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Anthony R Isles

Publications and source records attributed to Anthony R Isles.

13 recordsLinked to original sources
PubMed2026

Investigating the Contribution of the Imprinted Gene Asb4 to Parental Care.

Genomic imprinting is a form of epigenetic regulation that leads to expression from one parental allele only and, in animals, is unique to mammals. Imprinted gene expression is predominant in the brain and their roles in neural processes are becoming more appreciated. Recent analyses have indicated an enrichment of imprinted gene expression in the 'parental hub' circuitry. Specifically, imprinted genes were over-represented in the transcriptomic profile of galanin positive (Gal+) neurons in the medial preoptic area (MPOA) of the hypothalamus. One of those imprinted genes showing enriched expression in Gal+ neurons was the maternally expressed Asb4. Here, we propose that Asb4 supports normal activation of MPOA Gal+ neurons required for parental care. We aim to demonstrate abnormal parental behaviours-such as decreased pup retrieval and impaired nest building-and activity of MPOA Gal+ neurons in brain-specific maternal Asb4 knockout mice and hypothesis knockout animals will demonstrate a deficient behavioural phenotype in one or more parental behavioural characteristics.

Animals↗
PubMed2006

Genomic imprinting and the social brain.

Genomic imprinting refers to the parent-of-origin-specific epigenetic marking of a number of genes. This epigenetic mark leads to a bias in expression between maternally and paternally inherited imprinted genes, that in some cases results in monoallelic expression from one parental allele. Genomic imprinting is often thought to have evolved as a consequence of the intragenomic conflict between the parental alleles that occurs whenever there is an asymmetry of relatedness. The two main examples of asymmetry of relatedness are when there is partiality of parental investment in offspring (as is the case for placental mammals, where there is also the possibility of extended postnatal care by one parent), and in social groups where there is a sex-biased dispersal. From this evolutionary starting point, it is predicted that, at the behavioural level, imprinted genes will influence what can broadly be termed bonding and social behaviour. We examine the animal and human literature for examples of imprinted genes mediating these behaviours, and divide them into two general classes. Firstly, mother-offspring interactions (suckling, attachment and maternal behaviours) that are predicted to occur when partiality in parental investment in early postnatal offspring occurs; and secondly, adult social interactions, when there is an asymmetry of relatedness in social groups. Finally, we return to the evolutionary theory and examine whether there is a pattern of behavioural functions mediated by imprinted genes emerging from the limited data, and also whether any tangible predictions can be made with regards to the direction of action of genes of maternal or paternal origin.

Animals↗
PubMed2006

X-monosomy effects on visuospatial attention in mice: a candidate gene and implications for Turner syndrome and attention deficit hyperactivity disorder.

BACKGROUND: The loss of all, or part of an X chromosome, in Turner syndrome (TS, 45,XO) results in deficits in attentional functioning. METHODS: Using a 39,XO mouse model, we tested the hypothesis that X-monosomy and/or parental origin of the single X chromosome may influence visuospatial attentional functioning in a 5-choice serial reaction time task (5-CSRTT). RESULTS: Under attentionally demanding conditions 39,XO mice displayed impaired discriminative response accuracy and slowed correct reaction times relative to 40,XX mice; these deficits were alleviated in a version of the task with reduced attentional demands. Parental origin of the X did not affect performance of the 5-CSRTT. In contrast, the attentional phenotype was rescued in 40,XY*X mice possessing a single maternally inherited X chromosome and a small Y*X chromosome that comprises a complete pseudoautosomal region (PAR), and a small X-specific segment. CONCLUSIONS: Our findings are consistent with an X-monosomy effect on attention and suggest the existence of X-linked gene(s) that escape X-inactivation, are present on the small Y*X chromosome and impact on attentional functioning; the strongest candidate gene is Sts, encoding steroid sulfatase. The data inform the TS literature and indicate novel genetic mechanisms that may be of general significance to the neurobiology of attention.

