Circuit Contributions of Adult and Seizure-Induced Neurogenesis in the Dentate Gy

描述（由申请人提供）：正在进行的神经发生的非生物学证据已经彻底改变了成人大脑中神经可塑性的观点。由于海马在学习、记忆和认知中的作用，在齿状回（DG）中连续产生成年出生的齿状颗粒细胞（abGC）受到特别的关注。齿状颗粒细胞（GC）通过使用稀疏神经代码执行认知功能，例如空间环境中的模式分离和新奇检测。然而，GC活动的稀疏性是神秘的：超过95%的GC在任何环境中都不发射，而剩下的5%在所有环境中都活跃。计算模型和体内研究表明，abGC优先被激活，并可能包括这些功能性GC的大部分。该理论尚未得到充分的测试，并且如果发现得到支持，则介导abGC的这种优先活化的机制是未知的。在颞叶癫痫（TLE）动物模型中观察到abGC神经发生失调。在诱导TLE的脑损伤后早期，存在伴随abGC的异常整合的增加的产生。目前尚不清楚这些异常整合的细胞是否促进或保护癫痫发作活动，因为新生细胞对海马回路功能的确切贡献尚不清楚。该提议的中心假设是，abGCs是正常和癫痫脑中齿状回回路功能的重要调节器，并且此外，它们在这两种状态中的功能贡献是不同的。为了检验这一假设，我们将进行集中于两个特定目的的研究，这两个特定目的是：目的1）确定未成熟的abGC是否优先被传入刺激激活，以及目的2）确定abGC是否有助于在细胞中明显的传入刺激引起的细胞激活特异性的降低。 癫痫动物的齿状回。通过使用国家的最先进的光学和电子记录，和遗传策略，我们将检查相对电路的贡献和生理学的新生儿和成熟的GC在两个天真的动物和癫痫的动物模型。

DESCRIPTION (provided by applicant): Unambiguous evidence of ongoing neurogenesis has revolutionized views of neuroplasticity in the adult brain. Continual generation of adult-born dentate granule cells (abGCs) in the dentate gyrus (DG) has received particular attention due to the hippocampus' role in learning, memory and cognition. Dentate granule cells (GCs) perform cognitive functions such as pattern separation and novelty detection in spatial environments through the use of a sparse neural code. However, the nature of sparseness in GC activity is enigmatic: more than 95% of GCs do not fire in any environment, while the remaining 5% are active in all environments. Computational models and in vivo studies suggest that abGCs are preferentially activated and may comprise the majority of these functional GCs. This theory has not been sufficiently tested, and if found to be supported, the mechanisms mediating this preferential activation of abGCs are unknown. Dysregulation of abGC neurogenesis has been observed in animal models of temporal lobe epilepsy (TLE). Early following brain injuries that induce TLE, there is an increased production accompanied by aberrant integration of abGCs. It is unclear whether these aberrantly integrated cells promote or protect against seizure activity, as the exact contributions of newborn cells to hippocampal circuit function are unknown. The CENTRAL hypothesis of this proposal is that abGCs are important regulators of dentate gyrus circuit function in both the normal and epileptic brain, and furthermore, that their functional contributions in these two states is distinct. To test this hypothesis, we will conduct studies focused on two specific aims, which are: Aim 1) Determine whether immature abGCs are preferentially activated by afferent stimulation, and Aim 2) Determine whether abGCs contribute to the degradation in the specificity of cellular activation by afferent stimulation evident in the dentate gyrus of animals with epilepsy. Through the use of state-of-the-art optical and electrical recordings, and genetic strategies, we will examine the relative circuit contributions and physiology of both newborn and mature GCs in both na¿ve animals and in an animal model of epilepsy.