Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice.

The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2).

EphrinA5 regulates cell motility by modulating Snhg15/DNA triplex-dependent targeting of DNMT1 to the Ncam1 promoter.

Cell-cell communication is mediated by membrane receptors and their ligands, such as the Eph/ephrin system, orchestrating cell migration during development and in diverse cancer types. Epigenetic mechanisms are key for integrating external "signals", e.g.

Tripartite extended amygdala-basal ganglia CRH circuit drives locomotor activation and avoidance behavior.

An adaptive stress response involves various mediators and circuits orchestrating a complex interplay of physiological, emotional, and behavioral adjustments. We identified a population of corticotropin-releasing hormone (CRH) neurons in the lateral part of the interstitial nucleus of the anterior commissure (IPACL), a subdivision of the extended amygdala, which exclusively innervate the substantia nigra (SN). Specific stimulation of this circuit elicits hyperactivation of the hypothalamic-pituitary-adrenal axis, locomotor activation, and avoidance behavior contingent on CRH receptor type 1 (CRHR1) located at axon terminals in the SN, which originate from external globus pallidus (GPe) neurons.

Epigenetic mechanism of SETDB1 in brain: implications for neuropsychiatric disorders.

Neuropsychiatric disorders are a collective of cerebral conditions with a multifactorial and polygenetic etiology. Dysregulation of epigenetic profiles in the brain is considered to play a critical role in the development of neuropsychiatric disorders. SET domain, bifurcate 1 (SETDB1), functioning as a histone H3K9 specific methyltransferase, is not only critically involved in transcriptional silencing and local heterochromatin formation, but also affects genome-wide neuronal epigenetic profiles and is essential for 3D genome integrity.

Hyperfunction of the stress response system and novelty-induced hyperactivity correlate with enhanced cocaine-induced conditioned place preference in NCAM-deficient mice.

Several studies in humans and rodents suggest an association between impulsivity and activity of the stress response on the one hand and addiction vulnerability on the other. The neural cell adhesion molecule (NCAM) has been related to several neuropsychiatric disorders in humans. Constitutively NCAM-deficient (-/-) mice display enhanced novelty-induced behavior and hyperfunction of the hypothalamic-pituitary-adrenal axis.

Native Chromatin Immunoprecipitation (N-ChIP) in Primary Cortical Rat Astrocytes.

Chromatin immunoprecipitation (ChIP) in conjunction with qPCR or next generation sequencing (ChIP-seq) is used to detect protein-DNA interaction. Typically, DNA bound to a protein of interest is captured with an antibody against this protein, and DNA is then purified from DNA-protein complexes. Here, we describe a native Chromatin immunoprecipitation (N-ChIP) approach which is an efficient ChIP method with high resolution for histone modifications and a number of transcription factors.

Shorter telomeres associated with high doses of glucocorticoids: the link to increased mortality?

Objective: Patients with non-functioning pituitary adenomas exhibit high morbidity and mortality rates. Growth hormone deficiency and high doses of glucocorticoid substitution therapy have been identified as corresponding risk factors. Interestingly, high levels of endogenous cortisol in, e.

Sex dependent impact of gestational stress on predisposition to eating disorders and metabolic disease.

Objective: Vulnerability to eating disorders (EDs) is broadly assumed to be associated with early life stress. However, a careful examination of the literature shows that susceptibility to EDs may depend on the type, severity and timing of the stressor and the sex of the individual. We aimed at exploring the link between chronic prenatal stress and predisposition to EDs and metabolic disease.

The Role of mA/m-RNA Methylation in Stress Response Regulation.

N-methyladenosine (mA) and N,2'-O-dimethyladenosine (mAm) are abundant mRNA modifications that regulate transcript processing and translation. The role of both, here termed mA/m, in the stress response in the adult brain in vivo is currently unknown. Here, we provide a detailed analysis of the stress epitranscriptome using mA/m-seq, global and gene-specific mA/m measurements.

Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety.

