suppress the heat shock response, an effect occurring preferentially in the cortex in rats.

Although heat stress induces a variety of illnesses, there have been few studies designed to uncover the molecular mechanisms underlining the illnesses. We here demonstrate that heat activates ER stress, which inhibits heat shock responses (HSR) via translational block. In heat-stressed rats, ER stress responses, as represented by eIF2α phosphorylation and XBP1 splicing, occurred mainly in the cortex, where the HSR was substantially inhibited. Heat exposure also activated ER stress signals in primary cortical neurons. Since HSF1 knockdown enhanced heat-induced ER stress and subsequent cell death, HSR inhibition in turn augments ER stress, implying a vicious spiral of both stresses. Taken together, heat-induced ER stress impairs the HSR and enhances cell damage, thereby manifesting its unique effect on heat stress.

A network analysis of problematic smartphone use in Japanese young adults.

BACKGROUND: We aimed to explore the overall network structure of problematic smartphone use symptoms assessed by smartphone addiction scale-short version (SAS-SV) and to identify which items could play important roles in the network. METHODS: 487 college and university students filled out the study questionnaire, including SAS-SV. We constructed a regularized partial correlation network among the 10 items of SAS-SV. We calculated three indices of node centrality: strength, closeness, and betweenness, to quantify the importance of each SAS-SV item. RESULTS: We identified 34 edges in the estimated network. In the given network, one item pertaining to withdrawal symptom hadthe highest strength and high closeness centrality. Additionally, one item related to preoccupation was also found to have high centrality indices. CONCLUSION: Our results indicating the central role of one withdrawal symptom and one preoccupation symptom in the symptom network of problematic smartphone use in young adults were in line with a previous study targeting school-age children. Longitudinal study designs are required to elicit the role of these central items on the formation and maintenance of this behavioral problem.

[Promising therapy of neural stem cell transplantation for FASD model--neural network reconstruction and behavior recovery].

OBJECTIVES: It has been elucidated that psychiatric disorders are associated with impairment of the brain neural network. Reduction in brain size and hypoplasia of the basal ganglia and corpus callosum have been reported in Fetal Alcohol Spectrum Disorder (FASD). It is believed that the formation of the neural network is influenced by alcohol exposure during the fetal period. Additionally, it is well known that the functional expression of CNS consequences of prenatal alcohol exposure includes cognitive and attentional processes, as well as social behavioral problems. It has also been reported that abnormal 5-HT neuron development can be reversed by treatment with a 5-HT1A agonist in a prenatal alcohol exposure model. However, these treatments are prophylactic. Without early intervention, the consequences of FASD are permanent. Recently, emerging evidence suggest that many clinical symptoms observed in psychiatric disease are likely related to neural network disruptions including neurogenesis dysfunction. Neural stem cell (NSC) transplantation has been investigated in areas such as brain injury, stroke and neurodegenerative diseases and may be a way to reverse neurogenesis dysfunction. In the present work, we evaluated the usefulness of intravenous transplantation of NSCs in the FASD model rat focusing on the possibility of regenerative therapy, particularly regarding behavioral abnormalities, for FASD rats. RESULTS: Abnormal behaviors FASD model rats suggest that reduced social activity , and cognitive dysfunction are major symptoms in FASD patients. Intravenous NSC transplantation appeared to partially correct these behavioral abnormalities in FASD model rats. In the Amygdala areas intravenous NSC transplantation appears to have partially regaenerates expression of PSD95 in FASD model rats. CONCLUSIONS: The results suggest that intravenous NSC transplantation may be an advanced approach to recover neural network damage and CNS dysfunction in FASD and possibly other psychiatric disorders.

The common aspects of pathophysiolgy of alcoholism and depression.

Recent biological studies suggest the existence of the common pathophysiological aspects in alcoholism and depression. Postmortem studies have revealed the impairment of cAMP signaling in the patients with alcoholism. The similar alteration of cAMP signaling was also reported in postmortem brains of depressed patients. In this study, we supported the notion that neurogenesis would be essential in pathophysiology of both alcoholism and depression. Alcohol affected the function of neural stem cells (NSCs) and decreased neurogenesis at doses which did not affects cell survival, and treatment of antidepressant or moodstabilizer rescued the alcohol-induced suppression of neurogenesis. As the key mechanism of NSC differentiation change by ethanol and psychotropics, we focused on the transcriptional repressor, NRSF/REST activity change. Our in vitro studies demonstrated the NRSF/REST activation by ethanol and suppressive effect of antidepressants and lithium against its activation by ethanol. We further described the ERK reduction and ER stress in the cellular mechanism of NRSF/REST activation. All these findings suggested that cAMP-CREB cascade reduction and NRSF/REST activation may be common underlying mechanisms in the pathophysiology of alcoholism and depression.

