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

项目摘要：吸毒成瘾与糟糕的决策和高风险有关，这可能 坚持很好地禁欲，并有助于复发。这些不良的行为变化尤其是 在可卡因使用者中很明显，他们在实验室和实际中都表现出明显的冒险行为 世界设置。到目前为止，大多数临床前研究都集中在 对奖励的过度敏感促进了糟糕的决策和持续的药物使用；然而，我们只有一个 对编码与此相关的惩罚风险的大脑回路有初步的了解 不适应的选择。这个项目的长期目标是阐明药物诱导的神经生物学。 涉及惩罚的不适应决策，从而确定治疗的神经靶点 减少物质滥用者的冒险行为。与这一目标相关，我们实验室建立了一种大鼠模型 风险决策任务(RDT)，它概括了现实生活中的决策 既包括奖励，也包括惩罚风险。使用这个模型，我们的实验室显示慢性可卡因自身 给药导致受惩罚的冒险行为持续增加，多巴胺D2受体(D2R) 伏隔核(NAC)的功能在这种行为中起着关键作用。此外，初步数据显示 杏仁基底外侧核(BLA)和岛叶皮质在惩罚相关决策中的独特作用 (INS)，这两个项目都投射到新生的国家，并受到滥用药物的影响。拟议中的实验将 在这些发现的基础上，测试可卡因导致对惩罚风险不敏感的中心假设 是由NAC中的D2R功能减弱和NAC之间的通信中断所调节的 以及传递关于预期和惩罚概率的基本信息的传入结构。 这一假说将使用体内电生理学和光遗传学的组合进行测试，以允许两者 在体内操纵和实时监测决策行为过程中的神经活动。目标1将 确定NAC D2R功能改变是否介导了可卡因引起的对惩罚风险的不敏感 通过首先测试D2R激动剂是否恢复大鼠决策过程中NAC中改变的神经活动 有可卡因自我管理的历史。在第二个实验中，NAC中表达D2R的神经元将 在决策过程中进行光遗传操作，以测试这些神经元的抑制是否逆转 可卡因导致冒险行为增加。目标2将确定BLA和INS的功能障碍 NAC的传入导致可卡因引起的对惩罚风险的不敏感。这些实验将 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 可卡因自我管理后的惩罚。总而言之，这些发现将为我们提供关于 冒险行为背后的神经回路可能会因滥用药物而受损，从而揭示大脑 可以调整的目标，以减少与吸毒成瘾相关的适应不良风险承担。

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.