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Author: Cathy Fernandes (51)


Feb
2018

Repeated lipopolysaccharide exposure is often used in longitudinal preclinical models of depression. However, the potential phenotypic differences from acute depression-mimicking effects are rarely described. This study compared chronic lipopolysaccharide administration of doses previously used in depression research to a new mode of escalating dose injections.

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Dec
1969

Reduced fibroblast growth factor (FGF) signaling from the mid-hindbrain or isthmus organizer (IsO) during early embryonic development results in hypoplasia of the midbrain and cerebellar vermis. We previously reported evidence for reducedexpression and FGF signaling in the mid-hindbrain region of embryos heterozygous for, the gene mutated in CHARGE (Coloboma, Heart defects, choanal Atresia, Retarded growth and development, Genitourinary anomalies and Ear defects) syndrome. However,animals only exhibit mild cerebellar vermis anomalies.

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Aug
2017

Activity-dependent neuronal plasticity is a fundamental mechanism through which the nervous system adapts to sensory experience. Several lines of evidence suggest that parvalbumin (PV+) interneurons are essential in this process, but the molecular mechanisms underlying the influence of experience on interneuron plasticity remain poorly understood. Perineuronal nets (PNNs) enwrapping PV+ cells are long-standing candidates for playing such a role, yet their precise contribution has remained elusive.

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Jul
2017

Lamellipodin (Lpd) functions as an important signalling integrator downstream of growth factor and axon guidance receptors. Mechanistically, Lpd promotes actin polymerization by interacting with F-actin and the actin effectors Ena/VASP proteins and the SCAR/WAVE complex. Thereby, Lpd supports lamellipodia protrusion, cell migration and endocytosis.

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Dec
2017

The fundamental role of the brain-specific myelin transcription factor 1-like (MYT1L) gene in cases of intellectual disability and in the etiology of neurodevelopmental disorders is increasingly recognized. Yet, its function remains under-investigated. Here, we identify a network of helix-loop-helix (HLH) transcriptional regulators controlled by MYT1L, as indicated by our analyses in human neural stem cells and in the human brain.

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May
2017

Advanced paternal age (APA) at conception has been linked with autism and schizophrenia in offspring, neurodevelopmental disorders that affect social functioning. The current study explored the effects of paternal age on social development in the general population.
We used multilevel growth modeling to investigate APA effects on socioemotional development from early childhood until adolescence, as measured by the Strengths and Difficulties Questionnaire (SDQ) in the Twins Early Development Study (TEDS) sample.

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Mar
2017

The mechanisms underlying the neurodevelopmental deficits associated with CHARGE syndrome, which include cerebellar hypoplasia, developmental delay, coordination problems, and autistic features, have not been identified. CHARGE syndrome has been associated with mutations in the gene encoding the ATP-dependent chromatin remodeler CHD7. CHD7 is expressed in neural stem and progenitor cells, but its role in neurogenesis during brain development remains unknown.

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Feb
2017

Although the search for quantitative trait loci for behaviour remains a considerable challenge, the complicated genetic architecture of quantitative traits is beginning to be understood. The current project utilised heterogeneous stock (HS) male mice (n = 580) to investigate the genetic basis for brain weights, activity, anxiety and cognitive phenotypes. We identified 126 single nucleotide polymorphisms (SNPs) in genes involved in regulation of neurotransmitter systems, nerve growth/death and gene expression, and subsequently investigated their associations with changes in behaviour and/or brain weights in our sample.

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Dec
2016

Febrile seizures (FS) are the most common seizure type in children. Recurrent FS are a risk factor for developing temporal lobe epilepsy later in life and are known to have a strong genetic component. Experimental FS (eFS) can be elicited in mice by warm-air induced hyperthermia.

