POMC-specific knockdown of MeCP2 leads to adverse phenotypes in mice chronically exposed to high fat diet.

Methyl-CpG binding protein 2 (MeCP2) is an epigenetic factor associated with the neurodevelopmental disorders Rett Syndrome and MECP2 duplication syndrome. Previous studies have demonstrated that knocking out MeCP2 globally in the central nervous system leads to an obese phenotype and hyperphagia, however it is not clear if the hyperphagia is the result of an increased preference for food reward or due to an increase in motivation to obtain food reward. We show that mice deficient in MeCP2 specifically in pro-opiomelanocortin (POMC) neurons have an increased preference for high fat diet as measured by conditioned place preference but do not have a greater motivation to obtain food reward using a progressive ratio task, relative to wildtype littermate controls.

Perinatal exposure to high fat diet alters expression of MeCP2 in the hypothalamus.

Obesity is a complex disease that is the result of a number of different factors including genetic, environmental, and endocrine abnormalities. Given that monogenic forms of obesity are rare, it is important to identify other mechanisms that contribute to its etiology. Methyl-Cp-G binding protein 2 (MeCP2) is a neuroepigenetic factor that binds to methylated regions of DNA to influence transcription.

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.

Decreased sensitivity to the anorectic effects of leptin in mice that lack a Pomc-specific neural enhancer.

Enhancer redundancy has been postulated to provide a buffer for gene expression against genetic and environmental perturbations. While work in Drosophila has identified functionally overlapping enhancers, work in mammalian models has been limited. Recently, we have identified two partially redundant enhancers, nPE1 and nPE2, that drive proopiomelanocortin gene expression in the hypothalamus.

Correction: D-cycloserine improves synaptic transmission in an animal mode of Rett syndrome.

[This corrects the article DOI: 10.1371/journal.pone.

D-cycloserine improves synaptic transmission in an animal model of Rett syndrome.

Rett syndrome (RTT), a leading cause of intellectual disability in girls, is predominantly caused by mutations in the X-linked gene MECP2. Disruption of Mecp2 in mice recapitulates major features of RTT, including neurobehavioral abnormalities, which can be reversed by re-expression of normal Mecp2. Thus, there is reason to believe that RTT could be amenable to therapeutic intervention throughout the lifespan of patients after the onset of symptoms.

Impact of DNMT1 and DNMT3a forebrain knockout on depressive- and anxiety like behavior in mice.

DNA methylation has been shown to impact certain forms of synaptic and behavioral plasticity that have been implicated in the development in psychiatric disorders. DNA methylation is catalyzed by DNA methyltransferase (DNMT) enzymes that continue to be expressed in postmitotic neurons in the forebrain. Using a conditional forebrain knockout of DNMT1 or DNMT3a we assessed the role of these DNMTs in anxiety and depressive-like behavior in mice using an array of behavioral testing paradigms.

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.

GABAA receptor antagonism ameliorates behavioral and synaptic impairments associated with MeCP2 overexpression.

Methyl-CpG-binding protein 2 (MeCP2) is a ubiquitously expressed transcriptional regulator with functional importance in the central nervous system. Loss-of-function mutations in MECP2 results in the neurodevelopmental disorder, Rett syndrome, whereas increased expression levels are associated with the neurological disorder, MECP2 duplication syndrome. Previous characterization of a mouse line overexpressing Mecp2 demonstrated that this model recapitulated key behavioral features of MECP2 duplication syndrome with specific deficits in synaptic plasticity and neurotransmission.

Loss of histone deacetylase 2 improves working memory and accelerates extinction learning.

Histone acetylation and deacetylation can be dynamically regulated in response to environmental stimuli and play important roles in learning and memory. Pharmacological inhibition of histone deacetylases (HDACs) improves performance in learning tasks; however, many of these classical agents are "pan-HDAC" inhibitors, and their use makes it difficult to determine the roles of specific HDACs in cognitive function. We took a genetic approach using mice lacking the class I HDACs, HDAC1 or HDAC2, in postmitotic forebrain neurons to investigate the specificity or functional redundancy of these HDACs in learning and synaptic plasticity.

Differential effects of chronic social stress and fluoxetine on meal patterns in mice.

Both chronic stress and antidepressant medications have been associated with changes in body weight. In the current study, we investigate mechanisms by which stress and antidepressants interact to affect meal patterns. A group of mice was subjected to the chronic social defeat stress model of major depression followed by fluoxetine treatment and was subsequently analyzed for food intake using metabolic cages.

Voluntary running-wheel exercise decreases the threshold for rewarding intracranial self-stimulation.

Physical exercise has mood-enhancing and antidepressant properties although the mechanisms underlying these effects are not known. The present experiment investigated the effects of prolonged access to a running wheel on electrical self-stimulation of the lateral hypothalamus (LHSS), a measure of hedonic state, in rats. Rats with continuous voluntary access to a running wheel for either 2 or 5 weeks exhibited dramatic leftward shifts in the effective current 50 (ECu50; current value that supports half of maximum responding) of their LHSS current-response functions compared to their baselines, indicating a decrease in reward threshold, whereas control rats current-response functions after 2 or 5 weeks were not significantly different from baseline.

