Cholinergic neuron degeneration after HI: New target for delayed therapy of neonatal HI to improve Learning and Memory Deficits

缺氧缺血性脑病(HIE)是早产儿和新生儿获得性脑损伤的最常见原因 足月儿会导致终生疾病。每年有多达100万名婴儿因接受治疗而患上HIE 低温(TH)对那些有机会获得TH的患者提供了强大的生存益处。促红细胞生成素也证明了 无论是单独使用还是与TH一起使用都有效。然而，这两种疗法都必须及早开始。尽管取得了重大进展 在新生儿HI损伤研究中，一种在疾病急性期后有效的口服治疗方法 生物利用度一直难以捉摸。大多数受HIE影响的婴儿无法获得NICU护理、TH、EPO或任何其他 在必要的时间范围内进行即将到来的治疗。一种延迟的、易于管理的治疗HIE的方法将会 每年改变100万儿童的未来。HIE患者的长期随访显示是永久性的 学习和记忆缺陷，缺乏认知灵活性，以及执行功能障碍。前者的MRI研究 新生儿脑损伤表现为胆碱能基底前脑(CBF)变性，发生于 学习和记忆缺陷以及执行功能不佳。CBF对于正确的执行功能是必不可少的， 认知灵活性、学习和记忆、觉醒、空间学习、决策、大脑皮层调节 活动和默认模式网络。CBF是一种有趣的新的潜在治疗靶点 新生儿缺氧缺血性脑病是因为我们现在发现新生儿缺氧缺血性脑病加速了脑血流中胆碱能神经元的变性。 和纹状体。这些胆碱能神经元在缺氧缺血后1个月进入变性状态，与前脑一致 在新生儿HI模型中，我们发现认知灵活性较差的时间之前。很多事情都是众所周知的 关于成人神经退行性疾病中胆碱能神经元的变性。重要的是，胆碱能 神经元在细胞死亡之前有一个延长的前驱退变阶段，这是可以治疗的， 一种针对胆碱能神经退行性变的药物正在进行成人人体试验。LM11A-31口服生物利用度 P75NTR功能调节剂，抑制其神经退行性变特性，增强其 神经保护作用特别是在CBF中。根据目前的数据，我们假设启动治疗 新生儿缺氧缺血后应用LM11A-31可挽救或防止脑血流量胆碱能神经元变性 防止皮质胆碱能输入的退化，从而改善学习、记忆和认知。 我们通过使用高吞吐量的行为触摸屏测试系统解决了这一假设，该系统检测到 学习记忆障碍，快速测定LM11A-31疗效。我们的目标是：评估 LM11A-31在发育中的小鼠脑组织中的表达及其对新生儿缺氧缺血性脑病全脑病理的影响 尤其是在新生儿缺氧缺血性脑病后4天至10周给予受损的脑血流量。 2：确定HI4天-10周后使用LM11A-31是否能改善视觉辨别能力 并在HI后3-6个月进行逆转学习测试，以了解这是否与抢救CBF有关。

Hypoxic-ischemic (HI) encephalopathy (HIE), the most frequent cause of acquired brain injury in preterm and term infants causeslife-long morbidity. As many as 1 million infants/year suffer HIE with therapeutic hypothermia (TH) affording a strong survival benefit in those with access to TH. Erythropoietin is also proving effective both alone and with TH. However, both therapies must be started early. Despite significant progress in neonatal HI injury research, a therapy that is effective beyond the acute phase of the disease and is orally bioavailable has been elusive. Most babies affected by HIE have no access NICU care, TH, Epo or any other upcoming therapies within the necessary time frames. A delayed, easily administered therapy for HIE would change the future for 1 million children each year. Long term follow-up of HIE patients reveals permanent learning and memory deficits, lack of cognitive flexibility, and executive dysfunction. MRI studies of former infants with neonatal brain injury reveals degeneration in the cholinergic basal forebrain (cBF), occurring with learning and memory deficits and poor executive function. The cBF is essential for proper executive function, cognitive flexibility, learning and memory, arousal, spatial learning, decision-making, modulation of cortical activity and the default mode network. The cBF is an interesting and novel potential therapeutic target for neonatal HI because we now show that neonatal HI precipitates cholinergic neuronal degeneration in the cBF and striatum. These cholinergic neurons enter a degenerative state 1 month after HI in concert with forebrain injury and prior to time at which we find poor cognitive flexibility in the neonatal HI model. Much is known about degeneration of cholinergic neurons in adult neurodegenerative diseases. Importantly, cholinergic neurons have an extended prodromal phase of degeneration prior to cell death that is amenable to therapy, and a drug targeting cholinergic neurodegeneration is in adult human trials. LM11A-31 is an orally bioavailable modulator of p75NTr function that suppresses its neurodegenerative properties and enhances its neuroprotective actions specifically in the cBF. Based on current data, we hypothesize that initiating treatment with LM11A-31 after neonatal HI will rescue or prevent degeneration of cholinergic neurons in the cBF and prevent degeneration of cholinergic input to the cortex resulting in improved learning, memory, and cognition. We address the hypothesis by using a high through-put behavioral touchscreen testing system, that detects learning and memory deficits, to rapidly determine LM11A-31 efficacy. Our Aims are 1: To assess the effect of LM11A-31 in the developing mouse brain and its effect on pathology of neonatal HI throughout the brain, especially in the injured cBF, when given from 4 days to 10 weeks after neonatal HI. And 2: Determine whether use of LM11A-31 from 4 days-10 weeks after HI improves visual discrimination and reversal learning tested 3-6 months after HI and whether this correlates with rescue of the cBF.