Significance of epigenetics for understanding brain development, brain evolution and behaviour.

Two major environmental developments have occurred in mammalian evolution which have impacted on the genetic and epigenetic regulation of brain development. The first of these was viviparity and development of the placenta which placed a considerable burden of time and energy investment on the matriline, and which resulted in essential hypothalamic modifications. Maternal feeding, maternal care, parturition, milk letdown and the suspension of fertility and sexual behaviour are all determined by the maternal hypothalamus and have evolved to meet foetal needs under the influence of placental hormones. Viviparity itself provided a new environmental variable for selection pressures to operate via the co-existence over three generations of matrilineal genomes (mother, developing offspring and developing oocytes) in one individual. Also of importance for the matriline has been the evolution of epigenetic marks (imprint control regions) which are heritable and undergo reprogramming primarily in the oocyte to regulate imprinted gene expression according to parent of origin. Imprinting of autosomal genes has played a significant role in mammalian evolutionary development, particularly that of the hypothalamus and placenta. Indeed, many imprinted genes that are co-expressed in the placenta and hypothalamus play an important role in the co-adapted functioning of these organs. Thus the action and interaction of two genomes (maternal and foetal) have provided a template for transgenerational selection pressures to operate in shaping the mothering capabilities of each subsequent generation. The advanced aspects of neocortical brain evolution in primates have emancipated much of behaviour from the determining effects of hormonal action. Thus in large brain primates, most of the sexual behaviour is not reproductive hormone dependent and maternal care can and does occur outside the context of pregnancy and parturition. The neocortex has evolved to be adaptable and while the adapted changes are not inherited, the epigenetic predisposing processes can be. This provides each generation with the same ability to generate new adaptations while retaining a "cultural" predisposition to retain others. A significant evolutionary contribution to this epigenetic dimension has again been the matriline. The extensive neocortical development which takes place post-natally does so in an environment which is predominantly that of the caring guidance of the mother. Evidence for the epigenetic regulation of neocortical development is best illustrated by the GABA-ergic neurons and their long tangential migratory pathway from the ganglionic eminence, in contrast to the radial migration of principle neurons. GABA-ergic neurons play an integral role both in the developmental formation of canonical localised circuits and in synchronising widespread functional activity by the regulation of network oscillations. Such synchronisation enables distributed regions of the neocortex to coordinate firing. GABA-ergic dysfunction contributes to a broad spectrum of neurological and psychiatric disorders which can differ even across identical monozygotic twins. Moreover, major treatments for schizophrenia over the past 40 years have included the drugs lithium and valproate, both of which we now know are histone deacetylases. It is rarely the heritable dysfunctioning of these epigenetic mechanisms that is at fault, but the timing, duration and place where they are deployed. The timing and complexity in the development of the neocortex makes this region of the brain more vulnerable to perturbations.