Animals↗
PubMed2006

X-linked imprinting: effects on brain and behaviour.

Imprinted genes are monoallelically expressed in a parent-of-origin-dependent manner and can affect brain and behavioural phenotypes. The X chromosome is enriched for genes affecting neurodevelopment and is donated asymmetrically to male and female progeny. Hence, X-linked imprinted genes could potentially influence sexually dimorphic neurobiology. Consequently, investigations into such loci may provide new insights into the biological basis of behavioural differences between the sexes and into why men and women show different vulnerabilities to certain mental disorders. In this review, we summarise recent advances in our knowledge of X-linked imprinted genes and the brain substrates that they may act upon. In addition, we suggest strategies for identifying novel X-linked imprinted genes and their downstream effects and discuss evolutionary theories regarding the origin and maintenance of X-linked imprinting.

Animals↗
PubMed2005

Imprinted gene expression in the brain.

In normal mammals, autosomal genes are present in duplicate (i.e. two alleles), one inherited from the father, and one from the mother. For the majority of genes both alleles are transcribed (or expressed) equally. However, for a small subset of genes, known as imprinted genes, only one allele is expressed in a parent-of-origin dependent manner (note that the 'imprint' here refers to the epigenetic mechanism through which one allele is silenced, and is completely unrelated to classical 'filial imprinting' manifest at the behavioural level). Thus, for some imprinted genes expression is only (or predominantly) seen from the paternally inherited allele, whilst for the remainder, expression is only observed from the maternally inherited allele. Early work on this class of genes highlighted their importance in gross developmental and growth phenotypes. Recent studies in mouse models and humans have emphasised their contribution to brain function and behaviour. In this article, we review the literature concerning the expression of imprinted genes in the brain. In particular, we attempt to define emerging organisation themes, especially in terms of the direction of imprinting (i.e. maternal or paternal expression). We also emphasise the likely role of imprinted genes in neurodevelopment. We end by pointing out that, so far as discerning the precise functions of imprinted genes in the brain is concerned, there are currently more questions than answers; ranging from the extent to which imprinted genes might contribute to common mental disorders, to wider issues related to how easily the new data on brain may be accommodated within the dominant theory regarding the origins and maintenance of imprinting, which pits the maternal and paternal genomes against each other in an evolutionary battle of the sexes.

Animals↗
PubMed2005

An mTph2 SNP gives rise to alterations in extracellular 5-HT levels, but not in performance on a delayed-reinforcement task.

5-Hydroxytryptamine (5-HT) is an important neurotransmitter mediating many aspects of cognition and behaviour. One psychology in which 5-HT plays an important role is impulsive responding. Recently, we have demonstrated that variation in an aspect of impulsive behaviour, namely delayed gratification, has a clear genetic contribution. Here, we examined the neurobiological relevance of a recently discovered single nucleotide polymorphism (SNP) in the murine gene tryptophan hydroxylase (mTph2) by analysing extracellular levels of 5-HT in medial prefrontal cortex (mPFC) and ventral striatum (VS), key brain regions for impulsive behaviours. The allelic variants were associated with systematic effects on baseline 5-HT efflux in the mPFC and VS. We then went on to examine whether the mTph2 allelic variants gave rise to differences in impulsive behaviour. However, the mTph2 genotype, and therefore presumably baseline brain levels of 5-HT, did not predict impulsive choice, as indexed by sensitivity to delayed reinforcement. Consequently, the data do not support a role for the mTph2 C1473G polymorphism on this aspect of impulsive behaviour. Instead, they indicate that perturbations of the 5-HT system via heritable traits may have differential consequences for qualitatively distinct aspects of impulsive behaviour.

Animals↗
PubMed2005

Imprinted Nesp55 influences behavioral reactivity to novel environments.

