Modelling of salt intake reduction by incorporation of umami substances into Japanese foods: a cross-sectional study.

BACKGROUND: Evidence has demonstrated that excess sodium intake is associated with development of several non-communicable diseases. The main source of sodium is salt. Therefore, reducing salt intake in foods is an important global public health effort to achieve sodium reduction and improve health. This study aimed to model salt intake reduction with 'umami' substances among Japanese adults. The umami substances considered in this study include glutamate or monosodium glutamates (MSG), calcium diglutamate (CDG), inosinate, and guanylate. METHODS: A total of 21,805 participants aged 57.8 years on average from the National Health and Nutrition Survey was used in the analysis. First, we employed a multivariable linear regression approach with overall salt intake (g/day) as a dependent variable, adjusting for food items and other covariates to estimate the contribution of salt intake from each food item that was selected through an extensive literature review. Assuming the participants already consume low-sodium products, we considered three scenarios in which salt intake could be reduced with the additional umami substances up to 30%, 60% and 100%. We estimated the total amount of population-level salt reduction for each scenario by age and gender. Under the 100% scenario, the Japan's achievement rates against the national and global salt intake reduction goals were also calculated. RESULTS: Without compromising the taste, the 100% or universal incorporation of umami substances into food items reduced the salt intake of Japanese adults by 12.8-22.3% at the population-level average, which is equivalent to 1.27-2.22 g of salt reduction. The universal incorporation of umami substances into food items changed daily mean salt intake of the total population from 9.95 g to 7.73 g: 10.83 g to 8.40 g for men and 9.21 g to 7.17 g for women, respectively. This study suggested that approximately 60% of Japanese adults could achieve the national dietary goal of 8 g/day, while only 7.6% would meet the global recommendation of 5.0 g/day. CONCLUSIONS: Our study provides essential information on the potential salt reduction with umami substances. The universal incorporation of umami substances into food items would enable the Japanese to achieve the national dietary goal. However, the reduced salt intake level still falls short of the global dietary recommendation.

Salt intake reduction using umami substance-incorporated food: a secondary analysis of NHANES 2017-2018 data.

OBJECTIVE: Excessive salt intake raises blood pressure and increases the risk of non-communicable diseases (NCD), such as CVD, chronic kidney disease and stomach cancer. Reducing the Na content of food is an important public health measure to control the NCD. This study quantifies the amount of salt reduced by using umami substances, i.e. glutamate, inosinate and guanylate, for adults in the USA. DESIGN: The secondary data analysis was performed using data of the US nationally representative cross-sectional dietary survey, the National Health and Nutrition Examination Survey (NHANES) 2017-2018. Per capita daily salt intake corresponding to the NHANES food groups was calculated in the four hypothetical scenarios of 0 %, 30 %, 60 % and 90 % market share of low-Na foods in the country. The salt reduction rates by using umami substances were estimated based on the previous study results. SETTING: The USA. PARTICIPANTS: 4139 individuals aged 20 years and older in the USA. RESULTS: Replacing salt with umami substances could help the US adults reduce salt intake by 7·31-13·53 % (7·50-13·61 % for women and 7·18-13·53 % for men), which is equivalent to 0·61-1·13 g/d (0·54-0·98 g/d for women and 0·69-1·30 g/d for men) without compromising the taste. Approximately, 21·21-26·04 % of the US adults could keep their salt intake below 5 g/d, the WHO's recommendation in the scenario where there is no low-Na product on the market. CONCLUSIONS: This study provides essential information that the use of umami substances as a substitute for salt may help reduce the US adults' salt intake.

Calcium/calmodulin-dependent protein kinase IIα heterozygous knockout mice show electroencephalogram and behavioral changes characteristic of a subpopulation of schizophrenia and intellectual impairment.