Internet Addiction, Smartphone Addiction, and Hikikomori Trait in Japanese Young Adult: Social Isolation and Social Network.

Background: As the number of internet users increases, problems related to internet overuse are becoming more and more serious. Adolescents and youth may be particularly attracted to and preoccupied with various online activities. In this study, we investigated the relationship of internet addiction, smartphone addiction, and the risk of hikikomori, severe social withdrawal, in Japanese young adult. Methods: The subjects were 478 college/university students in Japan. They were requested to complete the study questionnaire, which consisted of questions about demographics, internet use, the Internet Addiction Test (IAT), the Smartphone Addiction Scale (SAS)-Short Version (SV), the 25-item Hikikomori Questionnaire (HQ-25), etc. We investigated the difference and correlation of the results between two groups based on the purpose of internet use or the total score of each self-rating scale, such as screened positive or negative for the risk of internet addiction, smartphone addiction, or hikikomori. Results: There was a trend that males favored gaming in their internet use while females used the internet mainly for social networking via smartphone, and the mean SAS-SV score was higher in females. Two-group comparisons between gamers and social media users, according to the main purpose of internet use, showed that gamers used the internet longer and had significantly higher mean IAT and HQ-25 scores. Regarding hikikomori trait, the subjects at high risk for hikikomori on HQ-25 had longer internet usage time and higher scores on both IAT and SAS-SV. Correlation analyses revealed that HQ-25 and IAT scores had a relatively strong relationship, although HQ-25 and SAS-SV had a moderately weak one. Discussion: Internet technology has changed our daily lives dramatically and altered the way we communicate as well. As social media applications are becoming more popular, users are connected more tightly to the internet and their time spent with others in the real world continues to decrease. Males often isolate themselves from the social community in order to engage in online gaming while females use the internet as to not be excluded from their communications online. Mental health providers should be aware of the seriousness of internet addictions and hikikomori.

Longitudinal observation of ten family members with idiopathic basal ganglia calcification: A case report.

BACKGROUND: Familial idiopathic basal ganglia calcification (FIBGC) is a rare autosomal dominant disorder that causes bilateral calcification of the basal ganglia and/or cerebellar dentate nucleus, among other locations. CASE SUMMARY: The aim of this study is to report 10 cases of FIBGC observed in a single family. Seven patients showed calcification on their computed tomography scan, and all of these patients carried the SLC20A2 mutation. However, individuals without the mutation did not show calcification. Three patients among the 7 with calcification were symptomatic, while the remaining 4 patients were asymptomatic. Additionally, we longitudinally observed 10 subjects for ten years. In this paper, we mainly focus on the clinical course and neuroradiological findings in the proband and her son. CONCLUSION: The accumulation of more case reports and further studies related to the manifestation of FIBGC are needed.

Antidepressant activities of escitalopram and blonanserin on prenatal and adolescent combined stress-induced depression model: Possible role of neurotrophic mechanism change in serum and nucleus accumbens.

BACKGROUND: There has been number of studies suggesting experiences of adversity in early life interrelated subsequent brain development, however, neurobiological mechanisms confer risk for onset of psychiatric illness remains unclear. METHODS: In order to elucidate the pathogenic mechanisms underlying early life adversity-induced refractory depression in more detail, we administered corticosterone (CORT) to adolescent rats with or without prenatal ethanol exposure followed by an antidepressant or antipsychotic and examined alterations in depressive and social function behaviors and brain-derived neurotrophic factor (BDNF) levels in serum, the hippocampus, anterior cingulate cortex, and nucleus accumbens. RESULTS: The combined stress exposure of prenatal ethanol and adolescent CORT prolonged immobility times in the forced swim test (FST), and increased investigation times and numbers in the social interaction test (SIT). A treatment with escitalopram reversed depression-like behavior accompanied by reductions in BDNF levels in serum and the nucleus accumbens, while a treatment with blonanserin ameliorated abnormal social interaction behavior with reductions in serum BDNF levels. LIMITATIONS: Further studies are needed to clarify the clinical evinces responding to these results, and many questions remain regarding the mechanisms by which refractory depression and antidepressant/antipsychotic treatments cause changes in serum and brain regional BDNF levels. CONCLUSION: These results strongly implicate changes in BDNF levels in serum and the nucleus accumbens in the pathophysiology and treatment of early life combined stress-induced depression and highlight the therapeutic potential of escitalopram and new generation antipsychotic blonanserin for treatment-resistant refractory depression.