Genomic imprinting results in parent-of-origin-dependent monoallelic expression of selected genes. Although their importance in development and physiology is recognized, few imprinted genes have been investigated for their effects on brain function. Gnas is a complex imprinted locus whose gene products are involved in early postnatal adaptations and neuroendocrine functions. Gnas encodes the stimulatory G-protein subunit Gsalpha and two other imprinted protein-coding transcripts. Of these, the Nesp transcript, expressed exclusively from the maternal allele, codes for neuroendocrine secretory protein 55 (Nesp55), a chromogranin-like polypeptide associated with the constitutive secretory pathway but with an unknown function. Nesp is expressed in restricted brain nuclei, suggesting an involvement in specific behaviors. We have generated a knockout of Nesp55 in mice. Nesp55-deficient mice develop normally, excluding a role of this protein in the severe postnatal effects associated with imprinting of the Gnas cluster. Behavioral analysis of adult Nesp55 mutants revealed, in three separate tasks, abnormal reactivity to novel environments independent of general locomotor activity and anxiety. This phenotype may be related to prominent Nesp55 expression in the noradrenergic locus coeruleus. These results indicate a role of maternally expressed Nesp55 in controlling exploratory behavior and are the first demonstration that imprinted genes affect such a fundamental behavior.

Adaptation, Psychological↗
PubMed2004

Imprinted genes and mother-offspring interactions.

A subset of mammalian genes is subject to genomic imprinting. These imprinted genes show parent of origin specific monoallelic or parental allele-biased expression, such that for some genes, it is mainly the maternally inherited allele that is expressed, whereas for others, expression occurs mainly from the paternal copy. Evolutionary theory predicts that these genes will have a role in the mother-offspring interaction in mammals, and indeed many imprinted genes have a role in growth and placental function, and consequently influence prenatal development. In addition to the developing foetus, there is increasing evidence to suggest that imprinted genes influence the pre-weaning mother-offspring relationship, and consequently the development of the offspring into adulthood. In this review, we present an overview of the role imprinted genes play in the mother-offspring relationship using examples from the human and animal literature.

Animals↗
PubMed2004

Common genetic effects on variation in impulsivity and activity in mice.

Impulsivity is a complex psychological construct that impacts on behavioral predispositions in the normal range and has been shown to have a genetic element through the examination of hereditary patterns of abnormal conditions such as attention deficit/hyperactivity disorder and obsessive compulsive disorder. In this study, we took advantage of the isogenic nature of inbred strains of mice to determine the contribution of genes to impulsive behaviors by examining the performance of four separate mouse strains in a novel murine delayed-reinforcement paradigm, during which the animals had to choose between rewards that were relatively small but available immediately and larger but progressively delayed rewards. To control for maternal effects, all the mice were cross-fostered to a common strain immediately after birth. Under these conditions, we found significant differences between the strains on behaviors indexing impulsive choice and on independent measures of locomotor activity, which subsequent heritability analysis showed could be related, in part, to genetic effects. Moreover, the two aspects of behavior were found to co-vary, with the more active animals also displaying more impulsive behavior. This was not attributable to mundane confounds related to individual task requirements but instead indicated the existence of common genetic factors influencing variation in both impulsivity and locomotor activity. The data are discussed in terms of the coexistence of impulsivity and hyperactivity, interactions between environmental and genetic effects, and possible candidate genes.

Animals↗
PubMed2004

Effects on fear reactivity in XO mice are due to haploinsufficiency of a non-PAR X gene: implications for emotional function in Turner's syndrome.