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Mar
2016

Epigenetic disruption has been implicated in many diseases of aging, and age-associated DNA methylation changes at specific genomic loci in humans are strongly correlated with chronological age. The aim of this study was to explore the specificity of selected age-associated differentially methylated positions (aDMPs) identified in human epidemiological studies by quantifying DNA methylation across multiple tissues in homologous regions of the murine genome. We selected four high-confidence aDMPs (located in the vicinity of the ELOVL2, GLRA1, MYOD1 and PDE4C genes) and quantified DNA methylation across these regions in four tissues (blood, lung, cerebellum and hippocampus) from male and female C57BL/6J mice, ranging in age from fetal (embryonic day 17) to 630 days.

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Dec
1969

An imbalance between excitatory (E) glutamate and inhibitory (I) GABA transmission may underlie neurodevelopmental conditions such as autism spectrum disorder (ASD) and schizophrenia. This may be direct, through alterations in synaptic genes, but there is increasing evidence for the importance of indirect modulation of E/I balance through glial mechanisms. Here, we used C57BL/6J mice to test the hypothesis that striatal glutamate levels can be shifted by N-acetylcysteine (NAC), which acts at the cystine-glutamate antiporter of glial cells.

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Sep
2015

Midbrain dopaminergic (mDA) neurons are implicated in cognitive functions, neuropsychiatric disorders, and pathological conditions; hence understanding genes regulating their homeostasis has medical relevance. Transcription factors FOXA1 and FOXA2 (FOXA1/2) are key determinants of mDA neuronal identity during development, but their roles in adult mDA neurons are unknown. We used a conditional knockout strategy to specifically ablate FOXA1/2 in mDA neurons of adult mice.

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Dec
1969

Human genetics has identified rare copy number variations and deleterious mutations for all neurexin genes (NRXN1-3) in patients with neurodevelopmental diseases, and electrophysiological recordings in animal brains have shown that Nrxns are important for synaptic transmission. While several mouse models for Nrxn1α inactivation have previously been studied for behavioral changes, very little information is available for other variants. Here, we validate that mice lacking Nrxn2α exhibit behavioral abnormalities, characterized by social interaction deficits and increased anxiety-like behavior, which partially overlap, partially differ from Nrxn1α mutant behaviors.

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Oct
2014

Alcohol abuse leads to serious health problems with no effective treatment available. Recent evidence suggests a role for ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) in alcoholism. Rasgrf2 is a calcium sensor and MAPK/ERK activating protein, which has been linked to neurotransmitter release and monoaminergic receptor adaptations.

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Dec
1969

The immune system plays an important role in the communication between the human body and the environment, in early development as well as in adulthood. Per se, research has shown that factors such as maternal stress and nutrition as well as maternal infections can activate the immune system in the infant. A rising number of research studies have shown that activation of the immune system in early life can augment the risk of some psychiatric disorders in adulthood, such as schizophrenia and depression.

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Oct
2014

Alcohol addiction is a major psychiatric disease, and yet, the underlying molecular adaptations in the brain remain unclear. Recent evidence suggests a functional role for the ras-specific guanine-nucleotide releasing factor 2 (Rasgrf2) in alcoholism. Rasgrf2(-/-) mice consume less alcohol and show entirely absent dopamine responses to an alcohol challenge compared to wild types (WT).

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Aug
2014

Epigenetic processes play a key role in the central nervous system and altered levels of 5-methylcytosine have been associated with a number of neurologic phenotypes, including Alzheimer's disease (AD). Recently, 3 additional cytosine modifications have been identified (5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine), which are thought to be intermediate steps in the demethylation of 5-methylcytosine to unmodified cytosine. Little is known about the frequency of these modifications in the human brain during health or disease.

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Mar
2014

Advanced paternal age is robustly associated with several human neuropsychiatric disorders, particularly autism. The precise mechanism(s) mediating the paternal age effect are not known, but they are thought to involve the accumulation of de novo (epi)genomic alterations. In this study we investigate differences in the frontal cortex transcriptome in a mouse model of advanced paternal age.

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May
2014

To clarify the basis of limited responses in children and adolescents to antidepressant treatments considered standard in the treatment of adult major depressive disorder, juvenile Sprague-Dawley rats were subjected to 21-day treatment with dissimilar antidepressant drugs fluoxetine, imipramine, or vehicle control. Total RNA was extracted from brain frontal cortices and hybridized to the Affymetrix 230.2 chip.

