Short and long-term impact of neonatal seizures on hippocampal granule cell integ

描述（由申请人提供）：海马体是位于大脑深处的一个结构，对记忆、语言发展、认知甚至想象都至关重要。令人惊讶的是，这是成人大脑中为数不多的产生新脑细胞的区域之一。这些新细胞对海马体的正常运作很重要。不幸的是，最近的研究表明，这些新细胞很容易癫痫发作。大脑中的癫痫活动会导致这些未成熟的细胞与其他脑细胞形成错误的连接。在成年人中，这些异常细胞可能导致认知问题，甚至可能导致癫痫。令人苦恼的是，儿童的情况可能更糟。首先，儿童的癫痫发作阈值比成人低得多。因此，儿童癫痫发作很常见。第二，儿童癫痫发生率较高的发育时期与海马发育的高峰期重叠。婴儿产生了大量的海马细胞，这些细胞在儿童早期经历了广泛的发育。在此期间的癫痫发作可能导致大量海马细胞的异常连接。相比之下，几乎所有其他大脑区域的神经元都是在出生时生成的。为了确定新生成的海马细胞是否特别容易受到损伤，以及这些细胞的破坏是否可以解释剧烈或反复发作的儿童所经历的严重认知缺陷，我们利用小鼠模型系统，其中新生成的海马细胞被标记为绿色荧光蛋白（GFP）。绿色荧光蛋白揭示了这些细胞的完整结构，通过选择性地标记新生成的细胞，可以在动物发育过程中跟踪假设为必须脆弱的群体，以评估它们如何与其他脑细胞联系。暴露于新生儿癫痫发作的未成熟细胞的发育将与使用共聚焦显微镜的正常动物细胞进行比较。这些研究将为新生儿癫痫发作的长期后果提供重要的见解，将告知临床医生如何积极地使用抗惊厥药物治疗癫痫发作的儿童，并将有助于确定海马细胞整合的破坏是否可能解释新生儿癫痫发作的负面后果。公共卫生相关性：儿童癫痫发作很常见。然而，这些癫痫发作的长期后果尚不清楚。在这里，我们将研究新生儿癫痫发作对大脑区域发展的影响，该区域对学习、语言发展、认知和想象力至关重要。这些研究将有助于确定新生儿癫痫发作是否以及如何损害年轻的大脑，并将指导减轻策略和治疗的发展。

DESCRIPTION (provided by applicant): The hippocampus is a structure located deep in the brain that is critical for memory, language development, cognition and even imagination. Surprisingly, this is one of the few regions of the adult brain where new brain cells are generated. These new cells are important for the proper functioning of the hippocampus. Unfortunately, recent studies demonstrate that these new cells are vulnerable to seizures. Seizure activity in the brain can cause these immature cells to form the wrong connections with other brain cells. In adults, these abnormal cells likely lead to cognitive problems and perhaps even the development of epilepsy. Distressingly, in children, the situation may be even worse. First, children exhibit a much lower seizure threshold than adults. Seizures in children, therefore, are common. Second, the developmental period during which children exhibit higher seizure incidence overlaps with the peak period of hippocampal development. Large numbers of hippocampal cells are generated in infants, and these cells undergo extensive development through early childhood. Seizures during this period could lead to the abnormal wiring of large numbers of hippocampal cells. In contrast, the generation of neurons in almost all other brain regions is largely complete by birth. To determine whether new hippocampal cells are uniquely vulnerable to insult, and whether disruption of these cells might account for the severe cognitive deficits experienced by children who have intense or recurrent seizures, we utilize a mouse model system in which newly generated hippocampal cells are labeled with green fluorescent protein (GFP). GFP reveals the complete structure of these cells, and by selectively labeling newly generated cells, the population hypothesized to be must vulnerable can be tracked as the animals develop to assess how they connect with other brain cells. The development of immature cells exposed to neonatal seizures will be compared to cells from normal animals using confocal microscopy. These studies will provide important insights into the long-term consequences of neonatal seizures, will inform clinicians about how aggressively to treat children having seizures with anticonvulsant drugs and will help to establish whether disrupted hippocampal cell integration might account for the negative consequences of neonatal seizures. PUBLIC HEALTH RELEVANCE: Seizures in children are common. The long term consequences of these seizures, however, are still unclear. Here, we will examine the impact of neonatal seizures on the development of a brain region critical for learning, language development, cognition and imagination. These studies will help to determine whether and how neonatal seizures harm young brains, and will guide the development of mitigating strategies and treatments.