The impact of MeCP2 loss- or gain-of-function on synaptic plasticity.

Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator of gene expression that is an important epigenetic factor in the maintenance and development of the central nervous system. The neurodevelopmental disorders Rett syndrome and MECP2 duplication syndrome arise from loss-of-function and gain-of-function alterations in MeCP2 expression, respectively. Several animal models have been developed to recapitulate the symptoms of Rett syndrome and MECP2 duplication syndrome.

A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission.

Rett syndrome and MECP2 duplication syndrome are neurodevelopmental disorders that arise from loss-of-function and gain-of-function alterations in methyl-CpG binding protein 2 (MeCP2) expression, respectively. Although there have been studies examining MeCP2 loss of function in animal models, there is limited information on MeCP2 overexpression in animal models. Here, we characterize a mouse line with MeCP2 overexpression restricted to neurons (Tau-Mecp2).

Opioid mechanisms that mediate the palatability of and appetite for salt in sodium replete and deficient states.

Sodium deficiency reliably produces a robust intake of saline in rats, which is associated with an increased preference for sodium solutions at hypertonic concentrations that would normally be avoided. The mechanisms underlying the shift to an increased preference for sodium in the deficient state are not well understood. The current experiments examined the role of opioids on changes of behavioral responses that are modified as a function of body sodium status by studying the intake of 0.

The role of MeCP2 in CNS development and function.

Rett syndrome is a neurodevelopmental disorder that is a direct consequence of functional mutations in the methyl-CpG-binding protein-2 (MeCP2) gene, which has focused attention on epigenetic mechanisms in neurons. MeCP2 is widely believed to be a transcriptional repressor although it may have additional functions in the CNS. Genetic mouse models that compromise MeCP2 function demonstrate that homeostatic regulation of MeCP2 is necessary for normal CNS functioning.

Mineralocorticoid receptor antagonism prevents hedonic deficits induced by a chronic sodium appetite.

Our laboratory has reported that manipulations that provoke a robust sodium appetite (e.g., sodium depletion, deoxycorticosterone acetate) decrease lateral hypothalamic self-stimulation (LHSS) reward if rats are denied access to hypertonic saline solutions.

Behavioral cross-sensitization between morphine-induced locomotion and sodium depletion-induced salt appetite.

In general terms, sensitization refers to the capacity of a repetitive stimulus of fixed strength to produce a progressive increase in the magnitude of a response with each stimulation. In the addiction literature cross-sensitization is the capacity of an agent with abuse potential to sensitize a behavioral response induced by another stimulus. In the present experiments we examined the effects of morphine pretreatment on furosemide-induced saline intake and conversely sodium appetite induction on morphine-induced locomotion.

Salt craving: the psychobiology of pathogenic sodium intake.

Ionic sodium, obtained from dietary sources usually in the form of sodium chloride (NaCl, common table salt) is essential to physiological function, and in humans salt is generally regarded as highly palatable. This marriage of pleasant taste and physiological utility might appear fortunate--an appealing taste helps to ensure that such a vital substance is ingested. However, the powerful mechanisms governing sodium retention and sodium balance are unfortunately best adapted for an environment in which few humans still exist.

The neural substrates of enhanced salt appetite after repeated sodium depletions.

Sodium appetite is associated with a form of behavioral plasticity in which animals experimentally depleted of sodium progressively increase their intake of hypertonic NaCl over several successive (on 2 to 4 occasions) depletion. The present experiment explored the nature of this plasticity by quantifying Fos immunoreactivity (Fos-ir) in structures implicated in the mediation of sodium appetite and in the signaling of reward. Rats were depleted of sodium with the diuretic furosemide three times (3F), one time (2V1F) or sham depleted (i.

The effects of deoxycorticosterone-induced sodium appetite on hedonic behaviors in the rat.

The authors tested the hypothesis that chronic treatment with a dose of deoxycorticosterone acetate (DOCA) known to elicit a robust sodium appetite can negatively affect the hedonic state of rats. Daily treatment with DOCA with no opportunity to ingest saline produced a rightward shift in the midpoint (effective current 50) of lateral hypothalamic self-stimulation (LHSS) current-response functions and reduced intakes of a palatable sucrose solution. Providing rats with 0.

Sucrose ingestion elicits reduced Fos expression in the nucleus accumbens of anhedonic rats.

Chronic mild stress (CMS), an animal model of depression associated with anhedonia, was used to examine nucleus accumbens (NAc) activation associated with a rewarding stimulus. Following 4 weeks of CMS in rats, NAc Fos-immunoreactivity was measured after ingestion of a fixed volume of sucrose. Fewer Fos-positive neurons were observed in the NAc in CMS versus control rats.

Induction of a salt appetite alters dendritic morphology in nucleus accumbens and sensitizes rats to amphetamine.

Sensitization to drugs, such as amphetamine, is associated with alterations in the morphology of neurons in the nucleus accumbens, a brain region critical to motivation and reward. The studies reported here indicate that a strong natural motivator, sodium depletion and associated salt appetite, also leads to alterations in neurons in nucleus accumbens. Medium spiny neurons in the shell of the nucleus accumbens of rats that had experienced sodium depletions had significantly more dendritic branches and spines than controls.