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Dec
1969

Copy number variants have emerged as an important genomic cause of common, complex neurodevelopmental disorders. These usually change copy number of multiple genes, but deletions at 2p16.3, which have been associated with autism, schizophrenia and mental retardation, affect only the neurexin 1 gene, usually the alpha isoform.

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Sep
2013

The autophosphorylation of alpha Ca2+ /calmodulin dependent protein kinase II (αCaMKII) is important for memory formation and is becoming increasingly implicated in the development of drug addiction. Previous work suggests that αCaMKII acts via the monoaminergic systems to facilitate the establishment of alcohol drinking behaviour. The present study aims to investigate whether αCaMKII autophosphorylation deficient αCaMKII(T286A) mice show a difference in the rewarding properties of alcohol (2 g/kg, i.

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Dec
1969

The aim of present study was to find genetic pathways activated during infection with bacterial meningitis (BM) and potentially influencing the course of the infection using genome-wide RNA expression profiling combined with pathway analysis and functional annotation of the differential transcription.
We analyzed 21 patients with BM hospitalized in 2008. The control group consisted of 18 healthy subjects.

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Aug
2013

The α-Ca(2+)/calmodulin-dependent protein kinase II (αCaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of αCaMKII works as a 'molecular memory' for a transient calcium activation, thereby accelerating learning. We investigated the role of αCaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice.

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Mar
2013

The gene WFS1 encodes a protein with unknown function although its functional deficiency causes different neuropsychiatric and neuroendocrine syndromes. In the present study, we aimed to find the functional networks influenced by the time-dependent silencing of WFS1 in HEK cells. We performed whole genome gene expression profiling (Human Gene 1.

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Dec
2012

Insulin-like growth factor 2 (Igf2) is a paternally expressed imprinted gene regulating fetal growth, playing an integral role in the development of many tissues including the brain. The parent-of-origin specific expression of Igf2 is largely controlled by allele-specific DNA methylation at CTCF-binding sites in the imprinting control region (ICR), located immediately upstream of the neighboring H19 gene. Previously we reported evidence of a negative correlation between DNA methylation in this region and cerebellum weight in humans.

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Sep
2012

miRNAs are short single-stranded non-coding RNAs involved in post-transcriptional gene regulation that play a major role in normal biological functions and diseases. Little is currently known about how expression of miRNAs is regulated. We surveyed variation in miRNA abundance in the hippocampus of mouse inbred strains, allowing us to take a genetic approach to the study of miRNA regulation, which is novel for miRNAs.

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Oct
2012

Common neurodevelopmental disorders (including autism, speech and language delay, schizophrenia, epilepsy and intellectual disability) have complex aetiology, which is predominantly genomic, but also environmental in origin. They share a paradox, in that high heritability is matched by lowered fecundity, placing them under negative genetic selection. This implicates variants of recent origin, such as de novo mutations or common, very low-risk polymorphisms that escape negative selection.

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Dec
1969

Disruption of the circadian rhythm is a key feature of bipolar disorder. Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations. Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour.

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Aug
2012

Amyloid-β peptide (Aβ) is the principal component of plaques in the brains of patients with Alzheimer's disease (AD), and the most toxic form of Aβ may be as soluble oligomers. We report here the results of a microarray study of gene expression profiles in primary mouse cortical neurons in response to oligomeric Aβ(1-42). A major and unexpected finding was the down-regulation of genes involved in the biosynthesis of cholesterol and other steroids and lipids (such as Fdft1, Fdps, Idi1, Ldr, Mvd, Mvk, Nsdhl, Sc4mol), the expression of which was verified by quantitative real-time RT-PCR (qPCR).

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Dec
1969

Methcathinone (ephedrone) is relatively easily accessible for abuse. Its users develop an extrapyramidal syndrome and it is not known if this is caused by methcathinone itself, by side-ingredients (manganese), or both. In the present study we aimed to clarify molecular mechanisms underlying this condition.

