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

项目摘要/摘要 可卡因使用障碍(CUD)没有FDA批准的治疗方法，将兴奋剂使用障碍放在一个独特的 治疗的弊端，需要对兴奋剂使用神经失调进行进一步的研究 干预措施。伏隔核(NAC)是价刺激加工和联想的核心 学习和可卡因对学习的失调是人类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，而且接受大量的谷氨酸能输入 从整个大脑整合复杂的信息，以驱动NAC的活动。长期的 可卡因暴露导致传入NAc的谷氨酸能突触强度可塑性及其可塑性 与与可卡因接触有关的适应不良行为有直接联系。虽然一大堆工作 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 在体外准备和个体输入NAC的过程中完成；然而，在这些 预测人口是一个动态的过程，它发生在快速的时间尺度上，并了解他们的 关系编码复杂的信息，需要在清醒和行为的动物中同时记录它们。 我将使用一系列的钙成像和病毒介导的表达方法来1.确定 调节和驱动nac内神经活动的谷氨酸能输入和2.理解这些信号是如何 促进对刺激的编码，以在基线和使用可卡因后驱动行为。首先，使用多站点 基底外侧杏仁核(BLA-NAC)、海马区(VHPC)谷氨酸能投射的纤维光度法 NAC)和内侧前额叶皮质(mPFC-NAC)，我将定义这些回路是如何同时存在的 被无条件和条件性刺激激活以驱动行为(目标1)。接下来，使用可卡因自我 我将定义这些回路是如何因反复接触药物而改变的，从而导致神经和 非药物刺激学习中的行为障碍(目标2)。作为一名未来的内科科学家，理解 导致上瘾的复杂因素，特别是与从毒品和非毒品中学习有关的因素 刺激是有效的CUD治疗和干预的关键组成部分。这项建议提供了 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。

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.