Ventral Paired Median Neurons' Role in State-Dependent Alcohol Memory

腹侧成对正中神经元在状态依赖性酒精记忆中的作用

• 批准号: 10418501
• 负责人: Kavin Milciades Nunez
• 金额: $ 1.5万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418501
• 关键词: ARNT gene; Affect; Alcohol dependence; Alcoholic Intoxication; Alcohols; Animals; Arousal; Award; Behavior; Behavioral; Calcium; Confocal Microscopy; Cues; Data Analyses; Data Set; Development; Disease; Dose; Drosophila genus; Drosophila melanogaster; Drug abuse; Ensure; Environment; Fellowship; Food deprivation (experimental); Genetic; Grant; Image; Imaging Techniques; Immunohistochemistry; Institution; Intoxication; Invertebrates; Knowledge; Lead; Mediating; Memory; Methods; Monitor; Moods; Mushroom Bodies; Neurons; Neurosciences; Norepinephrine; Nutritional; Octopamine; Odors; Olfactory Pathways; Output; Phase; Physiological; Process; Relapse; Research; Research Personnel; Research Project Grants; Resources; Retrieval; Rewards; Role; Sensory; Stains; Stimulus; Stress; Synapses; System; Testing; Training; Work; Writing; addiction; alcohol response; alcohol testing; analytical method; behavioral response; career; conditioning; craving; drug of abuse; experimental study; fly; in vivo calcium imaging; interest; large scale data; memory acquisition; memory process; memory retrieval; multisensory; neural circuit; neuroregulation; neurotransmission; preference; relating to nervous system; response; reward circuitry; signal processing; skill acquisition; skills

PROJECT SUMMARY/ABSTRACT Animals respond to changes in their external environment and promote pro-survival behavioral output. Shifts in an animal’s internal state, or a shift neuronal processing mediated through neuromodulation, drive these adaptive behavioral responses, affecting sensory and memory processing. State-dependent modulation can be harmful when it is related to drugs of abuse, particularly alcohol. This project aims to understand the mechanisms and circuit motifs that mediate state-dependent modulation of alcohol memory circuits. Understanding these circuit mechanisms will highlight how internal state, brought about by stress, mood, and physiological state, can affect drug abuse disorders, cravings, and relapse. Briefly, Drosophila melanogaster were conditioned with a spaced- training paradigm to associate an odor cue with an intoxicating dose of alcohol, and preference was tested the following day. Octopaminergic neurons, the invertebrate equivalent norepinephrine, were found to modulate olfactory reward memory circuits necessary for alcohol memory acquisition and retrieval in fruit flies. Thermogenetic inhibition of octopaminergic neurons showed that modulation occurred only when flies were in a food-deprived state, and this neuromodulation was necessary for the acquisition and retrieval of the alcohol memory. In-vivo calcium imaging will be used to assess the activity of the subset of octopamine neurons mediating this state-dependent modulation (satiated versus food-deprived states) and their downstream post- synaptic partners. Neuronal activity of the identified state-dependent octopaminergic circuit will be assessed during intoxication, naïve odor exposure, odor-alcohol pairings, and paired- or unpaired-odor re-cue. These experiments will highlight state-dependent mechanisms for memory processing, by which shifts in internal state can affect the acquisition and retrieval of memories related to drugs of abuse. The applicant will acquire training in calcium imaging and sophisticated data-analysis methods to follow-through on these experiments, with ongoing professional development training to help develop the applicant for the next stage of their career as a postdoctoral researcher. The applicant will continue to pursue mechanisms of state-dependent modulation and how that affects multi-sensory integration, to drive behavioral choices. In the postdoctoral phase, the applicant will gain proficiency in calcium imaging techniques, computational skills, and continued training in analytical methods to examine large-scale calcium imaging data sets. Additionally, the applicant will further their professional development and grow towards becoming an independent researcher at an academic institution.

项目总结/摘要 动物对外部环境的变化做出反应，并促进有利于生存的行为输出。变化 动物的内部状态，或通过神经调节介导的神经元处理的转变， 行为反应，影响感官和记忆处理。依赖状态的调制可能有害 当它与滥用药物有关时，特别是酒精。该项目旨在了解这些机制， 介导酒精记忆回路的状态依赖性调制的回路基序。了解这些电路 机制将突出内部状态，由压力，情绪和生理状态引起，可以影响 药物滥用障碍、渴望和复发。简单地说，果蝇是条件与间隔- 训练范例，将气味线索与酒精的醉人剂量联系起来，并测试偏好， 次日章鱼胺能神经元，无脊椎动物相当于去甲肾上腺素，被发现调节 嗅觉奖励记忆回路对果蝇酒精记忆的获得和恢复是必要的。 章鱼胺能神经元的产热抑制表明，只有当苍蝇处于一个 食物剥夺状态，这种神经调节对于酒精的获得和恢复是必要的。 记忆体内钙成像将用于评估章鱼胺神经元亚群的活性 介导这种依赖于状态的调节（饱足与食物剥夺状态）及其下游的后 突触伴侣将评估所识别的状态依赖性章鱼胺能回路的神经元活性 在中毒期间，原始气味暴露，气味-酒精配对，以及配对或未配对的气味重新提示。这些 实验将强调记忆处理的状态依赖机制，通过这种机制，内部状态的变化 会影响与滥用药物有关的记忆的获得和提取。申请人将获得培训 在钙成像和复杂的数据分析方法，以贯彻这些实验， 持续的专业发展培训，以帮助申请人发展其职业生涯的下一阶段， 博士后研究员。申请人将继续寻求依赖于状态的调制机制， 这如何影响多感官整合，以推动行为选择。在博士后阶段，申请人 将熟练掌握钙成像技术，计算技能，并继续接受分析培训， 检查大规模钙成像数据集的方法。此外，申请人将进一步 专业发展和成长为一个学术机构的独立研究员。