Genomic Imprinting and Motivated Behaviour

Barry Keverne
Sub-Dept of Animal Behaviour; Cambridge University

An important means of investigating genomic imprinting in the brain has been achieved by the construction of chimeras. Embryos constructed from a mixture of cells that are parthenogenic/normal (Pg) or proportion of chimeric cells not to exceed normal cells. The precise locations in the brain to which these chimeric cells, participate in development can be determined by the presence of a genetic marker (ß globin, or Lac Z). Using these techniques a clear and distinct patterning in brain development emerges. At birth, cells that are disomic for the paternal genome contribute substantially to those parts of the brain that are important for primary motivated behavior (hypothalamus, pre-optic area BNST and septum) and are excluded, from the developing neocortex and striatum. At the earliest stages of brain development (days 9-10), Ag cells are present in all neural tissues and as gestation progresses they proliferate extensively in the medio-basal forebrain, but at parturition are virtually absent from telencephalic structures. By contrast parthenogenetic cells are excluded from these medio-basal forebrain areas, but selectively accumulate in those regions where Ag cells are excluded, especially neocortex and striatum.

If genomic imprinting has any impact on behavior, these findings, along with human clinical findings of Prader-Willi syndrome, would point to paternally expressed imprinted genes influencing motivated behaviors such as sexual, feeding, aggressive and maternal behavior. We have recently investigated a paternally expressed gene (Peg 1) which has been mutated by inserting a promoterless b geo cassette into the 5' coding exon to study both the function and expression of the gene in mice. Inheritance of the mutation from the paternal, but not the maternal germ line, causes a severe impairment in maternal behavior, resulting in a complete loss of progeny in the first generation. Offspring survival improves with subsequent generations but all aspects of maternal behavior and ability to suckle the pups are impaired, resulting in a slower growth rate of non-mutant offspring. The brain phenotype of these null mutants has a smaller nuclear areas (PVN, SON, BNST) in the hypothalamus and fewer neurons staining positive for the peptide, oxytocin. Since the magno-cellular oxytocinergic neurons control milk let-down and the parvocellular oxytocinergic neurons are important for maternal behavior, these findings may account for the behavioral and nurturient phenotype.