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Jun
2012

Depression-Related Behavioral Tests.

Curr Protoc Mouse Biol 2012 Jun 1;2(2):119-27. Epub 2012 Jun 1.
Timothy R Powell, Cathy Fernandes, Leonard C Schalkwyk
Overlapping characteristics between human depressive phenotypes and mouse behaviors has led to the creation of mouse models that aim to investigate the pathophysiology and treatment of unipolar depression. Behavioral tests in mice are used to assess and quantify the extent to which a mouse model displays a depression-like phenotype. The forced swim test and tail suspension test, sucrose preference test, and novelty suppressed feeding tests all aim to measure different components of depression.

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Jan
2012

Mounting evidence suggest that epigenetic regulation of brain functions is important in the etiology of psychiatric disorders. These epigenetic regulatory mechanisms, such as DNA methylation and histone acetylation, are influenced by many pharmaceutical compounds including psychiatric drugs. It is therefore of interest to investigate how psychiatric drugs are of influence and what the potential is of new epigenetic drugs for psychiatric disorders.

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Dec
2011

The Wfs1 gene codes for a protein with unknown function, but deficiency in this protein results in a range of neuropsychiatric and neuroendocrine syndromes. In the present study we aimed to find the functional networks influenced by Wfs1 in the hypothalamus. We performed gene expression profiling (Mouse Gene 1.

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Dec
2011

Selecting an effective treatment for patients with major depressive disorder is a perpetual problem for psychiatrists. It is of particular interest to explore the interaction between genetic predisposition and environmental factors.
Mouse inbred strains vary in baseline performance in depression-related behaviour tests, which were originally validated as tests of antidepressant response.

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Dec
2011

Autophosphorylation of αCaMKII is regarded as a 'molecular memory' for Ca(2+) transients and a crucial mechanism in aversely, but less so in appetitively, motivated learning and memory. While there is a growing body of research implicating αCaMKII in general in behavioral responses to threat or fearful stimuli, little is known about the contribution of the autophosphorylation. The present study asked how αCaMKII autophosphorylation controls anxiety-like behavioral responses toward novel, potentially threatening stimuli.

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Aug
2011

Glycogen synthase kinase 3 (GSK3) is a widely expressed, constitutively active, serine/threonine kinase that is negatively regulated by both Wnt and insulin via two independent signalling pathways. GSK3 is an important mediator in many physiological processes including glycogen metabolism, apoptosis and gene transcription. In addition, GSK3 is implicated in diseases such as Alzheimer's, schizophrenia and cancer, where it exhibits deregulated activity.

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Aug
2011

Cannabis is one of the most commonly used illicit drugs, and despite the widely held belief that it is a safe drug, its long-term use has potentially harmful consequences. To date, the research on the impact of its use has largely been epidemiological in nature and has consistently found that cannabis use is associated with schizophrenia outcomes later in life, even after controlling for several confounding factors. While the majority of users can continue their use without adverse effects, it is clear from studies of psychosis that some individuals are more vulnerable to its effects than others.

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Mar
2011

Addiction is a debilitating psychiatric disorder, with a complex aetiology involving the interaction of inherited predispositions and environmental factors. Emerging evidence suggests that epigenetic alterations to the genome, including DNA methylation and histone modifications, are important mechanisms underlying addiction and the neurobiological response to addictive substances. In this review, we introduce the reader to epigenetic mechanisms and describe a potential role for dynamic epigenetic changes in mediating addictive behaviours via long-lasting changes in gene expression.

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Dec
2009

Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism, schizophrenia and early-onset bipolar disorder. In order to establish causality, this study used an animal model to investigate the effects of advanced paternal age on behavioural deficits in the offspring.
C57BL/6J offspring (n = 12 per group) were bred from fathers of two different ages, 2 months (young) and 10 months (old), and mothers aged 2 months (n = 6 breeding pairs per group).