Cognitive deficit remains an intractable symptom of schizophrenia, accounting for substantial disability. Despite this, little is known about the cause of cognitive dysfunction in schizophrenia. Recent studies suggest that schizophrenia patients show several changes in dentate gyrus structure and functional characteristic of immaturity. The immature dentate gyrus (iDG) has been replicated in several mouse models, most notably the CaMKIIα heterozygous mouse (CaMKIIα-hKO). The current study characterizes behavioral phenotypes of CaMKIIα-hKO mice and determines their neurophysiological profile using electroencephalogram (EEG) recording from hippocampus. CaMKIIα-hKO mice were hypoactive in home-cage environment; however, they displayed less anxiety-like phenotype, suggestive of impulsivity-like behavior. In addition, severe cognitive dysfunction was evident in CaMKIIα-hKO mice as examined by novel object recognition and contextual fear conditioning. Several EEG phenomena established in both patients and relevant animal models indicate key pathological changes associated with the disease, include auditory event-related potentials and time-frequency EEG oscillations. CaMKIIα-hKO mice showed altered event-related potentials characterized by an increase in amplitude of the N40 and P80, as well as increased P80 latency. These mice also showed increased power in theta range time-frequency measures. Additionally, CaMKIIα-hKO mice showed spontaneous bursts of spike wave activity, possibly indicating absence seizures. The GABAB agonist baclofen increased, while the GABAB antagonist CGP35348 and the T-Type Ca2+ channel blocker Ethosuximide decreased spike wave burst frequency. None of these changes in event-related potentials or EEG oscillations are characteristic of those observed in general population of patients with schizophrenia; yet, CaMKIIα-hKO mice likely model a subpopulation of patients with schizophrenia.

Factors associated with the risk perception of COVID-19 infection and severe illness: A cross-sectional study in Japan.

Understanding COVID-19 risk perception may help inform public health messaging aimed at encouraging preventive measures and improving countermeasures against the pandemic. We conducted an online survey of 29,708 Japanese adults in February 2021 and estimated the associations between COVID-19 risk perception and a broad array of individual factors. Two logistic regressions were constructed to estimate factors associated with the risk perception of COVID-19 (defined as responding that one might become infected within the next 6 months), and of severe illness among those who responded that they might become infected (defined as responding that one would become severely ill). After adjusting for covariates, those with a higher perceived risk of the COVID-19 vaccine had higher odds of risk perception for both infection and severe illness. Interestingly, those with higher odds of risk perception of being infected were more likely to report obtaining their information from healthcare workers whereas those with lower odds were more likely to report obtaining their information from the Internet or the government; those with lower odds of risk perception of being severely ill were more likely to report obtaining their information from the Internet. The higher the trust level in the government as a COVID-19 information source, the lower the odds of both risk perception of being infected and becoming severely ill. The higher the trust levels in social networking services as a COVID-19 information source, the higher the odds of risk perception of becoming severely ill. Public health messaging should address the factors identified in our study.

Identification of optimum combinations of media channels for approaching COVID-19 vaccine unsure and unwilling groups in Japan.

BACKGROUND: Optimizing media campaigns for those who were unsure or unwilling to take coronavirus disease (COVID-19) vaccines is required urgently to effectively present public health messages aimed at increasing vaccination coverage. We propose a novel framework for selecting tailor-made media channels and their combinations for this task. METHODS: An online survey was conducted in Japan during February to March, 2021, with 30,053 participants. In addition to their sociodemographic characteristics, it asked the attitude toward vaccination and information sources (i.e., media channels) for COVID-19 issues. Multinomial logic regression was fitted to estimate the combinations of the media channels and their odds ratio (OR) associated with vaccination attitudes. FINDINGS: The proportion of respondents who were unsure or unwilling to take the vaccination was skewed toward younger generation: 58.1% were aged under 35, while 28.1% were 65 years or older. Media channels such as "Non-medical and Non-TV" and "Non-medical and Non-government" were associated with the unsure group: OR (95% Confidence intervals, (CI)) = 1.75 (1.62, 1.89) and 1.53 (1.44, 1.62), respectively. In addition, media channels such as "Newspapers or the Novel Coronavirus Expert Meeting", "Medical or Local government", and "Non-TV" were associated with the unwilling group: OR (95% CI) were 2.00 (1.47, 2.75), 3.13 (2.58, 3.81), and 2.25 (1.84, 2.77), respectively. INTERPRETATION: To effectively approach COVID-19 vaccine unsure and unwilling groups, generation-specific online and offline media campaigns should be optimized to the type of vaccine attitude. FUNDING: Funded by the Ministry of Health, Labour and Welfare of Japan (H29-Gantaisaku-ippan-009) and the Japan Agency for Medical Research and Development (AMED) (JP20fk0108535).

Reasons for being unsure or unwilling regarding intention to take COVID-19 vaccine among Japanese people: A large cross-sectional national survey.

