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

大鼠吗啡戒断期间的神经特征和认知表现，以及赛洛西宾的后续影响

• 批准号: 10748587
• 负责人: VICTORIA Ivanova HONES
• 金额: $ 4.57万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-16 至 2026-08-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748587
• 关键词: Abstinence; Adult; Affect; Alcohol dependence; Anhedonia; Anxiety; Architecture; Attenuated; Behavior; Behavioral; Calcium; Cells; Chronic; Cognition; Cognitive; Cognitive deficits; Development; Electrophysiology (science); Epithalamic structure; Exhibits; Feasibility Studies; Functional disorder; Genetic Transcription; HTR2A gene; Habenula; Human; Hyperactivity; Image; Imaging technology; Impaired cognition; Impairment; Individual; Lateral; Memory; Memory impairment; Mental Depression; Mental disorders; Methods; Monitor; Morphine; Morphine Dependence; Naloxone; Neurons; Nicotine Dependence; Opiate Addiction; Opioid; Opioid replacement therapy; Overdose; Performance; Pharmaceutical Preparations; Population; Process; Psilocybin; Psychopathology; Rattus; Relapse; Research; Reversal Learning; Risk; Rodent; Rodent Model; Role; Series; Serotonin Agonists; Signal Transduction; Structure; Study models; Symptoms; System; Testing; Time Series Analysis; Withdrawal; addiction; behavioral response; brain remodeling; brain tissue; cognitive function; cognitive performance; cognitive system; cognitive task; cognitive testing; conventional therapy; experimental study; flexibility; imaging modality; improved; maladaptive behavior; mu opioid receptors; neural; neural circuit; neural correlate; neuromechanism; novel; object recognition; opioid withdrawal; pandemic disease; psychiatric symptom; receptor; receptor expression; response; serotonin receptor

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.

项目摘要 阿片类药物成瘾现象普遍存在，影响着大约 300 万美国成年人。目前可用 阿片类药物成瘾治疗，例如阿片类药物替代疗法，无法减缓阿片类药物的流行，并且 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治疗 致力于治疗，但几乎没有证据表明长期禁欲。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。对神经和神经系统有更深入的了解 成瘾背后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诱导的行为标记类似的行为标记 瘾。因此，这是研究成瘾相关的神经相关性的可靠且可行的模型 适应不良行为。一项新兴的研究表明，进化上保守的横向 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 多巴胺能和血清素能结构，两者都表现出成瘾功能障碍。然而，随着 传统的电生理方法记录外侧缰核神经活动，一直难以 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态进行为期一周的监测，从而简化了研究的可行性 外侧缰核神经反应。血清素激动剂，例如裸盖菇素，在以下方面已显示出有希望的结果： 降低酒精和尼古丁成瘾的复发率并改善不健康人群的认知功能 成年人。重要的是，已知外侧缰核过度活跃会导致厌恶，并且存在于戒断症状中。 5-羟色胺激动剂也被证明可以抑制外侧缰核的活动，这表明潜在的 未探索的治疗途径。 因此，通过使用钙成像，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，并且这些神经特征将与 认知任务的表现下降。此外，我假设裸盖菇素治疗将恢复 基线外侧缰核活动并提高认知能力。拟议的一系列实验将 填补了理解鸦片戒断期间驱动适应不良决策的神经回路的空白，如 以及阿片成瘾新疗法的行为和神经效应。