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明确证据已经彻底改变了成人大脑中神经可塑性的观点。由于海马体在学习、记忆和认知中的作用，在齿状回(DG)中成体出生的齿状颗粒细胞(AbGC)的持续生成受到了特别关注。齿状颗粒细胞(GC)通过使用稀疏的神经编码在空间环境中执行认知功能，如模式分离和新奇检测。然而，GC活动稀疏性的本质是神秘的：超过95%的GC在任何环境中都不会激发，而其余5%的GC在所有环境中都是活跃的。计算模型和体内研究表明，abGC优先被激活，并可能构成这些功能GC的大多数。这一理论还没有得到充分的检验，如果被发现得到支持，那么调节abGC优先激活的机制尚不清楚。在颞叶癫痫(TLE)的动物模型中观察到ABGC神经发生的失调。在导致TLE的早期脑损伤后，伴随着abGC的异常整合而产生的产物增加。目前尚不清楚这些异常整合的细胞是促进还是保护癫痫发作活动，因为新生细胞对海马区电路功能的确切贡献尚不清楚。这一设想的中心假设是，abGC是正常和癫痫脑中齿状回回路功能的重要调节者，而且它们在这两种状态下的功能贡献是不同的。为了验证这一假设，我们将围绕两个特定的目标进行研究：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是否有助于通过传入刺激明显降低细胞激活的特异性。 癫痫动物的齿状回。通过使用最先进的光学和电学记录，以及遗传策略，我们将在幼年动物和癫痫动物模型中检查新生和成熟GC的相对电路贡献和生理学。

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.