Genomic imprinting, action, and interaction of maternal and fetal genomes.

Mammalian viviparity (intrauterine development of the fetus) introduced a new dimension to brain development, with the fetal hypothalamus and fetal placenta developing at a time when the fetal placenta engages hypothalamic structures of the maternal generation. Such transgenerational interactions provide a basis for ensuring optimal maternalism in the next generation. This success has depended on genomic imprinting and a biased role of the matriline.

The post-natal chemosensory environment induces epigenetic changes in vomeronasal receptor gene expression and a bias in olfactory preference.

Vomeronasal stem cells are generated throughout the life of a mouse and differentiate into neurons that express one vomeronasal type 1 (V1r), one or two vomeronasal type 2 (V2r), or one olfactory receptor. Vomeronasal stem cells can be induced to differentiate into neurons by treatment with lipocalins from mouse urine or by epigenetic modification following treatment with histone deacetylase inhibitors. An important question is, do chemosensory signals, modify the detection capabilities of the vomeronasal organ and affect behaviour.

Epigenetics and brain evolution.

Fundamental aspects of mammalian brain evolution occurred in the context of viviparity and placentation brought about by the epigenetic regulation of imprinted genes. Since the fetal placenta hormonally primes the maternal brain, two genomes in one individual are transgenerationally co-adapted to ensure maternal care and nurturing. Advanced aspects of neocortical brain evolution has shown very few genetic changes between monkeys and humans.

Placental protection of the fetal brain during short-term food deprivation.

The fetal genome regulates maternal physiology and behavior via its placenta, which produces hormones that act on the maternal hypothalamus. At the same time, the fetus itself develops a hypothalamus. In this study we show that many of the genes that regulate placental development also regulate the developing hypothalamus, and in mouse the coexpression of these genes is particularly high on embryonic days 12 and 13 (days E12-13).

Epigenetically regulated imprinted genes and foetal programming.

Genomic imprinting is a widespread epigenetic phenomenon in mammals and many imprinted genes are expressed in the developing hypothalamus and placenta. The placenta and brain are very different structures with very different roles, but in the pregnant mother they functionally interact coordinating and ensuring the provision of nutrients, timing of parturition and priming of hypothalamus for maternal care and nurturing. This interaction has been evolutionarily fine-tuned to optimise infant survival such that when resources are poor, the mother 'informs' this condition to the foetus producing a thrifty phenotype that is adapted to survive scarce resources after birth.

Paternal influence on female behavior: the role of Peg3 in exploration, olfaction, and neuroendocrine regulation of maternal behavior of female mice.

Genomic imprinting represents a mechanism through which parent-of-origin effects on offspring development may be mediated. However, investigation of the influence of imprinted genes on behavior has been limited. Here the authors investigate the role of the maternally imprinted/paternally expressed gene, Peg3, in several aspects of behavior using both 129Sv- and B6-Peg3 mutant female mice.

Increased apoptosis during neonatal brain development underlies the adult behavioral deficits seen in mice lacking a functional paternally expressed gene 3 (Peg3).

Inactivation of the maternally imprinted, paternally expressed gene 3 (Peg3) induces deficits in olfactory function, sexual and maternal behaviors, oxytocin neuron number, metabolic homeostasis and growth. Peg3 is expressed in a number of developing hypothalamic and basal forebrain structures and is a component of the P53 apoptosis pathway. Peg3 inactivation in neuronal cell culture lines inhibits P53 mediated apoptosis, which is important in the early postnatal development and sexual differentiation of the brain.

The evolution of pheromonal communication.

Small-brained rodents have been the principle focus for pheromonal research and have provided comprehensive insights into the chemosensory mechanisms that underpin pheromonal communication and the hugely important roles that pheromones play in behavioural regulation. However, pheromonal communication does not start or end with the mouse and the rat, and work in amphibians reveals much about the likely evolutionary origins of the chemosensory systems that mediate pheromonal effects. The dual olfactory organs (the main olfactory epithelium and the vomeronasal organ), their receptors and their separate projection pathways appear to have ancient evolutionary origins, appearing in the aquatic ancestors of all tetrapods during the Devonian period and so pre-dating the transition to land.

The paternally expressed gene Peg3 regulates sexual experience-dependent preferences for estrous odors.

Sexual experience has marked and long-lasting effects on male behavior in mammals, regulating traits such as the anticipation and display of sexual behavior, aggression, and olfaction. The authors conducted urine preference, habituation-dishabituation, and partner choice tests with sexually experienced and naive male mice and found that wild-type males acquire adaptively significant preferences for the odors of receptive, estrous females with sexual experience, and that these preferences are matched by changes in main olfactory system responses involving the piriform cortex, as indicated by c-Fos expression. The authors also report that these experiential effects are disrupted in male mice carrying a knockout of the imprinted gene Peg3.

Visualisation of the vomeronasal pheromone response system.

Mammalian vomeronasal receptors respond to pheromones conveying information on gender, reproductive status and individual recognition. The question arises as to how this information is coded, which parts of the code require combinatorial activity and whether or not there are specific receptor neurons committed to sex discrimination. Are there receptor neurons that are committed to responding for female or male pheromones? Is there a sex difference for the proportion of these receptors, bearing in mind that it is very much in the male's interest to distinguish the restricted oestrous phase of the female's cycle in order to successfully mate? Perhaps more intriguing is the complexity of individual recognition and whether or not the vomeronasal receptors actually possess this capacity.

