PAIN: EARLY EXPERIENCE AND PRE-ATTENTION MECHANISMS

早产儿早期重复性疼痛，并可能导致大脑发育的永久性变化，伴随疼痛处理异常、焦虑增加、认知能力差、注意力缺陷障碍以及青春期或成年期的行为问题。新生大鼠的重复性疼痛与广泛分布的皮质和皮质下区域的神经元细胞死亡增加有关。青春期后，疼痛暴露的大鼠表现出更大的焦虑，过度警觉，注意力和认知缺陷，从而模仿前早产儿的长期行为结果。了解介导这些影响的机制可能会导致新的治疗措施，并改善早产的认知和行为结果。目标1：确定临界窗口将检验假设 重复性疼痛与神经细胞死亡的增加有关， 发展阶段（s）。神经元脆弱性的增加可能在不同的神经解剖区域受到发育调控，并将与成年大鼠的认知和行为结果相关。目标二：对细胞死亡机制的研究将检验这样的假设，即重复性疼痛通过激活经由兴奋性受体导致兴奋性毒性的信号传导通路而产生神经元细胞死亡。减少神经元细胞死亡的药理学操作将允许开发新的治疗方法，这也将与成人认知和行为相关。目标3：对人类前注意过程的评估将检验这一假设，即唤醒的异常调节有助于青少年或成年期的认知缺陷。将在早产青少年和匹配的足月出生青少年之间比较人类唤醒的测量，P50电位，并将其与注意力任务的表现相关联（心理警觉性测试） 和执行功能（操作性测试组合），并与相对额叶血流量（近红外光谱）。拟议的研究旨在将主要研究者确立为独立的临床科学家，并在转化神经科学中心的主持下提供指导。

Early repetitive pain in premature babies and may lead to permanent changes in brain development, with abnormal pain processing, increased anxiety, poor cognition, attention deficit disorder, and behavioral problems during adolescence or adulthood. Repetitive pain in newborn rats was associated with increased neuronal cell death in widely distributed cortical and subcortical areas. Following puberty, pain-exposed rats showed greater anxiety, hypervigilance, preattentional and cognitive deficits; thus mimicking the long-term behavioral outcomes of ex-preterm children. Understanding the mechanisms mediating these effects may lead to novel therapeutic measures and improve the cognitive and behavioral outcomes of premature birth. Aim 1: Determination of critical windows will test the hypothesis that repetitive pain is associated with increased neuronal cell death during the most sensitive developmental stage(s). Increased neuronal vulnerability may be developmentally regulated in different neuroanatomical areas, and will be correlated with cognitive and behavioral outcomes evaluated in adult rats. Aim 2: Investigation of cell death mechanisms will test the hypothesis that repetitive pain produces neuronal cell death by activating the signaling pathways leading to excitotoxicity via excitatory receptors. Pharmacological manipulations decreasing neuronal cell death will allow the development of novel therapeutic approaches, which will also be correlated with adult cognition and behavior. Aim 3: Assessment of pre-attentional processes in humans will test the hypothesis that abnormal regulation of arousal contributes to the cognitive deficits during adolescence or adulthood. A measure of arousal in humans, the P50 potential, will be compared between adolescents born preterm and matched term-born adolescents, and correlated with their performance of attentional tasks (Psychomotor Vigilance Test) and executive functions (Operant Test Battery), and with relative frontal lobe blood flow (Near Infrared Spectroscopy). The proposed research is designed to establish the Principal Investigator as an independent clinician scientist with the help of established mentoring under the auspices of the Center for Translational Neuroscience.