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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要可卡因使用障碍 (CUD) 尚无 FDA 批准的治疗方法，因此将兴奋剂使用障碍置于独特的地位治疗劣势，需要进一步研究兴奋剂使用神经失调的新机制干预措施。伏隔核 (NAc) 是基于价的刺激处理和联想的核心学习及其由可卡因引起的失调是人类 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可塑性区域，而且接收大量的谷氨酸输入来自整个大脑，整合复杂的信息以驱动 NAc 的活动。长期可卡因暴露导致 NAc 中谷氨酸能输入的突触强度具有可塑性，而这种可塑性与接触可卡因相关的适应不良行为直接相关。虽然工作量很大强调了接触可卡因后发生的突触特异性机制，这在很大程度上是在离体准备和 NAc 的单独输入中完成；然而，这些信息编码预测人口是一个动态过程，发生在快速的时间尺度上，并了解他们如何关系编码复杂的信息需要在清醒和行为的动物中同时记录。我将使用一系列钙成像和病毒介导的表达方法来 1. 识别调节和驱动 NAc 内神经活动的谷氨酸输入，以及 2. 了解这些信号是如何产生的促进刺激编码，以驱动基线和可卡因使用后的行为。一、使用多站点光纤光度测定法测定基底外侧杏仁核 (BLA-NAc)、海马 (vHPC- NAc）和内侧前额皮质（mPFC-NAc）进入 NAc，我将定义这些电路如何同时进行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，我将定义这些回路如何通过重复的药物暴露而改变，从而导致神经和非药物刺激的学习行为障碍（目标 2）。作为未来的医师科学家，了解导致成瘾的复杂因素，特别是与从毒品和非毒品中学习有关的因素刺激是有效 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此类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患者提供最佳护理。