BACKGROUND: Identifying and understanding reasons for being unsure or unwilling regarding intention to be vaccinated against coronavirus disease (COVID-19) may help to inform future public health messages aimed at increasing vaccination coverage. We analyzed a broad array of individual's psychological dispositions with regard to decision-making about COVID-19 vaccination in Japan. METHODS: A nationally representative cross-sectional web survey was conducted with 30053 Japanese adults aged 20 years or older at the end of February 2021. In addition to the question on the individual's intention to be vaccinated against COVID-19, respondents were asked about their sociodemographic, health-related, and psychological characteristics as well as information sources about COVID-19 and their levels of trust. Also, those who responded 'not sure' or 'no' regarding intention to take COVID-19 vaccine were asked why. Multinomial logistic regression with sparse group Lasso (Least Absolute Shrinkage and Selection Operator) penalty was used to compute adjusted odds ratios for factors associated with the intention (not sure/no versus yes). FINDINGS: The percentages of respondents who answered 'not sure' or 'no' regarding intention to be vaccinated against COVID-19 vaccine were 32.9% and 11.0%, respectively. After adjusting for covariates, the perceived risks of COVID-19, perceived risk of a COVID-19 vaccine, perceived benefits of a COVID-19 vaccine, trust in scientists and public authorities, and the belief that healthcare workers should be vaccinated were significantly associated with vaccination intention. Several sources of information about COVID-19 were also significantly associated with vaccination intention, including physicians, nurses, and television, medical information sites with lower odds of being unsure or unwilling, and internet news sites, YouTube, family members, and scientists and researchers with higher odds. The higher the level of trust in television as a source of COVID-19 information, the higher the odds of responding 'not sure' (odds ratio 1.11, 95% confidence interval 1.01-1.21). We also demonstrated that many respondents presented concerns about the side effects and safety of a COVID-19 vaccine as a major reason for being unsure or unwilling. To decide whether or not to get the vaccine, many respondents requested more information about the compatibilities between the vaccine and their personal health conditions, whether other people had been vaccinated, the effectiveness of vaccines against variants, and doctors' recommendations. INTERPRETATION: Our findings suggest that public health messaging based on the sociodemographic and psychological characteristics of those who are unsure or unwilling regarding intention to be vaccinated against COVID-19 vaccine may help to increase vaccine uptake amongst this population. FUNDING: The present work was supported in part by a grant from the Ministry of Health, Labour and Welfare of Japan (H29-Gantaisaku-ippan-009).

Sustained effects of rapidly acting antidepressants require BDNF-dependent MeCP2 phosphorylation.

The rapidly acting antidepressants ketamine and scopolamine exert behavioral effects that can last from several days to more than a week in some patients. The molecular mechanisms underlying the maintenance of these antidepressant effects are unknown. Here we show that methyl-CpG-binding protein 2 (MeCP2) phosphorylation at Ser421 (pMeCP2) is essential for the sustained, but not the rapid, antidepressant effects of ketamine and scopolamine in mice. Our results reveal that pMeCP2 is downstream of BDNF, a critical factor in ketamine and scopolamine antidepressant action. In addition, we show that pMeCP2 is required for the long-term regulation of synaptic strength after ketamine or scopolamine administration. These results demonstrate that pMeCP2 and associated synaptic plasticity are essential determinants of sustained antidepressant effects.

Computational identification of variables in neonatal vocalizations predictive for postpubertal social behaviors in a mouse model of 16p11.2 deletion.

Autism spectrum disorder (ASD) is often signaled by atypical cries during infancy. Copy number variants (CNVs) provide genetically identifiable cases of ASD, but how early atypical cries predict a later onset of ASD among CNV carriers is not understood in humans. Genetic mouse models of CNVs have provided a reliable tool to experimentally isolate the impact of CNVs and identify early predictors for later abnormalities in behaviors relevant to ASD. However, many technical issues have confounded the phenotypic characterization of such mouse models, including systematically biased genetic backgrounds and weak or absent behavioral phenotypes. To address these issues, we developed a coisogenic mouse model of human proximal 16p11.2 hemizygous deletion and applied computational approaches to identify hidden variables within neonatal vocalizations that have predictive power for postpubertal dimensions relevant to ASD. After variables of neonatal vocalizations were selected by least absolute shrinkage and selection operator (Lasso), random forest, and Markov model, regression models were constructed to predict postpubertal dimensions relevant to ASD. While the average scores of many standard behavioral assays designed to model dimensions did not differentiate a model of 16p11.2 hemizygous deletion and wild-type littermates, specific call types and call sequences of neonatal vocalizations predicted individual variability of postpubertal reciprocal social interaction and olfactory responses to a social cue in a genotype-specific manner. Deep-phenotyping and computational analyses identified hidden variables within neonatal social communication that are predictive of postpubertal behaviors.

