EARLY EXPERIENCE, STRESS NEUROBIOLOGY AND PREVENTION SCI

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本项目的目标：研究不良照顾(例如，高水平的母体排斥)对非人类灵长类动物的行为发育、应激生理和大脑的影响。在成年灵长类动物中，压力生理调节的改变(包括功能亢进和功能低下)与情感和生理障碍有关。我们研究了对以下婴儿发育结果的影响：1)下丘脑-垂体-肾上腺(HPA)轴功能：基础活动、对心理压力的反应以及社会或母体暗示对其进行缓冲的程度，2)情绪行为(恐惧、焦虑)，3)以上行为和神经内分泌变量的神经生物学基础(如CRF系统分析)。到目前为止，我们检测到了高基础皮质醇和早期(虐待发生率高)的行为痛苦迹象，随后在婴儿期HPA功能出现补偿性下调，并在青少年时期恢复。相比之下，受虐待动物的情绪变化似乎是持久的，因为我们在青春期的晚年仍然可以检测到不适当的恐惧反应(无论是雌性的过度冰冻，还是雄性的冲动攻击)。在被虐待的男性中检测到的高冲动与脑脊液5-羟色胺代谢产物5-HIAA的低水平有关。最近，我们还检测到，在经历高母体排斥反应的动物中，炎症标志物(即MAPK p-p38)水平增加。这些发现具有很高的相关性，因为除了精神病理学外，它们还将早期不良经历与晚年的躯体疾病联系起来，如炎症。此外，我们还收集了其他纵向数据，包括：a)生长和新陈代谢的测量；以及b)使用体内神经成像技术(结构MRI和DTI)测量神经发育：我们目前的DTI分析显示，护理经验较差的动物的脑白质完整性发生了变化。在这些动物中，我们检测到与对照组相比，大脑皮质区域的分数各向异性(FA)增加：额叶(前扣带回、背外侧前额叶和眶前叶皮质)、躯体感觉、顶叶和左侧视觉皮质。相比之下，腹侧纹状体和右侧视皮层的FA减少。这些FA的差异表明，早期接受不良照料的动物的脑白质结构的正常成熟存在变化。 综上所述，这些结果支持这样的观点，即早期的不良经历(如暴露在高水平的母体排斥或身体虐待中)会增加单核细胞中促炎症信号通路的激活，这可能会导致突触水平上大脑5-羟色胺水平的下降，进而可能导致焦虑或抑郁等行为变化。目前尚不清楚所观察到的大脑结构变化是否与这一途径有关，但考虑到5-羟色胺影响神经发育的证据，这当然是可能的(Whitaker-Azmetia 2001h)。需要进一步的研究来阐明早期不良经历对神经结构和功能产生如此深远和不同影响的机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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.