Recent work has indicated altered emotional functioning in Turner's syndrome (TS) subjects (45,XO). We examined the role of X-chromosome deficiency on fear reactivity in X-monosomic mice (39,XO), and found that they exhibited anxiogenic behaviour relative to normal females (40,XX). A molecular candidate for this effect is Steroid sulfatase (Sts) as this is located in the pseudoautosomal region (PAR) of the X-chromosome and consequently is normally biallelically expressed. In addition, the steroid sulfatase enzyme (STS) is putatively linked to fear reactivity by an effect on GABAA receptors via the action of neurosteroids. Real-time PCR demonstrated that levels of Sts mRNA were reduced by half in the brains of 39,XO mice compared with 40,XX, and that expression levels of a number of GABAA subunits previously shown to be important components of fear processing (Gabra3, Gabra1 and Gabrg2) were also altered. However, 40,XY*X mice, in which the Y*X is a small chromosome comprising of a complete PAR and a small non-PAR segment of the X-chromosome, exhibited the same pattern of fear reactivity behaviour as 39,XO animals, but equivalent expression levels of Sts, Gabra1, Gabra3 and Gabrg2 to 40,XX females. This showed that although Sts may cause alterations in GABAA subunit expression, these changes do not result in increased fear reactivity. This suggests an alternative X-chromosome gene, that escapes inactivation, is responsible for the differences in fear reactivity between 39,XO and 40,XX mice. These findings inform the TS data, and point to novel genetic mechanisms that may be of general significance to the neurobiology of fear.

Affective Symptoms↗
PubMed2003

Measuring impulsivity in mice using a novel operant delayed reinforcement task: effects of behavioural manipulations and d-amphetamine.

RATIONALE: The increasing use of genetically modified mice to probe genetic contributions to normal and abnormal behaviours requires the development of sensitive and selective behavioural tasks. OBJECTIVES: To develop a discrete trial assay of impulsivity (delayed reinforcement) that is tractable in mice utilising a mouse operant nine-hole box apparatus and to specify the task with respect to behavioural and pharmacological manipulations. METHODS: Mice were trained to respond with a nose-poke to one of two visual stimuli; one response resulted in a small quantity of reinforcer, the other in a larger quantity of reinforcer. As the session proceeded increasing delay was introduced onto the response leading to the large reward. Hence, the nature of the choice was a small quantity of reinforcer immediately versus a larger but progressively delayed amount of reinforcer. At stable baseline performance the mice were challenged with a variety of task manipulations and systemic d-amphetamine in order to discern aspects of the underlying psychological and neurochemical substrates of the choice behaviour. RESULTS: The mice showed a systematic shift in responding away from the large reinforcer with increasing delay (0, 2, 4, 8, 12 s), such that at the longest delay >80% of nose-pokes were for the smaller, immediate reinforcer. Task manipulations indicated that behaviour was controlled in a trial discrete manner by the contingency between delay and reward and was not due to non-specific factors such as satiation. d-Amphetamine had complex, dose dependent effects on choice behaviour which revealed dissociations between impulsive choice and hyperactivity. CONCLUSIONS: We have successfully developed an assay of impulsivity in mice that will be of utility to examine impulsive behaviours and their genetic substrates. In addition, our data provided evidence of distinct dopaminergic mechanisms mediating aspects of impulsivity and hyperactivity.

Amphetamine↗
PubMed2002

A possible role for imprinted genes in inbreeding avoidance and dispersal from the natal area in mice.

The expression of a subset of mammalian genes is subject to parent of origin effects (POE), most of which can be explained by genomic imprinting. Analysis of mutant animals has demonstrated that a number of imprinted genes influence brain development and behaviour. Here we provide evidence for POE on olfactory related behaviour and sensitivity to maternal odour cues. This was investigated by examining the odour preference behaviour of reciprocal cross F(1) mice made by embryo transfer to genetically unrelated foster parents. We determined that both adult males and females show an avoidance of female urinary odours of their genetic maternal but not paternal origin. This was found not to be due to any previous exposure to these odours or due to self-learning, but may be related to direct effects on the olfactory system, as reciprocal F(1) males show differential sensitivity to female odour cues. Currently the most robust theory to explain the evolution of imprinting is the conflict hypothesis that focuses on maternal resource allocation to the developing foetus. Kinship considerations are also likely to be important in the selection of imprinted genes and we discuss our findings within this context, suggesting that imprinted genes act directly on the olfactory system to promote post-weaning dispersal from the natal area.

Animals↗