Functional and structural analysis of aberrant adult neurogenesis

海马齿状颗粒细胞是大脑中为数不多的成年期持续产生的神经细胞类型之一。尽管神经发生的功能意义尚不清楚，但最近的工作表明，成年出生的神经元短暂地表现出生理特征(即高兴奋性和可塑性)，使它们能够促进特定形式的海马依赖行为，包括上下文学习、认知灵活性和模式分离。众所周知，与记忆和学习相关的损害在患有癫痫的人中表现得过于明显。有趣的是，先前的研究表明，癫痫发作会显著增加齿状回中新神经元的积累。鉴于齿状回也是调节进入海马区的信息流的“门”，一个未探索的问题是，继发于反复发作的非典型神经发生是否可能有助于改变海马体介导的行为。*这项建议的目的将是研究异常癫痫诱导的神经发生对行为和认知表现的功能影响。为了解决这个问题，我们将使用一种名为点燃的动物模型，在该模型中，每天对某些大脑区域进行电刺激会导致运动性癫痫的逐渐发展。我们之前已经发现，点燃会导致神经发生的戏剧性变化，从而改变海马体功能--这一过程可能会导致学习和记忆功能以及情绪行为的损害。为了扩展这些观察，我们将评估点燃对需要功能性神经发生的行为的影响，例如模式分离和背景辨别。我们还将绘制点燃后新生神经元上突触输入的解剖学和神经化学特征图，并确定点燃是否影响这些细胞整合到参与学习和记忆的电路中。最后，我们将研究阻断异常神经发生是否可以逆转点燃的行为后果。该提案中概述的研究将深入了解支配成人神经发生的基本机制，以及新生神经元如何在正常和病理条件下影响行为。**

Hippocampal dentate granule cells are among the few neuronal cell types in the brain that are continuously generated throughout adulthood. Although the functional significance of neurogenesis remains unclear, recent work suggests that adult-born neurons transiently exhibit physiological characteristics (i.e. heightened excitability and plasticity) that enable them to contribute to specific forms of hippocampal-dependent behaviors, including contextual learning, cognitive flexibility, and pattern separation. It is well established that memory and learning-related impairments are overrepresented in individuals afflicted with epilepsy. Interestingly, previous work has shown that seizures dramatically increase the accumulation of new neurons in the dentate gyrus. Given that the dentate gyrus also operates as a "gate" that regulates the flow of information entering into the hippocampus, an unexplored question is whether atypical neurogenesis secondary to recurrent seizures might contribute to alterations in hippocampal-mediated behavior.*******The aim of this proposal will be to examine the functional impact of aberrant seizure-induced neurogenesis on behavior and cognitive performance. To address this question, we will use an animal model called kindling, in which daily electrical stimulation of certain brain regions results in the gradual progression of motor seizures. We have previously found that kindling causes dramatic changes in neurogenesis that alters hippocampal function--a process that may contribute to impairments in learning and memory function, as well as emotional behavior. To extend on these observations, we will assess the impact of kindling on behaviors that require functional neurogenesis, such as pattern separation and contextual discrimination. We will also map the anatomy and neurochemical characteristics of synaptic inputs on newborn neurons after kindling, and determine if kindling affects the integration of these cells into circuits that are involved in learning and memory. Finally, we will examine whether blocking aberrant neurogenesis can reverse the behavioral consequences of kindling. The studies outlined in this proposal will provide insight into the fundamental mechanisms that govern adult neurogenesis and how newborn neurons can influence behavior under normal and pathological conditions.**