Neural circuits and mechanisms underlying maladaptive risk-taking following cocaine self-administration

可卡因自我给药后适应不良冒险的神经回路和机制

基本信息

批准号：
10004014
负责人：
Caitlin Anne Orsini
金额：
$ 24.9万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004014
关键词：
Abstinence Address Affect Agonist Amygdaloid structure Attenuated Behavior Behavioral Brain Characteristics Chronic Cocaine Cocaine Dependence Cocaine Users Communication Coupled Cues Data Decision Making Development Disease Dopamine D2 Receptor Drug Addiction Drug usage Electrophysiology (science)Exhibits Female Foundations Functional disorder Goals Human Hypersensitivity Impairment Insula of Reil Knowledge Laboratories Learning Life Mediating Mental disorders Modeling Monitor Neurobiology Neurons Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Phase Play Positioning Attribute Probability Process Punishment Rattus Recording of previous events Relapse Research Rewards Risk Risk-Taking Rodent Role Self Administration Sex Differences Structure Testing Time Training addiction cocaine use cost drug of abuse experimental study in vivo information processing insight male neural circuit neuromechanism novel novel therapeutics optogenetics pre-clinical research prevent programs real time monitoring receptor function relating to nervous system sex substance abuser targeted treatment time use

项目摘要

Project Summary: Drug addiction is associated with poor decision-making and elevated risk-taking, which can persist well into abstinence and contribute to relapse. These adverse behavioral changes are particularly evident in cocaine users, who exhibit pronounced elevations in risk-taking both in the laboratory and in real world settings. The majority of preclinical research to date has focused on the mechanisms by which hypersensitivity to reward promotes poor decision-making and continued drug use; however, we have only a rudimentary understanding of the brain circuits that encode the risk of punishment associated with these maladaptive choices. The long term goal of this project is to elucidate the neurobiology of drug-induced maladaptive decision-making involving punishment and, thereby, identify neural targets for therapeutically attenuating risk-taking in substance abusers. Relevant to this goal, our laboratory has established a rat model of risk-taking (the “Risky Decision-Making Task”; RDT) that recapitulates real-life decision-making in that it incorporates both reward and risk of punishment. Using this model, our lab showed that chronic cocaine self- administration causes lasting increases in punished risk-taking behavior and that dopamine D2 receptor (D2R) function in the nucleus accumbens (NAc) plays a critical role in this behavior. Further, preliminary data reveal unique roles in punishment-related decision-making for the basolateral amygdala (BLA) and insular cortex (INS), both of which project to the NAc and are impacted by drugs of abuse. The proposed experiments will build on these findings and test the central hypothesis that cocaine-induced insensitivity to risk of punishment is mediated both by attenuated D2R function in the NAc and by disrupted communication between the NAc and afferent structures that convey essential information regarding anticipation and probability of punishment. This hypothesis will be tested using a combination of in vivo electrophysiology and optogenetics to allow both in vivo manipulation and real-time monitoring of neural activity during decision-making behavior. Aim 1 will determine whether alterations in NAc D2R function mediate cocaine-induced insensitivity to risk of punishment by first testing whether a D2R agonist restores altered neural activity in the NAc during decision-making in rats with a history of cocaine self-administration. In a second experiment, D2R-expressing neurons in the NAc will be optogenetically manipulated during decision-making to test whether inhibition of these neurons reverses cocaine-induced increases in risk-taking. Aim 2 will determine whether dysfunction in the BLA and INS afferents to the NAc contributes to cocaine-induced insensitivity to risk of punishment. These experiments will determine how activation or silencing of these circuits affects risk-taking and neural encoding of risk of punishment following cocaine self-administration. Collectively, these findings will provide insight into how the neural circuitry underlying risk-taking may become compromised by drugs of abuse and, thus, reveal brain targets that could be modulated to reduce maladaptive risk-taking associated with drug addiction.

项目摘要：吸毒成瘾与决策失误和冒险行为增加有关，这可能会导致这些不良行为改变尤其容易导致戒毒。这在可卡因使用者中很明显，他们在实验室和现实中的冒险行为都表现出明显的升高迄今为止，大多数临床前研究都集中在其机制上。对奖励的过度敏感会导致糟糕的决策和持续的吸毒；然而，我们只有一个对编码与这些相关的惩罚风险的大脑回路有初步的了解该项目的长期目标是阐明药物诱导的神经生物学。涉及惩罚的适应不良决策，从而确定治疗的神经目标与此目标相关，我们的实验室建立了大鼠模型。风险承担（“风险决策任务”；RDT），概括了现实生活中的决策我们的实验室利用这个模型，结合了奖励和惩罚风险，证明了慢性可卡因会自我影响。给药会导致受惩罚的冒险行为持续增加，并且多巴胺 D2 受体 (D2R) 此外，初步数据显示，伏隔核（NAc）的功能在这种行为中发挥着关键作用。基底外侧杏仁核 (BLA) 和岛叶皮层在惩罚相关决策中的独特作用（INS），两者都投射到 NAc 并受到滥用药物的影响。拟议的实验将。以这些发现为基础，检验可卡因导致对惩罚风险不敏感的中心假设由 NAc 中 D2R 功能减弱和 NAc 之间通讯中断介导以及传递有关预期和惩罚概率的基本信息的传入结构。该假设将通过体内电生理学和光遗传学的结合进行测试，以允许目标 1 将在体内操纵和实时监测决策行为期间的神经活动。确定 NAc D2R 功能的改变是否介导可卡因引起的对惩罚风险的不敏感首先测试 D2R 激动剂是否可以恢复大鼠决策过程中 NAc 中改变的神经活动在第二个实验中，NAc 中表达 D2R 的神经元将具有自我施用可卡因的历史。在决策过程中进行光遗传学操作，以测试这些神经元的抑制是否逆转可卡因引起的冒险行为增加将决定 BLA 和 INS 是否出现功能障碍。 NAc 的传入有助于可卡因引起的对惩罚风险的不敏感。确定这些回路的激活或沉默如何影响风险承担和风险的神经编码总的来说，这些发现将有助于了解可卡因自我给药后的惩罚。冒险行为背后的神经回路可能会受到滥用药物的损害，从而揭示大脑可以调节目标以减少与毒瘾相关的适应不良的冒险行为。