Methamphetamine and adult hippocampal neurogenesis

甲基苯丙胺与成人海马神经发生

• 批准号: 9043006
• 负责人: Chitra D Mandyam
• 金额: $ 22.3万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043006
• 关键词: Abstinence; Acute; Adult; Affect; Attention; Behavioral Model; Biological Models; Brain; Brain Diseases; Brain Injuries; Cells; Clinical; Collaborations; Dose; Electrophysiology (science); Embryonic Development; Generations; Genetic; Glial Fibrillary Acidic Protein; Glioma; Goals; Green Fluorescent Proteins; Health; Hippocampus (Brain); Individual; Injection of therapeutic agent; Intake; Isoxazoles; Label; Learning; Mammals; Mediating; Methamphetamine; Methamphetamine dependence; Modeling; National Institute of Mental Health; Neurobiology; Neuronal Plasticity; Neurons; Pathogenesis; Pharmaceutical Preparations; Play; Process; Rattus; Recovery; Recovery of Function; Relapse; Research; Retroviridae; Rodent Model; Role; Saline; Self Administration; Staging; Techniques; Testing; Transgenic Organisms; Valganciclovir; Vertebral column; Withdrawal; addiction; adult neurogenesis; base; brain repair; cell injury; craving; density; dentate gyrus; disorder later incidence prevention; drug relapse; drug seeking behavior; functional plasticity; granule cell; innovation; insight; killings; methamphetamine effect; nerve stem cell; neurogenesis; neuron development; neuronal replacement; postsynaptic; pre-clinical; prevent; progenitor; receptor; relating to nervous system; repaired; research study; response; self-renewal; stem cell biology; voltage clamp

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.

描述（由申请人提供）：该提案的总体目标是确定成年海马神经发生在扩展访问甲基苯丙胺摄入后的恢复过程中的重要性。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发展，但迄今为止，很少有治疗方法可以扭转药物诱导的神经可塑性变化，从而传达了复发的脆弱性。了解成瘾复发阶段构成的神经塑性变化可以帮助产生更好的成瘾治疗选择。在戒断期间加速脑修复的一种潜在机制是刺激成人神经干细胞的神经元的产生，这是一种称为成人海马神经发生的过程。神经干细胞持续存在于成年海马亚颗粒区（SGZ）。成年海马神经发生与甲基苯丙胺成瘾的某些方面有关，因为加强甲基苯丙胺剂量减少了SGZ中神经干细胞的增殖，分化和神经发生。然而，从甲基苯丙胺中戒断对海马神经发生的这些阶段的影响尚不清楚。此外，尚不清楚在戒断期间是否可以刺激成年神经发生的过程。可以在退出期间替换的神经元的类型及其将其集成到预先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扩展甲基苯丙胺摄入量的情况下专门标记，刺激或抑制成人生成的神经元。使用这些方法，我们将测试中心假设，即海马神经发生有助于通过神经元替代脱离甲基苯丙胺后戒断后修复。因此，抑制此过程会损害恢复并刺激此过程将增加恢复并减少或防止复发。 AIM 1中的研究将表征甲基苯丙胺自我给药后成人生成神经元的长期生存和整合。 AIM 2中的实验将确定成年神经发生对于预防复发至关重要。在AIM 3中，我们将确定戒断期间成年神经发生是否有助于功能恢复并防止复发。