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.

项目总结/摘要 可卡因使用障碍（CUD）没有FDA批准的治疗方法，将兴奋剂使用障碍置于独特的地位。 治疗缺点，需要进一步研究兴奋剂使用神经失调， 干预措施。中脑核（NAc）是基于价的刺激处理和联想的核心。 学习和可卡因对其的失调是人类CUD发展的主要组成部分 动物模型。NAc不仅是一个令人难以置信的塑料区域，而且还接收大量谷氨酸能输入 整合复杂的信息以驱动NAc的活动。长期 可卡因暴露导致进入NAc的突触能输入的突触强度的可塑性， 与接触可卡因导致的适应不良行为有直接联系虽然大量的工作 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 在离体制备和对NAc的单独输入中完成;然而，这些内的信息编码 预测人口是一个动态的过程，发生在一个快速的时间尺度上，并了解他们的 关系编码复杂的信息需要它们在清醒和行为的动物中同时记录。 我将使用一系列的钙成像和病毒介导的表达方法1。识别 调节和驱动NAc内神经活动的神经元能输入; 2.了解这些信号如何 促进刺激的编码，以在基线和可卡因使用后驱动行为。首先，使用多站点 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，我将定义这些回路是如何同时 由无条件和条件刺激激活以驱动行为（目标1）。接下来，使用可卡因自我- 管理，我将定义这些电路是如何改变反复药物暴露，导致神经和 非药物刺激的学习行为障碍（目标2）。作为一个未来的物理学家， 导致成瘾的复杂因素，特别是当它们与从药物和非药物中学习有关时， 刺激是有效CUD治疗和干预的关键组成部分。该提案提供了 在实验室回答这些问题所需的技术培训，同时还提供理论培训 在我的临床实践中为病人提供最佳护理。