The interplay between corticotropin-releasing hormone (CRH) and the dopaminergic system has predominantly been studied in addiction and reward, while CRH-dopamine interactions in anxiety are scarcely understood. We describe a new population of CRH-expressing, GABAergic, long-range-projecting neurons in the extended amygdala that innervate the ventral tegmental area and alter anxiety following chronic CRH depletion. These neurons are part of a distinct CRH circuit that acts anxiolytically by positively modulating dopamine release.

Placental miR-340 mediates vulnerability to activity based anorexia in mice.

Anorexia nervosa (AN) is a devastating eating disorder characterized by self-starvation that mainly affects women. Its etiology is unknown, which impedes successful treatment options leading to a limited chance of full recovery. Here, we show that gestation is a vulnerable window that can influence the predisposition to AN.

A Methyl-Balanced Diet Prevents CRF-Induced Prenatal Stress-Triggered Predisposition to Binge Eating-like Phenotype.

Binge eating (BE) is a common aberrant form of eating behavior, characterized by overconsumption of food in a brief period of time. Recurrent episodes of BE constitute the BE disorder, which mostly affects females and is associated with early-life adversities. Here, we show that corticotropin releasing factor (CRF)-induced prenatal stress (PNS) in late gestation predisposes female offspring to BE-like behavior that coincides with hypomethylation of hypothalamic miR-1a and downstream dysregulation of the melanocortin system through Pax7/Pax3.

Histone Modifications in Major Depressive Disorder and Related Rodent Models.

Major depressive disorder (MDD) is a multifactorial disease, weakly linked to multiple genetic risk factors. In contrast to that, environmental factors and "gene × environment" interaction between specific risk genes and environmental factors, such as severe or early stress exposure, have been strongly linked to MDD vulnerability. Stressors can act on the interface between an organism and the environment, the epigenome.

Sequencing on the SOLiD 5500xl System - in-depth characterization of the GC bias.

Different types of sequencing biases have been described and subsequently improved for a variety of sequencing systems, mostly focusing on the widely used Illumina systems. Similar studies are missing for the SOLiD 5500xl system, a sequencer which produced many data sets available to researchers today. Describing and understanding the bias is important to accurately interpret and integrate these published data in various ongoing research projects.

DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition.

Background: Early childhood malnutrition affects 113 million children worldwide, impacting health and increasing vulnerability for cognitive and behavioral disorders later in life. Molecular signatures after childhood malnutrition, including the potential for intergenerational transmission, remain unexplored.

Methods: We surveyed blood DNA methylomes (~483,000 individual CpG sites) in 168 subjects across two generations, including 50 generation 1 individuals hospitalized during the first year of life for moderate to severe protein-energy malnutrition, then followed up to 48 years in the Barbados Nutrition Study.

Early effects of a high-caloric diet and physical exercise on brain volumetry and behavior: a combined MRI and histology study in mice.

Excessive intake of high-caloric diets as well as subsequent development of obesity and diabetes mellitus may exert a wide range of unfavorable effects on the central nervous system (CNS) in the long-term. The potentially harmful effects of such diets were suggested to be mitigated by physical exercise. Here, we conducted a study investigating early effects of a cafeteria-diet on gray and white brain matter volume by means of voxel-based morphometry (VBM) and region-of-interest (ROI) analysis.

Neuronal Deletion of Kmt2a/Mll1 Histone Methyltransferase in Ventral Striatum is Associated with Defective Spike-Timing-Dependent Striatal Synaptic Plasticity, Altered Response to Dopaminergic Drugs, and Increased Anxiety.

Lysine (K) methyltransferase 2a (Kmt2a) and other regulators of H3 lysine 4 methylation, a histone modification enriched at promoters and enhancers, are widely expressed throughout the brain, but molecular and cellular phenotypes in subcortical areas remain poorly explored. We report that Kmt2a conditional deletion in postnatal forebrain is associated with excessive nocturnal activity and with absent or blunted responses to stimulant and dopaminergic agonist drugs, in conjunction with near-complete loss of spike-timing-dependent long-term potentiation in medium spiny neurons (MSNs). Selective ablation of Kmt2a, but not the ortholog Kmt2b, in adult ventral striatum/nucleus accumbens neurons markedly increased anxiety scores in multiple behavioral paradigms.