Behavioral Analysis of SNAP-25 and Synaptobrevin-2 Haploinsufficiency in Mice.

In central synapses, synaptobrevin-2 (also called VAMP-2) is the predominant synaptic vesicle SNARE protein that interacts with the plasma membrane SNAREs, SNAP-25 and syntaxin-1 to execute exocytosis. Mice deficient in synaptobrevin-2 or SNAP-25 show embryonic lethality, which precludes investigation of the complete loss-of-function of these proteins in the adult nervous system. However, mice that carry heterozygous null mutations survive into adulthood and are fertile. In order to elucidate how loss-of-function mutations in these proteins may result in human disease phenotypes it is important to develop bona fide animal models. Therefore, given the importance of these two critical SNAREs in central synaptic transmission and their association with several neurological or neuropsychiatric disorders, we performed a comprehensive behavioral analysis of SNAP-25 heterozygous null (SNAP-25+/-) mice as well as the synaptobrevin-2 heterozygous null (+/-) mice. This analysis revealed only mild phenotypes, SNAP-25 (+/-) mice exhibited marked hypoactivity, whereas synaptobrevin-2 (+/-) mice showed enhanced performance on the rotarod. The two mouse lines did not manifest significant deficits in anxiety-related behaviors, learning and memory measures, or prepulse inhibition. The rather mild behavioral deficits indicate that these key proteins, SNAP25 and synaptobrevin-2, are expressed in excess to circumvent the impact of potential fluctuations in expression levels on nervous system function.

Hippocampal Pathophysiology: Commonality Shared by Temporal Lobe Epilepsy and Psychiatric Disorders.

Accumulating evidence points to the association of epilepsy, particularly, temporal lobe epilepsy (TLE), with psychiatric disorders, such as schizophrenia. Among these illnesses, the hippocampus is considered the regional focal point of the brain, playing an important role in cognition, psychosis, and seizure activity and potentially suggesting common etiologies and pathophysiology of TLE and schizophrenia. In the present review, we overview abnormal network connectivity between the dentate gyrus (DG) and the Cornus Ammonis area 3 (CA3) subregions of the hippocampus relative to the induction of epilepsy and schizophrenia. In light of our recent finding on the misguidance of hippocampal mossy fiber projection in the rodent model of schizophrenia, we discuss whether ectopic mossy fiber projection is a commonality in order to evoke TLE as well as symptoms related to schizophrenia.

Inactivation of NMDA Receptors in the Ventral Tegmental Area during Cocaine Self-Administration Prevents GluA1 Upregulation but with Paradoxical Increases in Cocaine-Seeking Behavior.

Cocaine self-administration increases expression of GluA1 subunits in ventral tegmental area (VTA) dopamine neurons, which subsequently enhance the motivation for cocaine. This increase in GluA1 may be dependent on concomitant NMDA receptor (NMDAR) activation during self-administration, similar to cocaine-induced long-term potentiation in the VTA. In this study, we used viral-mediated expression of a dominant-negative GluN1 subunit (HSV-dnGluN1) in VTA neurons to study the effect of transient NMDAR inactivation on the GluA1 increases induced by chronic cocaine self-administration in male rats. We found that dnGluN1 expression in the VTA limited to the 3 weeks of cocaine self-administration prevents the subsequent increase in tissue GluA1 levels when compared with control infusions of HSV-LacZ. Surprisingly, dnGluN1 expression led to an enhancement in the motivation to self-administer cocaine as measured using a progressive ratio reinforcement schedule and to enhanced cocaine seeking measured in extinction/reinstatement tests following an extended 3 week withdrawal period. Despite blocking tissue GluA1 increases in cocaine self-administering animals, the HSV-dnGluN1 treatment resulted in increased membrane levels of GluA1 and GluN2B, along with markedly higher locomotor responses to intra-VTA infusions of AMPA, suggesting a paradoxical increase in VTA AMPA receptor responsiveness. Together, these data suggest that NMDARs mediate cocaine-induced increases in VTA GluA1 expression, but such transient NMDAR inactivation also leads to compensatory scaling of synaptic AMPA receptors that enhance the motivational for cocaine.SIGNIFICANCE STATEMENT Dopamine neurons in the ventral tegmental area (VTA) are critical substrates of drug rewards. Animal models indicate that chronic cocaine use enhances excitatory glutamatergic input to these neurons, making them more susceptible to environmental stimuli that trigger drug craving and relapse. We previously found that self-administration of cocaine increases AMPA glutamate receptors in the VTA, and this effect enhances motivation for cocaine. Here we report that the mechanism for this upregulation involves NMDA receptor activity during cocaine use. While interference with NMDA receptor function blocks AMPA receptor upregulation, it also produces a paradoxical enhancement in membrane AMPA receptor subunits, AMPA responsiveness, and the motivation for cocaine. Thus, pharmacotherapy targeting NMDA receptors may inadvertently produce substantial adverse consequences for cocaine addiction.

