INVESTIGATING FUNCTION OF NOVEL DRUG-INDUCED SYNAPTIC CHANGES IN THE VTA

研究新型药物引起的 VTA 突触变化的功能

基本信息

批准号：
9769671
负责人：
KEVIN T BEIER
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769671
关键词：
Acute Addictive Behavior Advisory Committees Anatomy Animals Area Award Behavior Therapy Behavioral Biological Assay Brain Clinical Cocaine Combination Drug Therapy Cues Data Development Dopamine Dose Drug Addiction Drug Screening Drug abuse Economic Burden Electrophysiology (science)Equilibrium Fellowship Functional disorder Genetic Techniques Globus Pallidus Goals Habenula Intervention K-Series Research Career Programs Knowledge Lateral Learning Maintenance Maps Measures Medial Mentors Midbrain structure Modeling Modification Nature Neurons Nucleus Accumbens Optics Output Paper Pathway interactions Pharmaceutical Preparations Phase Play Population Procedures Property Prosencephalon Publishing Rabies virus Recurrence Relapse Research Rewards Role Self Administration Signal Transduction Site Slice Stress Structure Substance abuse problem Synapses Synaptic plasticity Techniques Testing Therapeutic Training Ventral Tegmental Area Withdrawal Withdrawal Symptom Work addiction base behavioral sensitization career cocaine use design dopaminergic neuron drug abuse prevention drug of abuse drug relapse experimental study gamma-Aminobutyric Acid genetic approach genetic technology in vivo neuronal circuitry novel novel therapeutics optogenetics post-doctoral training prevent psychostimulant public health relevance reduce symptoms response social virus genetics

项目摘要

DESCRIPTION (provided by applicant): Drug abuse is a major global problem with often devastating societal consequences. While therapeutics designed to treat drug addiction have focused on medicinal intervention with concurrent behavioral therapy, much progress remains to be made in reducing this major social and economic burden. All drugs of abuse appear to work on the dopamine (DA) pathway in the brain, which is normally activated by neurons in the ventral tegmental area (VTA) that function, in part, to signal reward. However, DA neurons are not a homogenous population, but rather are composed of multiple subtypes with distinct functions. During the first few years of my postdoctoral fellowship, using a new rabies virus-based transsynaptic tracing approach, I constructed a detailed input-output map of VTA-DA neurons, including the inputs to specific subpopulations of VTA-DA neurons. In a subsequent set of pilot experiments, I conducted a brain-wide input screen using the rabies virus to identify the locus of synaptic changes onto VTA-DA neurons that occur after a single administration of a variety of drugs. Preliminary data from this screen suggest that certain inhibitory inputs (from the globus pallidus external segment, or GPe, and the medial shell of the nucleus accumbens) are altered by a single dose of cocaine, and that these changes occur specifically onto the VTA-DA neurons projecting to the lateral shell of the nucleus accumbens. In addition, these changes occur in animals that display behavioral sensitization, suggesting that these inputs may be specifically modified in this aspect of addictive behaviors. To more rigorously understand the roles of these inputs in addiction, I propose to analyze the roles of these synaptic adaptations in a self-administration model of addiction. First, I will examine the nature of the plasticity occurrng from these defined synapses onto VTA-DA neurons. Secondly, I will use the knowledge of these changes to direct optogenetic and chemogenetic manipulations in-vivo in an attempt to prevent or reverse the drug- induced behavioral alterations occurring with cocaine self-administration. Lastly, in the independent phase, I will use the self-administration model, but now focus on the role of lateral habenula inputs to the midbrain for the development and expression of cocaine withdrawal. As the LHb contains unique subtypes that project either to VTA-DA neurons or GABA neurons in the rostrotegmental area (RMTg), I will analyze the effects of self-administration and withdrawal on the LHbVTA-DA and LHbRMTg-GABA connections, the role that each input plays in withdrawal, and if manipulations of each subtype can either exaggerate or alleviate symptoms of withdrawal. As my preliminary data suggest that the rabies virus can be used as a non-biased technique to screen for drug-induced synaptic alterations, the immense power of this technique in generating hypotheses will be highly useful in generating a unique research plan independent from that of my postdoctoral mentor.

描述（由适用提供）：药物滥用是一个主要的全球问题，经常造成毁灭性的社会后果。尽管旨在治疗药物成瘾的治疗旨在通过同时进行行为疗法进行医学干预，但在减少这一主要的社会和经济伯恩伯恩（Burnen）方面仍有很多进展。所有滥用药物似乎都在大脑中的多巴胺（DA）途径上起作用，该途径通常被腹侧段盖区域（VTA）中的神经元激活，部分作用以表达奖励。但是，DA神经元不是同质种群，而是由具有不同功能的多种亚型组成。在我博士后奖学金的头几年中，我使用了新的基于狂犬病病毒的透射性跟踪方法，我构建了VTA-DA神经元的详细输入输出图，包括对VTA-DA神经元特定亚群的输入。在随后的一组试验实验中，我使用狂犬病病毒进行了整个大脑输入筛查，以鉴定突触变化的源头对VTA-DA神经元进行了多种药物后发生的VTA-DA神经元。来自此屏幕的初步数据表明，某些抑制性输入（来自pallidus pallidus外部段或GPE，以及伏隔核的内侧壳）通过单一剂量的可卡因改变了，这些变化特别发生在vta-da神经元上，投影到核孔的后期壳中。此外，这些变化发生在表现出行为敏感性的动物中，表明这些输入可能在加性行为的这一方面进行了特异性修改。为了更严格地理解这些投入在成瘾中的作用，我建议分析这些突触适应的作用成瘾的自我管理模型。首先，我将检查这些定义的突触发生的可塑性的性质，直达VTA-DA神经元。其次，我将利用这些变化的知识来指导视觉遗传和化学遗传操作，以防止或逆转可卡因自我给药发生的药物诱导的行为改变。最后，在独立阶段，我将使用自我管理模型，但现在专注于向中脑向中脑输入的作用，以开发和表达可卡因戒断。 As the LHb contains unique subtypes that project either to VTA-DA neurons or GABA neurons in the rostrotegmental area (RMTg), I will analyze the effects of self-administration and withdrawal on the LHbVTA-DA and LHbRMTg-GABA connections, the role that each input plays in withdrawal, and if manipulations of each subtype can either exaggerate or减轻戒断的症状。由于我的初步数据表明，兔子病毒可以用作筛选药物诱导的突触改变的无偏见技术，因此该技术在产生假设方面的巨大功能将在产生独特的研究计划中非常有用，而独立于我的后精神。