br Concluding remarks Early life provides

Concluding remarks Early life provides a sensitive window for programming lifelong emotional and cognitive processing, which has profound influence over threat-processing and social behaviors. In altricial species, this period of purchase Cy3.5 maleimide development favors forming attachments to a caregiver, regardless of the quality of care, in order to ensure the infant receives access to warmth, protection, and food. However, attachments formed in threatening or traumatic contexts have unique consequences for the development of social behavior and learning about threat. In the clinical literature, this has been demonstrated in individuals with a history of abuse or disordered attachment who exhibit compromised fear and social behavior, as well as vulnerability to later-life mental health disorders (Bowlby, 1984; Bremner, 2003; Famularo et al., 1992; Graham et al., 1999; Nemeroff and Vale, 2005; Pechtel et al., 2014). Animal models across a variety of species have allowed us to assess the mechanisms by which caregiver abuse engenders neurobehavioral deficits, with programming of the stress system as a point of convergence in adult outcomes (Andersen and Teicher, 2008; Denenberg, 1963; Famularo et al., 1992; Harlow and Harlow, 1965; Hofer, 1994; Levine, 1957; Levine et al., 1985; Teicher et al., 2003). Here we have focused on two very selective models of caregiver abuse in rodents, namely, rough handling by the mother given low nesting resources, and repeated presentations of paired odor-shock during the sensitive period for attachment. Both of these manipulations produces latent changes in amygdala function and depressive-like behavior, aberrant fear expression, and social behavior deficits (Perry et al., in press; Raineki et al., 2010b,c; Raineki et al., 2015; Roth et al., 2014; Sevelinges et al., 2007, 2011, 2008). Importantly, these effects are not produced when a pup experiences shock without the mother (Sarro et al., 2014a; Tyler et al., 2007). These results suggest that caregiver abuse during the sensitive period for attachment produces a unique outcome, with the social dimension of early abuse, rather than pain alone, predisposing amygdala development towards an impaired phenotype. In the clinical population, the amygdala has also been implicated in the pathogenesis of psychiatric sequelae. For instance, patients with depression also show alterations in amygdala function and its connectivity with other brain areas (Elzinga et al., 2003; Frijling et al., 2016; Jedd et al., 2015; McEwen, 2003; Ressler and Mayberg, 2007; Savitz and Drevets, 2009; Sibille et al., 2009; Teicher et al., 2003). In light of the relationship between attachment, the amygdala, and long-term mental health outcomes, we may predict that early life is not only a sensitive period for rodent amygdala development, but also for humans. The amygdala undergoes major development progress throughout the first seven years of life in children but continues to develop into adolescence (Giedd et al., 1996; Humphrey, 1968; Letcher et al., 2009; Lupien et al., 2009; Tottenham and Sheridan, 2009; Uematsu et al., 2012; Ulfig et al., 2003). This suggests that early life may be a period of rapid change and, likewise, heightened vulnerability of the amygdala to environmental influence, as well as multiple interconnected brain regions, including the hippocampus and PFC (Ehrlich and Josselyn, 2016; Ehrlich et al., 2012; Lupien et al., 2009). Future work will be necessary to fully uncover the unique role of the caregiver in programming brain regions relevant for adaptive threat processing and social behavior.
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Acknowledgments
Introduction Early rearing environments play an important role in the development of the hypothalamic-pituitary-adrenal (HPA) axis, a central system in the body’s ability to appropriately respond and adapt to stress (Gunnar et al., 2009). Across several species, early adverse caregiving is followed by alterations to diurnal cortisol activity, such as flattened diurnal slopes with blunted morning and elevated evening levels (Gunnar and Vazquez, 2001; Sánchez et al., 2005). These early alterations in cortisol activity have been correlated with long-term future physiological and psychological outcomes, such as inflammation and increased rates of psychiatric disorders (e.g. anxiety and depression; Loman and Gunnar, 2010). Children with a history of early parental deprivation as a result of institutional (i.e., “orphanage”) caregiving are at significantly elevated risk for long-term alterations to stress physiology and socio-emotional functioning (Loman and Gunnar, 2010). Nonetheless, many previously-institutionalized (PI) children that have been adopted, exhibit tremendous rebound in a number of developmental domains (Loman and Gunnar, 2010; Nelson et al., 2007; Tottenham, 2012), raising the possibility that the HPA axis may also exhibit change in the post-adoption home. Though much research has demonstrated flattened diurnal cortisol profiles for younger PI children, some work has shown that there is also dynamic change in the HPA axis observed into early adolescence (Kertes et al., 2008; Quevedo et al., 2012), which is suggested to be another sensitive period for HPA axis programming (Hostinar and Gunnar, 2013).