TrkB Signaling in Dorsal Raphe Nucleus is Essential for Antidepressant Efficacy and Normal Aggression Behavior.

Brain-derived neurotrophic factor (BDNF) and its high affinity receptor, tropomyosin receptor kinase B (TrkB), have important roles in neural plasticity and are required for antidepressant efficacy. Studies examining the role of BDNF-TrkB signaling in depression and antidepressant efficacy have largely focused on the limbic system, leaving it unclear whether this signaling is important in other brain regions. BDNF and TrkB are both highly expressed in the dorsal raphe nucleus (DRN), a brain region that has been suggested to have a role in depression and antidepressant action, although it is unknown whether BDNF and TrkB in the dorsal raphe nucleus are involved in these processes. We combined the adeno-associated virus (AAV) with the Cre-loxP site-specific recombination system to selectively knock down either Bdnf or TrkB in the DRN. These mice were then characterized in several behavioral paradigms including measures of depression-related behavior and antidepressant efficacy. We show that knockdown of TrkB, but not Bdnf, in the DRN results in loss of antidepressant efficacy and increased aggression-related behavior. We also show that knockdown of TrkB or Bdnf in this brain region does not have an impact on weight, activity levels, anxiety, or depression-related behaviors. These data reveal a critical role for TrkB signaling in the DRN in mediating antidepressant responses and normal aggression behavior. The results also suggest a non-cell autonomous role for BDNF in the DRN in mediating antidepressant efficacy.

MeCP2 and histone deacetylases 1 and 2 in dorsal striatum collectively suppress repetitive behaviors.

Class I histone deacetylases (HDACs) Hdac1 and Hdac2 can associate together in protein complexes with transcriptional factors such as methyl-CpG-binding protein 2 (MeCP2). Given their high degree of sequence identity, we examined whether Hdac1 and Hdac2 were functionally redundant in mature mouse brain. We demonstrate that postnatal forebrain-specific deletion of both Hdac1 and Hdac2 in mice impacts neuronal survival and results in an excessive grooming phenotype caused by dysregulation of Sap90/Psd95-associated protein 3 (Sapap3; also known as Dlgap3) in striatum. Moreover, Hdac1- and Hdac2-dependent regulation of Sapap3 expression requires MECP2, the gene involved in the pathophysiology of Rett syndrome. We show that postnatal forebrain-specific deletion of Mecp2 causes excessive grooming, which is rescued by restoring striatal Sapap3 expression. Our results provide new insight into the upstream regulation of Sapap3 and establish the essential role of striatal Hdac1, Hdac2 and MeCP2 for suppression of repetitive behaviors.

Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior.

The biological underpinnings and the pathological lesions of psychiatric disorders are centuries-old questions that have yet to be understood. Recent studies suggest that schizophrenia and related disorders likely have their origins in perturbed neurodevelopment and can result from a large number of common genetic variants or multiple, individually rare genetic alterations. It is thus conceivable that key neurodevelopmental pathways underline the various genetic changes and the still unknown pathological lesions in schizophrenia. Here, we report that mice defective of the nicastrin subunit of γ-secretase in oligodendrocytes have hypomyelination in the central nervous system. These mice have altered dopamine signaling and display profound abnormal phenotypes reminiscent of schizophrenia. In addition, we identify an association of the nicastrin gene with a human schizophrenia cohort. These observations implicate γ-secretase and its mediated neurodevelopmental pathways in schizophrenia and provide support for the "myelination hypothesis" of the disease. Moreover, by showing that schizophrenia and obsessive-compulsive symptoms could be modeled in animals wherein a single genetic factor is altered, our work provides a biological basis that schizophrenia with obsessive-compulsive disorder is a distinct subtype of schizophrenia.

