Methamphetamine and adult hippocampal neurogenesis

描述（由申请方提供）：本提案的总体目标是确定成人海马神经发生对甲基苯丙胺长期摄入后恢复过程的重要性。 了解成瘾和复发的神经生物学基础的研究已经取得了显着进展，但迄今为止，很少有治疗方法可以逆转药物诱导的神经可塑性变化，这些变化传达了复发的脆弱性。了解成瘾复发阶段的神经可塑性变化可以帮助产生更好的成瘾治疗方案。 在戒断过程中加速大脑修复的一个潜在机制是刺激成年神经干细胞产生神经元--这一过程被称为成年海马神经发生。神经干细胞存在于成年海马颗粒下区（SGZ）。成年海马神经发生参与甲基苯丙胺成瘾的某些方面，因为甲基苯丙胺的强化剂量减少了SGZ中神经干细胞的增殖、分化和神经发生。然而，甲基苯丙胺戒断对海马神经发生这些阶段的影响尚不清楚。此外，目前还不清楚在戒断过程中是否可以刺激成年神经发生的过程;戒断过程中可以取代的神经元类型以及它们整合到先前存在的电路中的能力。 在拟议的研究中，创新的遗传，电生理和免疫组织化学技术和行为模型将被用来专门标记，刺激或抑制成人产生的神经元在设置扩展访问甲基苯丙胺摄入量。使用这些方法，我们将测试我们的中心假设，海马神经发生有助于修复后，通过神经元替代延长访问甲基苯丙胺撤出;因此，抑制这一过程将损害恢复和刺激这一过程将增加恢复和减少或防止复发。目标1中的研究将描述甲基苯丙胺自我给药后成人产生的神经元的长期存活和整合。 目标2中的实验将确定成人神经发生是否对预防复发至关重要。 在目标3中，我们将确定戒断期间的成年神经发生是否有助于功能恢复并防止复发。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to determine the importance of adult hippocampal neurogenesis to the recovery process following extended access methamphetamine intake. Research into understanding the neurobiological basis of addiction and relapse has significantly progressed, but to date few treatments are known to reverse the drug-induced neuroplasticity changes that convey vulnerability to relapse. Understanding the neuroplastic changes that underlie the relapse stage of addiction can help generate better treatment options for addiction. One potential mechanism to accelerate brain repair during withdrawal is stimulating the generation of neurons from adult neural stem cells - a process known as adult hippocampal neurogenesis. Neural stem cells persist in the adult hippocampal subgranular zone (SGZ). Adult hippocampal neurogenesis is involved in some aspects of methamphetamine addiction, as reinforcing doses of methamphetamine reduce proliferation, differentiation and neurogenesis of neural stem cells in the SGZ. However, the effects of withdrawal from methamphetamine on these stages of hippocampal neurogenesis are unknown. Furthermore, it is unclear if the process of adult neurogenesis can be stimulated during withdrawal; the types of neurons that can be replaced during withdrawal and their ability to integrate into preexisting circuitry. In the proposed studies, innovative genetic, electrophysiological and immunohistochemical techniques and behavioral models will be used to specifically label, stimulate or inhibit adult-generated neurons in the setting of extended access methamphetamine intake. Using these approaches, we will test our central hypothesis that hippocampal neurogenesis contributes to repair after withdrawal from extended access methamphetamine via neuronal replacement; thus, inhibiting this process will impair recovery and stimulating this process will augment recovery and reduce or prevent relapse. Studies in Aim 1 will characterize the long-term survival and integration of adult-generated neurons after methamphetamine self-administration. Experiments in Aim 2 will determine if adult neurogenesis is critical to the prevention of relapse. In Aim 3, we will determine whether adult neurogenesis during withdrawal contributes to functional recovery and prevents relapse.