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 阿片类药物成瘾无处不在且广泛，影响了大约300万美国成年人。目前可用 阿片类药物成瘾疗法，例如阿片类药物替代疗法，无法减缓不断增长的阿片类药物大流行和 保持成瘾和过量的风险。此外，可用的阿片类药物成瘾治疗需要长期 致力于治疗，几乎没有长期禁欲的证据。最后，阿片类药物替代疗法是 无法减轻成瘾引起的认知障碍。对神经和 基于成瘾的认知系统对于开发更好的目标治疗是必要的 阿片类药物成瘾。 阿片类药物成瘾的啮齿动物模型表现出类似于人阿片类药物的行为标志物 瘾。因此，这是一个可靠且可行的模型，用于研究与成瘾相关的神经相关性 适应不良的行为。一项新兴的研究表明，进化保守的横向 啮齿动物中的Habenula在成瘾中高度涉及。外侧Habenula的独特之处在于它直接调节 多巴胺能和血清素能结构都表现出功能障碍。但是，与 传统的电生理方法记录横向habenula神经活动，很难 清楚地评估了大量神经元的反应。成像技术的最新进展已有 允许对单个神经元钙动力学进行长达一周的监测，从而减轻研究的可行性 外侧Habenula神经反应。 5-羟色胺激动剂，例如psilocybin，在 降低酒精和尼古丁成瘾的复发率，并提高不健康的认知功能 成年人。重要的是，已知侧向抗抗瘤过度活跃会驱动厌恶，并出现在戒断中。 血清素能激动剂也已被证明是安静 未开发的治疗大道。 因此，随着钙成像的使用，我假设侧向Habenula神经元动力学将转移到一个 戒断吗啡后的多动态状态，这些神经特征将与 认知任务的表现下降。此外，我假设psilocybin治疗将恢复 基线侧向habenula活性并改善认知性能。提出的一系列实验将 填补差距，了解在鸦片戒断期间推动不良适应决定的神经回路 以及新型阿片成瘾治疗的行为和神经效应。