Postnatal Loss of Mef2c Results in Dissociation of Effects on Synapse Number and Learning and Memory.

BACKGROUND: Myocyte enhancer factor 2 (MEF2) transcription factors play critical roles in diverse cellular processes during central nervous system development. Studies attempting to address the role of MEF2 in brain have largely relied on overexpression of a constitutive MEF2 construct that impairs memory formation or knockdown of MEF2 function that increases spine numbers and enhances memory formation. Genetic deletion of individual MEF2 isoforms in brain during embryogenesis demonstrated that Mef2c loss negatively regulates spine numbers resulting in learning and memory deficits, possibly as a result of its essential role in development. METHODS: To investigate MEF2C function in brain further, we genetically deleted Mef2c during postnatal development in mice. We characterized these conditional Mef2c knockout mice in an array of behavioral paradigms and examined the impact of postnatal loss of Mef2c on long-term potentiation. RESULTS: We observed increased spine numbers in hippocampus of the conditional Mef2c knockout mice. However, the postnatal loss of Mef2c did not impact learning and memory, long-term potentiation, or social and repetitive behaviors. CONCLUSIONS: Our findings demonstrate a critical role for MEF2C in the regulation of spine numbers with a dissociation of learning and memory, synaptic plasticity, and measures of autism-related behaviors in postnatal brain.

Mouse Model of Chromosome 15q13.3 Microdeletion Syndrome Demonstrates Features Related to Autism Spectrum Disorder.

The chromosome 15q13.3 microdeletion is a pathogenic copy number variation conferring epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients. Here, we report that mice with a heterozygous deletion on a C57BL/6 background (D/+ mice) demonstrated phenotypes including enlarged/heavier brains (macrocephaly) with enlarged lateral ventricles, decreased social interactions, increased repetitive grooming behavior, reduced ultrasonic vocalizations, decreased auditory-evoked gamma band EEG, and reduced event-related potentials. D/+ mice had normal body weight, activity levels, sensory gating, and cognitive abilities and no signs of epilepsy/seizures. Our results demonstrate that D/+ mice represent ASD-related phenotypes associated with 15q13.3 microdeletion syndrome. Further investigations using this chromosome-engineered mouse model may uncover the common mechanism(s) underlying ASD and other neurodevelopmental/psychiatric disorders representing the 15q13.3 microdeletion syndrome, including epilepsy, intellectual disability, and schizophrenia. SIGNIFICANCE STATEMENT: Recently discovered pathologic copy number variations (CNVs) from patients with neurodevelopmental/psychiatric disorders show very strong penetrance and thus are excellent candidates for mouse models of disease that can mirror the human genetic conditions with high fidelity. A 15q13.3 microdeletion in humans results in a range of neurodevelopmental/psychiatric disorders, including epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). The disorders conferred by a 15q13.3 microdeletion also have overlapping genetic architectures and comorbidity in other patient populations such as those with epilepsy and schizophrenia/psychosis, as well as schizophrenia and ASD. We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients, which allowed us to investigate the potential causes of neurodevelopmental/psychiatric disorders associated with the CNV.

Selective role for DNMT3a in learning and memory.

Methylation of cytosine nucleotides is governed by DNA methyltransferases (DNMTs) that establish de novo DNA methylation patterns in early embryonic development (e.g., DNMT3a and DNMT3b) or maintain those patterns on hemimethylated DNA in dividing cells (e.g., DNMT1). DNMTs continue to be expressed at high levels in mature neurons, however their impact on neuronal function and behavior are unclear. To address this issue we examined DNMT1 and DNMT3a expression following associative learning. We also generated forebrain specific conditional Dnmt1 or Dnmt3a knockout mice and characterized them in learning and memory paradigms as well as for alterations in long-term potentiation (LTP) and synaptic plasticity. Here, we report that experience in an associative learning task impacts expression of Dnmt3a, but not Dnmt1, in brain areas that mediate learning of this task. We also found that Dnmt3a knockout mice, and not Dnmt1 knockouts have synaptic alterations as well as learning deficits on several associative and episodic memory tasks. These findings indicate that the de novo DNA methylating enzyme DNMT3a in postmitotic neurons is necessary for normal memory formation and its function cannot be substituted by the maintenance DNA methylating enzyme DNMT1.

