Contribution of BLA-mPFC pathway to risky choice and compulsive cocaine seeking

BLA-mPFC 通路对风险选择和强迫性可卡因寻求的贡献

• 批准号: 10730229
• 负责人: Justin Ryan Yates
• 金额: $ 42万
• 依托单位: NORTHERN KENTUCKY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730229
• 关键词: 3-Dimensional; Address; Amygdaloid structure; Animal Model; Behavior; Behavioral; Catheters; Characteristics; Cocaine; Decision Making; Disease; Dose; Drug usage; Economics; Education; Extinction; Female; Food; Funding; Genetic; Glutamates; Goals; Grant; Implant; Imprisonment; Individual; Infusion procedures; Injections; Institution; Intervention; Kentucky; Measures; Medial; Mediating; Methamphetamine; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neural Pathways; Neurobiology; Neurons; Neurosciences Research; Overdose; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Prefrontal Cortex; Probability; Psychological reinforcement; Punishment; Rattus; Recovery; Relapse; Research; Rewards; Risk; Risk Behaviors; Role; Shock; Substance Use Disorder; Testing; Training; United States National Institutes of Health; Universities; Viral Vector; Withdrawal; addiction; antagonist; behavioral construct; cocaine seeking; cocaine self-administration; conditioned place preference; design; designer receptors exclusively activated by designer drugs; effective therapy; efficacious treatment; enhanced green fluorescent protein; experience; experimental study; flexibility; foot; genetic approach; male; meetings; neural circuit; neuromechanism; novel; pain sensitivity; receptor; reinforcer; response; stimulant use disorder; substance misuse; substance use; undergraduate student; vector control

Project Summary/Abstract This is a resubmission of a renewal application for an AREA R15 grant to continue research funded in DA047610 (“Contribution of NMDA NR2B subunit to risky choice and economic demand for cocaine” now titled “Contribution of BLA-mPFC pathway to risky choice and compulsive cocaine seeking”). The purpose of the R15 grant is to stimulate research at primarily educational institutions like Northern Kentucky University (NKU) that support baccalaureate training but are not recipients of major NIH support. Risky choice is characteristic of several psychiatric conditions, including substance use disorders (SUDs). Substance misuse can be considered a risky behavior as individuals can become incarcerated for their drug use or can ultimately die from overdose. Understanding the neurobiology of risky choice is important for designing effective treatment interventions for individuals that are at risk for developing SUDs. During our current funding period, we have shown that the GluN2B subunit of the glutamate N-methyl-D-aspartate (NMDA) receptor mediates risky choice as assessed in the risky decision task (RDT), and it mediates addiction-like behaviors as measured in cocaine self-administration and in methamphetamine conditioned place preference. Because the RDT uses foot shock as punishment, determining if a rat displays increased risky choice or insensitivity to shock is difficult. Thus, the first goal of the current proposal is to use a novel task to measure risky choice. To this end, rats will be tested in an equivalent expected value (EEV) task, in which reinforcer magnitude and reinforcement probability will be adjusted across concurrently available reinforcers such that the expected utility (value) of each alternative is equivalent. Because the expected value is equivalent across reinforcer alternatives, there is no suboptimal choice. However, risky choice can be measured by the percentage of responses for the lower probability/larger reward alternative. To further elucidate the neurocircuitry of risky choice, we will determine if chemogenetic inhibition of medial prefrontal cortex (mPFC)-projecting basolateral amygdala (BLA) neurons and/or BLA- projecting mPFC neurons decreases risky choice in the EEV task (Specific Aim 1). Specific Aims 2 and 3 will utilize the same chemogenetic approach from Specific Aim 1 to determine if the reciprocal connections between the BLA and the mPFC mediate compulsive cocaine seeking and resurgence of cocaine seeking (model of relapse-like behavior). Renewed funding will allow us to answer these critical questions and will allow undergraduate students to continue gaining research experience in behavioral neuroscience research at NKU.

项目摘要/摘要 这是对R15地区资助的继续研究的续期申请的重新提交 DA047610(《NMDANR2B亚基对可卡因风险选择和经济需求的贡献》，现标题为 “BLA-mPFC通路对冒险选择和强迫性寻求可卡因的贡献”)。该计划的目的是 R15拨款是为了刺激北肯塔基大学(NKU)等主要教育机构的研究 他们支持学士学位培训，但不接受NIH的主要支持。高风险的选择是 几种精神疾病，包括物质使用障碍(SUDS)。物质滥用可能是 被认为是一种危险的行为，因为个人可能因吸毒而入狱或最终死亡 因为服药过量。了解风险选择的神经生物学对于设计有效的治疗方法很重要。 对有发生肥皂泡风险的个人进行干预。在我们目前的资助期内，我们有 研究表明，谷氨酸N-甲基-D-天冬氨酸(NMDA)受体的GluN2B亚单位参与风险选择 正如风险决策任务(RDT)中所评估的那样，它介导了可卡因中的成瘾行为 自我给药和在甲基苯丙胺条件性位置偏爱。因为RDT使用脚部电击 作为惩罚，很难确定一只老鼠是否表现出风险更高的选择或对冲击不敏感。因此， 当前提案的第一个目标是使用一项新任务来衡量风险选择。为此，将对老鼠进行测试 在等效期望值(EEV)任务中，增强剂的大小和增援概率将为 在同时可用的增强剂之间进行调整，以使每个替代方案的预期效用(值)为 等价物。由于各增强剂备选方案的期望值相等，因此不存在次最优 选择。然而，风险选择可以通过较低概率/较大概率的响应百分比来衡量 奖励替代方案。为了进一步阐明风险选择的神经回路，我们将确定化学发生是否 抑制内侧前额叶皮质(MPFC)投射杏仁基底外侧核(BLA)神经元和/或BLA- 投射mPFC神经元减少了EEV任务中的风险选择(特定目标1)。具体目标2和3将 利用来自特定目标1的相同的化学发生方法来确定相互联系是否 BLA和mPFC在强迫性寻求可卡因和可卡因再寻求中的作用 (旧病复发的行为模式)。新的资金将使我们能够回答这些关键问题，并将使 本科生继续在NKU获得行为神经科学研究方面的研究经验。