In a small fraction of mammalian genes--at present estimated at less than 1% of the total--one of the two alleles that is inherited by the offspring is partially or completely switched off. The decision as to which one is silenced depends on which allele was inherited from the mother and which from the father. These idiosyncratic loci are known as imprinted genes, and their existence is an evolutionary enigma, as they effectively nullify the advantages of diploidy. Although they are small in number, these genes have important effects on physiology and behaviour, and many are expressed in the brain. There is increasing evidence that imprinted genes influence brain function and behaviour by affecting neurodevelopmental processes.

Imprinted genes show differential expression between maternal and paternal alleles as a consequence of epigenetic modification that can result in 'parent-of-origin' effects on phenotypic traits. There is increasing evidence from mouse and human studies that imprinted genes may influence behavior and cognitive functioning. Previous work in girls with Turner syndrome (45,XO) has suggested that there are X-linked parent-of-origin effects on brain development and cognitive functioning, although the interpretation of these data in terms of imprinted gene effects has been questioned. We used a 39,XO mouse model to examine the influence of the parental origin of the X chromosome on cognitive behaviors and expression of X-linked genes in brain. Our findings confirm the existence of X-linked imprinted effects on cognitive processes and identify a new maternally expressed imprinted gene candidate on the X chromosome, Xlr3b, which may be of importance in mediating the behavioral effects.

Attentional functioning in mice was assessed in an analogue of the five-choice serial reaction time task in which the requirement was to detect brief visual stimuli presented across five spatial locations. Two hybrid strains of mice were assessed; F1 C57Bl/6xDBA/2 and C57Bl/6x129sv. Both strains acquired the task to high levels of performance with, in particular, no problems due to premature responding. At performance, systematic manipulation of the task parameters indicated a pattern of effects consistent with the task, taxing aspects of visuospatial attention. There were some differential effects of task manipulations at baseline across strain. However, the pattern of effects suggested these were likely to be the result of effects on factors other than attentional functioning per se, such as behavioural reactivity and inhibition. There was evidence in both strains of specific, centrally mediated effects of scopolamine on attentional functioning, with the C57Bl/6xDBA/2 hybrid showing greater sensitivity to the drug manipulation. Specific effects on discriminative accuracy were observed at doses of 0.02 and 0.2 mg/kg scopolamine. At the 2 mg/kg dose, large reductions in accuracy were associated with large effects on other measures, including omissions and response latencies, suggestive of nonspecific effects on task performance. These data indicate, for the first time, the utility of operant methods in assessing visuospatial attentional functioning in mice. They confirm the importance of cholinergic mechanisms in attentional processes across species, and suggest interactions between cholinergic mechanisms and genotype in the expression of attentional phenotypes.

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Attention Deficit Hyperactivity Disorder (ADHD) is a developmental condition characterised by severe inattention, pathological impulsivity and hyperactivity; it is relatively common affecting up to 6% of children, and is associated with a risk of long-term adverse educational and social consequences. Males are considerably more likely to be diagnosed with ADHD than females; the course of the disorder and its associated co-morbidities also appear to be sensitive to sex. Here, I discuss fundamental biological (genetic and endocrine) mechanisms that have been shown to, or could theoretically, contribute towards these sexually dimorphic phenomena. Greater understanding of how and why the sexes differ with respect to ADHD vulnerability should allow us to identify and characterise novel protective and risk factors for the disorder, and should ultimately facilitate improved diagnosis, prognosis and treatment.

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by deficits in attention, increased motor impulsivity, and hyperactivity. Preliminary work in mice and humans has suggested the X-linked gene STS (which encodes the enzyme steroid sulfatase) as a mediator of attentional functioning and as a candidate gene for ADHD.MethodsThe effects of modulating the murine steroid sulfatase axis pharmacologically (through administration of the substrate dehydroepiandrosterone sulfate [DHEAS], 0–40mg/kg, or acute inhibition of the enzyme by COUMATE, 10mg/kg) or genetically (through loss of the gene in 39,XY*O mice) were assayed using the 5-choice serial reaction time task (5-CSRTT) a test of visuospatial attention and response control, and a locomotor activity paradigm.ResultsDHEAS administration improved 5-CSRTT performance under attentionally demanding conditions, whereas steroid sulfatase inhibition impaired accuracy under the same conditions. Loss of Sts expression constitutively throughout development in 39,XY*O mice resulted in deficits in 5-CSRTT performance at short stimulus durations and reduced anticipatory responding. Neither the pharmacologic nor the genetic manipulations affected basic locomotor activity.ConclusionsThese data provide converging evidence indicating a role for steroid sulfatase in discrete aspects of attentional functioning and are suggestive of a role in motor impulsivity. The findings provide novel insights into the neurobiology of attention and strengthen the notion of STS as a candidate gene for the attentional component of ADHD.

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.