Pharmacological modulation of astrocytes and the role of cell type-specific histone modifications for the treatment of mood disorders.

Astrocytes orchestrate arrangement and functions of neuronal circuits and of the blood-brain barrier. Dysfunctional astrocytes characterize mood disorders, here showcased by deregulation of the astrocyte end-feet protein Aquaporin-4 around blood vessels and, hypothetically, of the astrocyte-specific phagocytic protein MEGF10 to shape synapses. Development of mood disorders is often a result of 'gene × environment' interactions, regulated among others by histone modifications and related modulator enzymes, which rapidly promote adaptive responses.

Neuronal Kmt2a/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory.

Neuronal histone H3-lysine 4 methylation landscapes are defined by sharp peaks at gene promoters and other cis-regulatory sequences, but molecular and cellular phenotypes after neuron-specific deletion of H3K4 methyl-regulators remain largely unexplored. We report that neuronal ablation of the H3K4-specific methyltransferase, Kmt2a/Mixed-lineage leukemia 1 (Mll1), in mouse postnatal forebrain and adult prefrontal cortex (PFC) is associated with increased anxiety and robust cognitive deficits without locomotor dysfunction. In contrast, only mild behavioral phenotypes were observed after ablation of the Mll1 ortholog Kmt2b/Mll2 in PFC.

Effects of a high-caloric diet and physical exercise on brain metabolite levels: a combined proton MRS and histologic study.

Excessive intake of high-caloric diets as well as subsequent development of obesity and diabetes mellitus may exert a wide range of unfavorable effects on the central nervous system (CNS). It has been suggested that one mechanism in this context is the promotion of neuroinflammation. The potentially harmful effects of such diets were suggested to be mitigated by physical exercise.

Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains.

To investigate epigenetic contributions to Huntington's disease (HD) pathogenesis, we carried out genome-wide mapping of the transcriptional mark, trimethyl-histone H3-lysine 4 (H3K4me3) in neuronal nuclei extracted from prefrontal cortex of HD cases and controls using chromatin immunoprecipitation followed by deep-sequencing. Neuron-specific mapping of the genome-wide distribution of H3K4me3 revealed 136 differentially enriched loci associated with genes implicated in neuronal development and neurodegeneration, including GPR3, TMEM106B, PDIA6 and the Notch signaling genes hairy and enhancer of split 4 (HES4) and JAGGED2, supporting the view that the neuronal epigenome is affected in HD. Importantly, loss of H3K4me3 at CpG-rich sequences on the HES4 promoter was associated with excessive DNA methylation, reduced binding of nuclear proteins to the methylated region and altered expression of HES4 and HES4 targeted genes MASH1 and P21 involved in striatal development.

Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition.

Three-dimensional chromosomal conformations regulate transcription by moving enhancers and regulatory elements into spatial proximity with target genes. Here we describe activity-regulated long-range loopings bypassing up to 0.5 Mb of linear genome to modulate NMDA glutamate receptor GRIN2B expression in human and mouse prefrontal cortex.

Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporal dementia.

Neurodegenerative diseases, such as frontotemporal dementia (FTD), are often associated with behavioral deficits, but the underlying anatomical and molecular causes remain poorly understood. Here we show that forebrain-specific expression of FTD-associated mutant CHMP2B in mice causes several age-dependent neurodegenerative phenotypes, including social behavioral impairments. The social deficits were accompanied by a change in AMPA receptor (AMPAR) composition, leading to an imbalance between Ca(2+)-permeable and Ca(2+)-impermeable AMPARs.

Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology.

Fragile X syndrome (FXS), the most common cause of inherited mental retardation and autism, is caused by transcriptional silencing of FMR1, which encodes the translational repressor fragile X mental retardation protein (FMRP). FMRP and cytoplasmic polyadenylation element-binding protein (CPEB), an activator of translation, are present in neuronal dendrites, are predicted to bind many of the same mRNAs and may mediate a translational homeostasis that, when imbalanced, results in FXS. Consistent with this possibility, Fmr1(-/y); Cpeb1(-/-) double-knockout mice displayed amelioration of biochemical, morphological, electrophysiological and behavioral phenotypes associated with FXS.