This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Goal of this project: to study the impact of poor caregiving (e.g., high levels of maternal rejection) on the development of behavior, stress physiology and the brain of nonhuman primates. Altered stress physiology regulation (both hyper- and hypo-functioning) is associated with affective and physiological disorders in adult primates. We have studied the effects on the following infant developmental outcomes: 1) hypothalamic-pituitary-adrenal(HPA) axis functionality: basal activity, reactivity to psychological stress and how well social or maternal cues 'buffer' it, 2) emotional behavior (fear, anxiety), 3) neurobiological substrates underlying the above behavioral and neuroendocrine variables (e.g. analysis of CRF systems). So far we have detected high basal cortisol and behavioral signs of distress at early ages (when abuse rates are high) followed by a compensatory down regulation of HPA function during the infant period, with recovery during the juvenile period. In contrast, the emotional alterations of abused animals seem enduring, since we inappropriate fear responses (either excessive freezing in females, or impulsive aggression in males) are still detected at later ages, during the adolescent period. The high impulsivity detected in abused males was associated with low levels of the CSF serotonin metabolite 5-HIAA. More recently we have also detected increased levels of inflammation markers (i.e., MAPK p-p38) in animals that experienced high rates of maternal rejection. These findings are of high relevance because they link early adverse experiences with somatic disorders later in life, such as inflammation, in addition to psychopathology. In addition, we have collected other longitudinal data, including: a) measures of growth and metabolism; and b) measures of neurodevelopment using in vivo neuroimaging techniques (structural MRI and DTI): Our current DTI analysis revealed alterations in brain white matter integrity in the animals with poor caregiving experiences. In these animals, we detected increased fractional anisotropy (FA, a measure of microstructural organization/integrity) in cortical regions: frontal lobe (anterior cingulate, dorsolateral prefrontal and orbitofrontal cortices), somatosensory, parietal and left visual cortices, in comparison to controls. In contrast, FA was reduced in the ventral striatum and right visual cortex. These differences in FA indicate the existence of alterations in normal maturation of brain white matter structure in animals that received poor early caregiving. Taken together these results support the idea that early adverse experiences (such as exposure to high levels of maternal rejection or physical abuse) increase activation of pro-inflammatory signaling pathways in monocytes which could lead to decreases in the levels of brain 5-HT available at the synaptic level, which may then lead to behavioral alterations such as anxiety or depression. It is unclear as to whether or not the brain structural alterations observed are associated with this pathway, but it is certainly possible given the evidence that 5-HT affects neurodevelopment (Whitaker-Azmetia 2001h). Further research is necessary to clarify the mechanisms through which early adverse experiences can have such far reaching and diverse effects on neural structure and function.
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