Neural Signatures and Cognitive Performance During Rat Morphine Withdrawal, and Subsequent Impact of Psilocybin

项目摘要 阿片成瘾普遍存在，影响着大约300万美国成年人。目前可用 阿片成瘾治疗，如阿片类药物替代疗法，未能减缓日益增长的阿片类药物流行和 保持上瘾和服药过量的风险。此外，现有的阿片成瘾治疗需要长期的 承诺接受治疗，几乎没有长期禁欲的证据。最后，阿片类药物替代疗法是 无法缓解成瘾引起的认知障碍。更深入地了解神经和 形成成瘾的认知系统对于开发更好的针对性治疗方法是必要的。 阿片成瘾。 阿片成瘾的啮齿动物模型表现出与人类阿片成瘾相似的行为标志。 上瘾。因此，这是一个可靠和可行的模型来研究成瘾相关的神经关联。 适应不良的行为。一项新的研究表明，进化上保守的侧翼 啮齿类动物的缰核与成瘾密切相关。外侧缰核的独特之处在于它直接调节 多巴胺和5-羟色胺能结构，这两种结构在成瘾时都表现出功能障碍。但是，有了 传统的电生理方法记录外侧缰核的神经活动，已经很难实现 清楚地评估大量神经元的反应。成像技术的最新进展已经 允许对单个神经元钙动力学进行为期一周的监测，从而简化了研究 外侧缰核神经反应。5-羟色胺激动剂，如裸盖菇素，在 降低酒精和尼古丁成瘾复发率并改善不健康人群的认知功能 成年人。重要的是，众所周知，外侧缰核过度活动会导致厌恶情绪，并出现在戒断状态。 5-羟色胺能激动剂也被证明可以抑制外侧缰核的活动，这表明 未开发的治疗途径。 因此，随着钙成像的使用，我假设外侧缰核神经元动力学将转变为 吗啡戒断后的过度活跃状态，这些神经信号将与 认知任务成绩下降。此外，我假设裸盖菇素治疗将恢复 基线外侧缰核活动和改善认知能力。拟议的一系列实验将 填补了解在阿片类药物戒断过程中驱动不良适应决定的神经电路的空白，如 以及一种新的阿片成瘾治疗方法的行为和神经效应。

PROJECT ABSTRACT Opioid addiction is pervasive and widespread, affecting roughly three million U.S. adults. Currently available opioid addiction treatments, such as opioid replacement therapy, fail to slow the growing opioid pandemic and maintain the risk of addiction and overdose. Moreover, available opioid addiction treatments require long-term commitment to treatment with little evidence of long-lasting abstinence. Lastly, opioid replacement therapy is unable to alleviate addiction-induced cognitive impairments. A deeper understanding of the neural and cognitive systems that underlie addiction is necessary for the development of better targeted treatments for opioid addiction. The rodent model of opioid addiction exhibits behavioral markers analogous to those induced in human opioid addiction. Hence, this is a reliable and feasible model for studies of the neural correlates of addiction-related maladaptive behaviors. An emerging body of research suggests that the evolutionarily conserved lateral habenula in rodents is highly implicated in addiction. The lateral habenula is unique in that it directly regulates dopaminergic and serotonergic structures, both of which exhibit dysfunction in addiction. However, with traditional electrophysiological methods of recording lateral habenula neural activity, it has been difficult to clearly assess responses of large populations of neurons. More recent advances in imaging technology have allowed for week-long monitoring of individual neuron calcium dynamics, easing the feasibility of studying the lateral habenula neural responses. Serotonin agonists, such as psilocybin, have shown promising results in reducing the rates of relapse in alcohol and nicotine addiction and improving cognitive function in unhealthy adults. Importantly, lateral habenula hyperactivity is known to drive aversion and is present in withdrawal. Serotonergic agonists have also been shown to quiet lateral habenula activity, suggesting a potential unexplored treatment avenue. Hence, with the use of calcium imaging, I hypothesize that lateral habenula neuron dynamics will shift to a hyperactive state following morphine withdrawal, and that these neural signatures will correlate with decreased performance on cognitive tasks. Additionally, I hypothesize that psilocybin treatment will reinstate baseline lateral habenula activity and improve cognitive performance. The proposed series of experiments will fill the gap in understanding the neural circuitry that drives maladaptive decisions during opiate withdrawal, as well as the behavioral and neural effect of a novel treatment for opiate addiction.