Elucidating the role of the endogenous opioid dynorphin in reward seeking

阐明内源性阿片类强啡肽在寻求奖励中的作用

• 批准号: 10722734
• 负责人: Raajaram Gowrishankar
• 金额: $ 17.46万
• 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: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722734
• 关键词: Address; Affect; Amygdaloid structure; Award; Behavior; Behavior Control; Behavioral Model; Biosensor; Brain; Brain region; Budgets; Cessation of life; Committee Members; Consumption; Corpus striatum structure; Cues; Data; Development; Drug usage; Dynorphins; Fentanyl; Fiber; Genetic; Goals; Head; Image; Intake; Internal Ribosome Entry Site; Intervention; Kinetics; Light; Link; Measures; Mediating; Mentors; Messenger RNA; National Institute of Drug Abuse; Neurons; Neurosciences; Operant Conditioning; Opioid; Opioid Antagonist; Oral; Pattern; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Photometry; Population; Postdoctoral Fellow; Predisposition; Principal Investigator; Property; Receptor Signaling; Recreation; Regulation; Relapse; Research; Resolution; Rewards; Role; Scientific Societies; Self Administration; Shapes; Signal Transduction; Substance Use Disorder; Sucrose; Testing; Therapeutic Agents; Training; Validation; calmodulin-dependent protein kinase II; career; career development; conditioning; drug reward; endogenous opioids; fentanyl seeking; fentanyl self-administration; imaging approach; in vivo; in vivo calcium imaging; in vivo two-photon imaging; kappa opioid receptors; knowledge base; neural circuit; neuromechanism; novel; opioid use; opioid use disorder; optogenetics; overdose death; preference; prevent; programs; receptor expression; substance use; symposium; transmission process; two-photon

Project Summary: The primary goal of this training proposal is to understand how dynorphinergic regulation of circuits in the dorsomedial striatum (DMS) enhances seeking behaviors for natural (sucrose) and drug (fentanyl) rewards. Enhanced dynorphin-kappa opioid receptor (dyn-KOR) signaling and aberrant striatal activity is associated with the transition from recreational to persistent opioid-seeking. Yet how dyn neuron activity and subsequent -KOR modulation of the striatum regulates sucrose or fentanyl-seeking is unknown. During the first phase of my postdoctoral research, using a combination of pharmacology, genetics, in vivo photometry and optogenetics, I identified that retrograde dyn transmission at BLA inputs to the DMS enhances BLA-DMS activity, and promotes natural reward-seeking behaviors. However, when exactly dyn neuron activity and release are engaged in reward-seeking is unknown. Hence, I will obtain training in, and use in vivo two-photon imaging to understand how DMS dyn ensembles encode reward-seeking for sucrose, (Aim 1A, K99). I will also extensively characterize and use a novel dyn biosensor using in vivo photometry to determine if the pattern of ensemble activity is reflected in subsequent DMS dyn release, (Aim 1B, K99). Furthermore, because aberrant dyn-KOR signaling is linked to maladaptive opioid-seeking, and my preliminary data suggests a role for dyn-KOR activity to enhance sucrose-seeking, I will develop and use an oral fentanyl self-administration paradigm in conjunction with in vivo photometry to dissect when BLA-DMS terminals are engaged during fentanyl-seeking (Aim 2A, K99). I will also multiplex conditional deletions of dyn in the DMS, or KOR in the BLA, and stimulate dyn release in the DMS, with in vivo photometry during fentanyl-seeking to determine whether enhanced dyn-KOR signaling negatively modulates fentanyl-seeking (Aim 2B, K99). For the R00 “independent” phase of my proposal, I propose to extend the findings from Aims 1 and 2 in my own lab. I will delineate how DMS dyn ensemble activity encodes fentanyl- seeking, manipulate specific ensembles to control behavior via spatial light modulation, and dissect the necessity for BLA inputs in the DMS to induce dyn release during fentanyl-seeking (Aim 3, R00). The proposed studies specifically address how elevated endogenous dynorphin-KOR signaling, via its control of activity in the DMS, regulates natural and fentanyl reward-seeking. During the proposed K99 training period, I will be trained in in vivo two-photon calcium imaging approaches, opioid biosensor imaging and oral self-administration. Additionally, I will actively participate in scientific society conferences, obtain career development training (budgeting and administrative tasks), and continue to further my scholarly knowledge base (planned interactions with my mentor and committee members). Altogether, this award will greatly facilitate the development of my own research program, thereby preparing me for an independent neuroscience career as a principal investigator.

项目总结: