Anticonvulsants, ischemic seizures and regeneration in the immature brain

描述(由申请人提供)：新生儿中风影响每4000个足月新生儿中的一个，并经常导致认知障碍。伴有癫痫发作的新生儿中风和抗惊厥药物(通常是苯巴比妥)在之后的几个月内被给予治疗。我们的中心假设是，新生儿卒中后海马神经发生受损导致认知功能障碍，而抗惊厥药物调节卒中后神经发生和认知结局。更具体地说，我们假设增加GABA信号的抗惊厥剂减少了海马神经发生并损害了认知结果，而抑制组蛋白脱乙酰酶的抗惊厥药增加了海马神经发生并改善了认知结果。方法：我们将使用最近开发的未成熟小鼠缺血性癫痫发作和脑损伤的模型。P12 CD1小鼠将接受单侧颈动脉结扎和BrdU标记，我们将测量这些动物的认知功能、新生海马细胞的萎缩和成熟。在一个单独的动物队列中，我们将在一项新的空间任务后使用Arc-BrdU-Neun联合标记来评估中风后新生神经元的整合。在这个模型中，我们将确定长期给予增强GABA传递或抑制组蛋白脱乙酰酶的药物对萎缩、神经发生、认知障碍和慢性癫痫的影响。意义：未成熟大脑的中风会导致认知障碍，这种障碍通常会持续到成年。即使是部分减少认知障碍的干预，也会显著提高生活质量，降低国家医疗保健成本。这项工作将确定哪种抗惊厥药物更有可能改善新生儿中风后的认知结果，反之，哪种抗惊厥药物应该避免。这项工作还将揭示关于GABA和组蛋白脱乙酰酶在新生儿中风后神经发生和恢复中的作用的机械性见解。PI作为临床科学家和儿科神经学家的背景、培训和经验使她独特地适合并高度积极地开展这项重要的研究。

DESCRIPTION (provided by applicant): Neonatal stroke affects one in 4000 term births and frequently results in cognitive impairments. Neonatal strokes present with seizures, and anticonvulsants (usually phenobarbital) are administered for months afterward. Our central hypothesis is that impaired hippocampal neurogenesis after neonatal stroke contributes to cognitive dysfunction, and anticonvulsants modulate both post-stroke neurogenesis and cognitive outcome. More specifically we hypothesize that anticonvulsants increasing GABA signaling decrease hippocampal neurogenesis and impair cognitive outcome, and anticonvulsants inhibiting histone deacetylase increase hippocampal neurogenesis and improve cognitive outcome. Approach: We will use a recently developed immature mouse model of ischemic seizures and brain injury. P12 CD1 mice will receive unilateral carotid ligation and BrdU labeling, and we will measure cognitive function, atrophy, and maturation of newborn hippocampal cells in the same animals. In a separate cohort of animals we will assess post-stroke integration of newborn neurons utilizing Arc-BrdU-NeuN co-labeling after a novel spatial task. We will determine the impact of chronically administered drugs that enhance GABA transmission or inhibit histone deacetylase upon atrophy, neurogenesis, cognitive impairment and chronic seizures in this model. Significance: Stroke in the immature brain causes cognitive impairment that often persists into adulthood. An intervention providing even partial reduction of cognitive impairment would result in significantly improved quality of life and decreased national healthcare costs. This work will determine which anticonvulsant is more likely to improve cognitive outcome after neonatal stroke and conversely which anticonvulsant should be avoided. This work will also reveal mechanistic insights regarding the role of GABA and histone deacetylase in neurogenesis and recovery after neonatal stroke. The background, training, and experience of the PI as a clinician scientist and pediatric neurologist make her uniquely suited and highly motivated to carry out this important research.