Methamphetamine and adult hippocampal neurogenesis

甲基苯丙胺与成人海马神经发生

• 批准号: 9066260
• 负责人: Chitra D Mandyam
• 金额: $ 0.98万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066260
• 关键词: Abstinence; Acute; Adult; Affect; Attention; Behavioral Model; Biological Models; Brain; Brain Diseases; Brain Injuries; Cells; Clinical; Collaborations; Dose; 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; 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)：本提案的总体目标是确定成人海马区神经发生在长期摄入甲基苯丙胺后恢复过程中的重要性。对成瘾和复发的神经生物学基础的研究已经取得了重大进展，但到目前为止，很少有治疗方法能逆转药物诱导的神经可塑性变化，这些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选择。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。神经干细胞持续存在于成年海马颗粒下带(SGZ)。成年海马神经发生与甲基苯丙胺成瘾的某些方面有关，因为强化剂量的甲基苯丙胺减少了SGZ中神经干细胞的增殖、分化和神经发生。然而，停用甲基苯丙胺对海马神经发生的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人神经发生的过程；在戒断过程中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被用于在延长获得甲基苯丙胺摄入量的背景下专门标记、刺激或抑制成人产生的神经元。使用这些方法，我们将检验我们的中心假设，即海马区神经发生有助于通过神经元替代戒断长期接触的甲基苯丙胺后的修复；因此，抑制这一过程将损害恢复，而刺激这一过程将增强恢复，减少或防止复发。目标1中的研究将表征在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，我们将确定成人戒断过程中的神经再生是否有助于功能恢复和防止复发。