Accumbal integration of brain wide glutamatergic inputs and their dysregulation by cocaine self-administration

全脑谷氨酸能输入的累积整合及其可卡因自我给药的失调

• 批准号: 10620183
• 负责人: Stephanie Cajigas
• 金额: $ 3.29万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620183
• 关键词: Adenoviruses; Air; Amygdaloid structure; Animal Model; Animals; Area; Association Learning; Aversive Stimulus; Basic Science; Behavior; Behavior Control; Behavioral; Brain; Calcium; Cell Nucleus; Clinical Sciences; Cocaine; Cocaine use disorder; Complex; Cues; Decision Making; Desire for food; Development; Disadvantaged; Disease Progression; Drug Exposure; Exhibits; FDA approved; Fiber; Fiber Optics; Future; Glutamates; Goals; Hippocampus; Image; Impairment; Implant; Individual; Intervention; Laboratories; Learning; Link; Medial; Mediating; Mediator; Mentors; Neurobiology; Neurons; Nucleus Accumbens; Optics; Outcome; Pathway interactions; Patient Care; Patients; Pattern; Pharmaceutical Preparations; Photometry; Physicians; Population Projection; Prefrontal Cortex; Preparation; Process; Psychiatry; Research; Response to stimulus physiology; Rewards; Scientist; Severities; Signal Transduction; Site; Stimulus; Sucrose; Symptoms; Synapses; Technology; Training; Treatment outcome; Viral; addiction; awake; behavioral impairment; behavioral response; calcium indicator; clinical practice; cocaine exposure; cocaine seeking; cocaine self-administration; cocaine use; doctoral student; experience; human model; individualized medicine; insight; maladaptive behavior; negative affect; neural; non-drug; novel; optical fiber; recruit; response; stimulant use; stimulant use disorder; stimulus processing

Project Summary/Abstract Cocaine use disorder (CUD) has no FDA approved therapies putting stimulant use disorders at a unique treatment disadvantage, necessitating further research on stimulant use neural dysregulation for novel interventions. The nucleus accumbens (NAc) is at the core of valence-based stimulus processing and associative learning, and its dysregulation by cocaine is a primary component underlying the development of CUD in human and animal models. The NAc is not only an incredibly plastic area but receives numerous glutamatergic inputs from across the brain that integrate complex information in order to drive the activity of the NAc. Long-term cocaine exposure leads to plasticity in synaptic strength of glutamatergic inputs into the NAc and this plasticity has been directly linked to maladaptive behaviors associated with cocaine exposure. While a large body of work has highlighted the synapse-specific mechanisms that occur following cocaine exposure, this has been largely done in ex-vivo preparations and on individual inputs into the NAc; however, information encoding within these projection populations is a dynamic process that occurs on a fast timescale and understanding how their relationship encodes complex information requires their simultaneous recording in awake and behaving animals. I will be using a range of calcium imaging and viral-mediated expression approaches to 1. identify the glutamatergic inputs that modulate and drive neural activity within the NAc and 2. understand how these signals facilitate the encoding of stimuli to drive behavior at baseline and following cocaine use. First, using multisite fiber photometry in glutamatergic projections from the basolateral amygdala (BLA-NAc), Hippocampus (vHPC- NAc) and medial prefrontal cortex (mPFC-NAc) into the NAc, I will define how these circuits are simultaneously activated by unconditioned and conditioned stimuli to drive behavior (Aim 1). Next, using cocaine self- administration, I will define how these circuits are altered by repeated drug exposure, leading to neural and behavioral impairments in learning for non-drug stimuli (Aim 2). As a future physician-scientist, understanding the complex factors that contribute to addiction, especially as they relate to learning from drug and non-drug stimuli, are a critical component of effective CUD treatment and intervention. This proposal with provide the technical training needed to answer such questions in the laboratory, while also providing the theoretical training to provide optimal care for patients in my clinical practice.

项目摘要/摘要 可卡因使用障碍（CUD）没有FDA批准的疗法，将刺激性使用障碍置于独特 治疗劣势，需要进一步研究刺激性使用神经失调的新型 干预措施。伏隔核（NAC）是基于价的刺激加工和联想的核心 学习及其对可卡因的失调是人类CUD发展的主要组成部分 和动物模型。 NAC不仅是一个令人难以置信的塑料区域，而且接收了许多谷氨酸能输入 从整个大脑整合复杂信息以驱动NAC的活动。长期 可卡因的暴露导致谷氨酸能输入的突触强度可塑性，而这种可塑性 已经与与可卡因暴露有关的不良适应行为直接相关。而大量的工作 已经强调了可卡因暴露后发生的突触特异性机制，这在很大程度上是 在前体准备和NAC的单个输入中完成；但是，在其中编码的信息 投影群体是一个动态过程，发生在快速时间范围内，并了解他们的 关系编码复杂的信息需要同时记录在清醒和表现动物中。 我将使用一系列钙成像和病毒介导的表达方法1。 调节NAC内神经活动和2的谷氨酸能输入。了解这些信号如何 促进刺激的编码以驱动基线和可卡因使用后的行为。首先，使用多站点 来自基底外侧杏仁核（BLA-NAC），海马（VHPC- NAC）和内侧前额叶皮层（MPFC-NAC）进入NAC，我将定义这些电路如何同时定义 通过无条件和条件刺激激活以驱动行为（AIM 1）。接下来，使用可卡因自我 管理，我将定义这些电路如何通过反复暴露而改变，导致神经和 非药物刺激学习的行为障碍（AIM 2）。作为未来的医师科学家，理解 导致成瘾的复杂因素，尤其是在与药物和非药物学习有关 刺激是有效的CUD治疗和干预的关键组成部分。该提议提供 需要在实验室回答此类问题的技术培训，同时还提供理论培训 在我的临床实践中为患者提供最佳护理。