Lithium-induced suppression of transcription repressor NRSF/REST: effects on the dysfunction of neuronal differentiation by ethanol.

Lithium, a mood-stabilizing drug, is widely used to treat bipolar affective disorder. Recent studies have demonstrated that lithium has neuroprotective and neurotrophic properties, which may relate to its clinical effectiveness. Ethanol is a deleterious agent that causes various kinds of neuronal damage to both the developing and adult brain. In this study, we investigated the potential of lithium to produce recovery of ethanol-induced suppressed neuronal differentiation at ethanol concentrations lower than those that affect the viability of neural stem cells (NSCs). We evaluated the effect of lithium on neuronal differentiation of NSCs obtained from rat embryos. To elucidate the molecular mechanisms underlying the altered neuronal differentiation induced by lithium and ethanol, we focused on neuron-restrictive silencer factor (NRSF), which represses transcription of neuronal genes in the terminal stage of NSC differentiation. Lithium increased neuronal differentiation and decreased ethanol-induced suppression of neuronal differentiation of NSCs. Furthermore, lithium reduced the DNA binding activity and protein level of NRSF enhanced by ethanol. Based on our findings, we speculate that lithium may be efficacious in the treatment of ethanol-induced neurological deficits.

Neuroprotective effects of Yi-Gan San against beta amyloid-induced cytotoxicity on rat cortical neurons.

INTRODUCTION: Recent clinical studies have demonstrated that Yi-Gan San (YGS, Yokukan-San in Japanese), a Chinese herbal medicine, alleviates various dementia-related symptoms. However, Chinese herbal medicines have rarely been investigated scientifically and the underlying mechanism of YGS remains uncertain. In this study, we investigated the effect of YGS on beta amyloid protein (Abeta)-induced cytotoxicity in a primary culture of rat cortical neurons. METHODS: Cortical neurons prepared from rat embryos were exposed to Abeta in the presence or absence of YGS. The protective effect of YGS was measured as the % of control (unexposed neurons) by using MTT assay and LDH assay. RESULTS: Abeta significantly decreased the number of surviving cortical neurons at a dose of 20 microM and higher. In the presence of 20 microM Abeta, YGS concentrations of 10(-5) g/L (W/V) and higher significantly increased the number of viable neurons. CONCLUSION: Our study demonstrated a neuroprotective effect of Yi-Gan San against Abeta-induced cytotoxicity. Since according to traditional herbal medicine beliefs, YGS most likely exerts its clinical effects not through a single constituent but as a mixture of several herbal ingredients, the true mechanism of this neuroprotective action remains unclear. However, our results suggest that this Chinese herbal medicine might be a valuable treatment for clinical symptoms associated with dementia having fewer side effects and possible additional neuroprotective effects in the elderly.

[Epigenetic regulation in alcohol-related brain damage].

Ethanol is a deleterious agent that causes various kinds of neuronal damage to both the developing and adult brain. Recent research on alcoholism implicates impaired function of neural stem cell (NSC) in the pathogenesis of ethanol-induced brain dysfunction. We previously reported that the differentiation of NSCs into neurons was significantly influenced by ethanol. We also found that neuron-restrictive silencer factor/repressor element 1-silencing transcription factor (NRSF/ REST) binding activity potentiated by ethanol underlies the mechanism of ethanol inhibition of neuronal differentiation. Epigenetics refers to post-translational modifications of DNA and nuclear proteins that produce lasting alterations in patterns of gene expression. Epigenetic mechanism plays a critical role of neuronal plasticity and there is clear evidence that dysfunction of epigenetic mechanism also contributes to neurological and psychiatric illness. We will review epigenetic regulation in pathogenesis of psychiatric illness including alcoholism. We also demonstrated that trichostatin A, histone deacetylase inhibitor, reduced the ethanol-induced suppression of neuronal differentiation of NSCs. We suggest that ethanol alters the function of neural differentiation through the mechanism of potentiation of NRSF/REST binding and histone modifications.