Epigenetics, brain evolution and behaviour.

Molecular modifications to the structure of histone proteins and DNA (chromatin) play a significant role in regulating the transcription of genes without altering their nucleotide sequence. Certain epigenetic modifications to DNA are heritable in the form of genomic imprinting, whereby subsets of genes are silenced according to parent-of-origin. This form of gene regulation is primarily under matrilineal control and has evolved partly to co-ordinate in-utero development with maternal resource availability.

Natural variations in postpartum maternal care in inbred and outbred mice.

The role of maternal care in mediating variation in offspring phenotype has been examined in the rat and demonstrates that mother-infant interactions are critical for inducing long-term changes in behavior. Though phenotypic differences between mice strains are often attributed to genetic factors, the influence of early maternal environment has not been extensively explored. To understand maternal influence on phenotype in mice, we must first explore the nature of differences in behavior.

Genomic imprinting mediates sexual experience-dependent olfactory learning in male mice.

Mammalian imprinted genes are generally thought to have evolved as a result of conflict between parents; however, recent knockout studies suggest that coadaptation between mother and offspring may have been a significant factor. We present evidence that the same imprinted gene that regulates mammalian maternal care and offspring development also regulates male sexual behavior and olfaction. We have shown that the behavior of male mice carrying a knockout of the imprinted gene Peg3 does not change with sexual experience and that the mice are consequently unable to improve their copulatory abilities or olfactory interest in female odor cues after mating experience.

Urinary pheromones promote ERK/Akt phosphorylation, regeneration and survival of vomeronasal (V2R) neurons.

The G protein-coupled pheromone receptor neurons (V1R and V2R) of the vomeronasal organ (VNO) are continually replaced throughout the lifetime of the mouse. Moreover, active signalling of V2Rs via the transient receptor potential 2(TRPC2) channel is necessary for regeneration of receptors, as the TRPC2 null mutant mouse showed a 75% reduction of V2Rs by the age of two months. Here we describe V2R mediated signalling in a neuronal line established from vomeronasal stem cells taken from postnatal female mice.

Genes, brains and mammalian social bonds.

Recent studies of monogamous species have revealed the role of the neuropeptides oxytocin and vasopressin in activating reward mechanisms of the brain that are involved in establishing partner recognition and selective 'bonding'. The evolutionary history of these findings resides, at a mechanistic level, in the reciprocal bonding between mother and infant that is common to all mammals. However, in Old World primates, where mother and infant alone would not survive, living in large social groups brings extended family relationships and provides for alloparenting.

Suppression of prolactin does not reduce infant care by parentally experienced male common marmosets (Callithrix jacchus).

High levels of prolactin have been found to correlate with the expression of paternal care in a variety of taxa. However, in mammals, there is little experimental evidence that prolactin is causally involved in the stimulation or maintenance of paternal care. Here, we suppressed prolactin production in paternally experienced common marmoset fathers in their family groups during the first 2 weeks after their infants were born.

Vasopressin, oxytocin and social behaviour.

Understanding the neurobiology of social behaviour in mammals has been considerably advanced by the findings from two species of vole, one of which is monogamous and pair bonds whereas the other species is promiscuous and fails to form any long-lasting social relationships. The combination of neurobehavioural studies and molecular genetics has determined behavioural differences between the two species linked to the neural distribution of vasopressin 1A receptor in the male brain. More importantly, vasopressin 1A receptor gene transfer including the upstream regulatory sequence has enhanced male social affiliation in a non-monogamous species.

Understanding well-being in the evolutionary context of brain development.

Much of the work on well-being and positive emotions has tended to focus on the adult, partly because this is when problems are manifest and well-being often becomes an issue by its absence. However, it is pertinent to ask if early life events might engender certain predispositions that have consequences for adult well-being. The human brain undergoes much of its growth and development postnatally until the age of seven and continues to extend its synaptic connections well into the second decade.

Coadaptation in mother and infant regulated by a paternally expressed imprinted gene.

This study investigates how a targeted mutation of a paternally expressed imprinted gene regulates multiple aspects of foetal and post-natal development including placental size, foetal growth, suckling and post-natal growth, weaning age and puberty onset. This same mutation in a mother impairs maternal reproductive success with reduced maternal care, reduced maternal food intake during pregnancy, and impaired milk let-down, which in turn reduces infant growth and delays weaning and onset of puberty. The significance of these coadaptive traits being synchronized in mother and offspring by the same paternally expressed imprinted gene ensures that offspring that have extracted 'good' maternal nurturing will themselves be both well provisioned and genetically predisposed towards 'good' mothering.

Something in the air? New insights into mammalian pheromones.

Olfaction is the dominant sensory modality for most animals and chemosensory communication is particularly well developed in many mammals. Our understanding of this form of communication has grown rapidly over the last ten years since the identification of the first olfactory receptor genes. The subsequent cloning of genes for rodent vomeronasal receptors, which are important in pheromone detection, has revealed an unexpected diversity of around 250 receptors belonging to two structurally different classes.