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

项目摘要 阿片类药物成瘾是普遍和广泛的，影响了大约300万美国成年人。当前可用 阿片类药物成瘾治疗，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病， 保持成瘾和过量的风险。此外，现有的阿片类药物成瘾治疗需要长期的 致力于治疗，几乎没有持久禁欲的证据。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 认知系统的基础成瘾是必要的发展更有针对性的治疗， 阿片类药物成瘾 阿片类药物成瘾的啮齿动物模型表现出与人类阿片类药物中诱导的行为标志物类似的行为标志物 成瘾因此，这是一个可靠的和可行的模型，为研究成瘾相关的神经相关性， 适应不良的行为一个新兴的研究机构表明，进化上保守的横向 啮齿类动物的缰与成瘾密切相关外侧缰的独特之处在于它直接调节 多巴胺能和多巴胺能结构，两者都表现出成瘾功能障碍。但随着 传统的记录外侧缰核神经活动的电生理方法， 清楚地评估大量神经元的反应。成像技术的最新进展 允许对单个神经元钙动力学进行为期一周的监测，从而简化了研究神经元钙动力学的可行性。 外侧缰核神经反应5-羟色胺激动剂，如裸盖菇素，已经显示出有希望的结果， 降低酒精和尼古丁成瘾的复发率，改善不健康人群的认知功能， 成年人了重要的是，外侧缰核活动过度被认为是厌恶的驱动力，并且存在于退缩中。 5-羟色胺能激动剂也被证明可以抑制外侧缰核的活动，这表明了一种潜在的 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移到一个新的水平。 吗啡戒断后的过度活跃状态，这些神经信号将与 认知任务的表现下降。另外，我假设裸盖菇素治疗可以恢复 基线侧缰活动和改善认知表现。拟议的一系列实验将 填补了理解神经回路的差距，神经回路在阿片类药物戒断期间驱动适应不良的决定， 以及阿片类药物成瘾的新疗法对行为和神经的影响。

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.