Methamphetamine and adult hippocampal neurogenesis

描述（由申请人提供）：本提案的总体目标是确定成人海马神经发生对长期摄入甲基苯丙胺后恢复过程的重要性。对成瘾和复发的神经生物学基础的研究取得了重大进展，但迄今为止，已知的治疗方法很少能逆转药物诱导的神经可塑性变化，这种变化传递了复发的易感性。了解成瘾复发阶段背后的神经可塑性变化有助于产生更好的成瘾治疗方案。在戒断期间加速大脑修复的一个潜在机制是刺激成体神经干细胞产生神经元，这一过程被称为成体海马神经发生。神经干细胞持续存在于成体海马亚颗粒区（SGZ）。成人海马神经发生与甲基苯丙胺成瘾的某些方面有关，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，戒断甲基苯丙胺对这些海马神经发生阶段的影响尚不清楚。此外，目前尚不清楚戒断期间是否可以刺激成人神经发生过程；在戒断期间可以被替换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用于在长期获取甲基苯丙胺摄入的情况下特异性地标记、刺激或抑制成人产生的神经元。使用这些方法，我们将验证我们的中心假设，即海马神经发生有助于通过神经元替代从延长接触甲基苯丙胺戒断后的修复；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。Aim 1的研究将描述自我服用甲基苯丙胺后成人生成的神经元的长期存活和整合。Aim 2的实验将确定成人神经发生是否对预防复发至关重要。在Aim 3中，我们将确定戒断期间成人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.