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Mar
2010

The use of large scale behavioural batteries for the discovery of novel genes underlying behavioural variation has considerable potential. Building a broad behavioural profile serves to better understand the complex interplay of overlapping genetic factors contributing to various paradigms, underpinning a systems biology approach. We devised a battery of tests to dissect and characterise the genetic bases of behavioural phenotypes, but firstly undertook to evaluate several aspects considered potentially confounding for mapping quantitative traits.

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Aug
2009

Studying the causes and correlates of natural variation in gene expression in healthy populations assumes that individual differences in gene expression can be reliably and stably assessed across time. However, this is yet to be established. We examined 4-hour test-retest reliability and 10 month test-retest stability of individual differences in gene expression in ten 12-year-old children.

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Dec
1969

Microarrays are designed to measure genome-wide differences in gene expression. In cases where a tissue is not accessible for analysis (e.g.

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Jan
2009

In many studies using mice, investigators must determine pups' gender at a very early postnatal stage. The gender of mouse pups is typically assessed by measuring the anogenital distance, which is greater in males than in females. This method, however, has proven to be difficult and not completely reliable.

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Apr
2009

The nicotine discriminative stimulus has been linked to beta2-containing (beta2*) nicotinic receptors, with little evidence of a role for alpha7 nicotinic receptors, because nicotine discrimination was very weak in beta2 null mutant mice but normal in alpha7 mutants.
As both alpha7 and beta2* nicotinic receptors have been implicated in nicotine-stimulated dopamine overflow, this study focused on the dopamine-mediated element in the nicotine stimulus by examining cross-generalisation between amphetamine and nicotine.
Male alpha7 nicotinic receptor null mutant mice and wild-type controls were bred in-house and trained to discriminate nicotine (0.

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Mar
2008

The cholecystokinin B (2) receptor knockout (Cckbr KO) protects against allodynia induced by chronic constriction injury (CCI). The mechanism of this phenomenon is unknown, but must involve persistent changes in pain modulation and/or inflammatory pathways. We performed a gene expression study in two brain areas (midbrain and medulla) after surgical induction of CCI in Cckbr KO and wild-type (wt) control mice.

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Jul
2007

Immobility in the tail suspension test (TST) is considered a model of despair in a stressful situation, and acute treatment with antidepressants reduces immobility. Inbred strains of mouse exhibit widely differing baseline levels of immobility in the TST and several quantitative trait loci (QTLs) have been nominated. The labor of manual scoring and various scoring criteria make obtaining robust data and comparisons across different laboratories problematic.

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Sep
2005

This report includes the first sibling study of mouse behavior, and presents evidence for a heritable general cognitive ability (g) factor influencing cognitive batteries. Data from a population of male and female outbred mice (n = 84), and a replication study of male sibling pairs (n = 167) are reported. Arenas employed were the T-maze, the Morris water maze, the puzzle box, the Hebb-Williams maze, object exploration, a water plus-maze, and a second food-puzzle arena.

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Apr
2005

Quantitative trait locus (QTL) theory predicts that genetic influence on complex traits involves multiple genes of small effect size. To detect QTL associations of small effect size, large samples and systematic screens of thousands of DNA markers are required. An efficient solution is to genotype case and control DNA pools using SNP microarrays.

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Nov
2004

PWD/Ph is an inbred mouse strain derived from wild mice trapped in central Czech Republic. These mice are of the Mus musculus musculus subspecies, whose ancestors separated from those of Mus musculus domesticus about one million years ago. There is a high degree of variation in the genomic sequence and a wide range of phenotypes between PWD/Ph and standard laboratory inbred mouse strains, the genomes of which are principally Mus musculus domesticus in origin, making PWD/Ph mice an useful resource for complex trait research.

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Sep
2004

Large samples and systematic screens of thousands of DNA markers are needed to detect quantitative trait loci (QTLs) of small effect size. One approach to conduct systematic genome scans for association is to use microarrays which, although expensive and non-reusable, simultaneously genotype thousands of single-nucleotide polymorphisms (SNPs). This brief report provides proof of principle that groups of pooled DNA (for example cases and controls) can be genotyped reliably on a microarray.

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