Decoding transcriptional repressor complexes in the adult central nervous system.

Cells maintain precise gene expression by balancing transcriptional activation and repression. While much work has focused on elucidating transcriptional activation in the central nervous system (CNS), little is known about transcriptional repression. One means to repress gene expression is to initiate binding of transcription factors to DNA, which then recruit co-repressors as well as other accessory proteins, forming a multi-protein repressor complex. These multi-protein repressor complexes include histone modifying enzymes that trigger processes such as histone acetylation, methylation, and ubiquitylation, altering chromatin structures to impact gene expression. Within these complexes transcriptional repressor proteins per se do not exhibit enzymatic reactions to remodel chromatin structure, whereas histone modifying enzymes lack intrinsic DNA binding activity but have an ability to process post-translational modifications on histones. Thus, the mutual association between transcriptional repressors and histone modifying enzymes is essential to sculpt chromatin to favor transcriptional repression and down regulate gene expression. Additionally, co-repressors are integral components in the context of gene repression as they bridge the association of transcriptional repressors and histone modifying enzymes. In this review, we will discuss the roles of some of the major components of these repressor complex in the CNS as well as their cellular functions that may underlie fundamental behavior in animals.

Sensitivity of hippocampal 5-HT1A receptors to mild stress in BDNF-deficient mice.

Serotonin 1A (5-HT(1A)) receptors in brain play an important role in cognitive and integrative functions, as well as emotional states. Decreased brain-derived neurotrophic factor (BDNF) expression and/or function, particularly in hippocampus, are implicated in the pathophysiology of stress-related disorders such as major depression. BDNF(+/-) mice are more vulnerable to stress than wild-type mice, exhibiting behavioural despair after mild handling stress. We examined the effect of mild handling stress on 5-HT(1A) receptor function, as measured by 8-OH-DPAT stimulated [(35)S]GTPγS binding, in BDNF(+/-) mice and mice with a forebrain-specific reduction in BDNF (embryonic BDNF inducible knockout mice). Our data show a remarkable sensitivity of hippocampal 5-HT1A receptors to mild stress and a deficiency in BDNF. Other 5-HT(1A) receptor populations, specifically in frontal cortex and dorsal raphe, were resistant to the combined detrimental effects of mild stress and reductions in BDNF expression. Decreases in hippocampal 5-HT(1A) receptor function induced by mild stress in BDNF-deficient mice were prevented by administration of the selective serotonin reuptake inhibitor fluoxetine, which increased activation of TrkB, the high affinity receptor for BDNF, in wild-type and BDNF(+/-) mice. In hippocampal cultures, BDNF increased the capacity of 5-HT(1A) receptors to activate G proteins, an effect eliminated by the knockout of TrkB, confirming TrkB activation increases 5-HT(1A) receptor function. The mechanisms underlying the sensitivity of hippocampal 5-HT(1A) receptors to mild stress and decreased BDNF expression remain to be elucidated and may have important implications for the emotional and cognitive impairments associated with stress-related mental illness.

An essential role for histone deacetylase 4 in synaptic plasticity and memory formation.

Histone deacetylases (HDACs), a family of enzymes involved in epigenetic regulation, have been implicated in the control of synaptic plasticity, as well as learning and memory. Previous work has demonstrated administration of pharmacological HDAC inhibitors, primarily those targeted to class I HDACs, enhance learning and memory as well as long-term potentiation. However, a detailed understanding of the role of class II HDACs in these processes remains elusive. Here, we show that selective loss of Hdac4 in brain results in impairments in hippocampal-dependent learning and memory and long-term synaptic plasticity. In contrast, loss of Hdac5 does not impact learning and memory demonstrating unique roles in brain for individual class II HDACs. These findings suggest that HDAC4 is a crucial positive regulator of learning and memory, both behaviorally and at the cellular level, and that inhibition of Hdac4 activity may have unexpected detrimental effects to these processes.