Separation anxiety: at the neurobiological crossroads of adaptation and illness.

Physiological and adaptive separation anxiety (SA) is intimately connected with the evolutionary emergence of new brain structures specific of paleomammalians, the growth of neomammalian--and later hominid--brain and skull size, and the appearance of bipedalism. All these evolutionary milestones have contributed to expanding the behavioral repertoire and plasticity of prehuman and human beings, at the cost of more prolonged dependency of the infant and of the child on parental care. Separation anxiety disorder (SAD) can be seen as an exaggerated/inappropriate manifestation of SA that constitutes a gateway to poorer mental and physical health. By blending epidemiological, genetic-epidemiological, endophenotypic, and animal laboratory approaches, it is possible to delineate some of the mechanisms that link childhood-adolescence SA and SAD to health problems later in life. Causal mechanisms include gene-environment interplays and likely differential regulation of genes and functional net-works that simultaneously affect multiple behavioral and physical phenotypes after exposure to early-life adversity, including parental separation/loss.