Understanding how post-translational palmitoylation influences in vivo molecular and circuit dynamics during learning

了解翻译后棕榈酰化如何影响学习过程中的体内分子和电路动力学

基本信息

批准号：
10621801
负责人：
Jessica C Nelson
金额：
$ 24.9万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-25 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621801
关键词：
Ablation Acoustic Nerve Acoustics Acute Affect Age Anatomy Animals Auditory Axon BRAIN initiative Behavior Behavioral Behavioral Genetics Biochemical Biological Biological Assay Biological Process Brain Brain Diseases Calcium Cells Cognition Communication Complex Data Decision Making Depressed mood Disease Electrophysiology (science)Exhibits Fiber Food Foundations Genes Genetic Genetic Screening Hair Cells Heritability Hip region structure Human Huntington Disease Image Imaging Techniques Impairment Individual Invertebrates Knowledge Laboratories Larva Lasers Learning Maps Microscopy Modeling Molecular Molecular Genetics Molecular Target Neurobehavioral Manifestations Neurons Pathway interactions Pennsylvania Play Population Post-Translational Protein Processing Potassium Channel Process Protein Dynamics Proteins Research Role Schizophrenia Source Startle Reaction Stimulus Synapses Synaptic plasticity System Testing Time Training Transgenic Organisms Universities Vertebrates Visualization Zebrafish autism spectrum disorder awake career cognitive task drug of abuse examination questions experimental study habituation human disease in vivo insight interest knockout gene member mutant neural circuit neuronal cell body novel optogenetics palmitoylation response screening sound synaptic function

项目摘要

Habituation is a simple form of learning in which animals reduce responsiveness to repetitive stimuli. Habituation forms a foundation for normal cognition; without the ability to filter irrelevant stimuli, animals are unable to perform more complex cognitive tasks. Indeed, habituation learning is impaired in a wide range of heritable human disorders that present with more complex cognitive symptoms, including Schizophrenia, Autism Spectrum Disorders and Huntington’s Disease. Habituation learning is also a significant component of our innate decision-making: habituation to particular foods or drugs of abuse influences our responses to these stimuli and our decisions to seek them. Beyond its relevance for human behavior and disease, habituation can provide a simple and accessible model for examining some of the most exciting mysteries that inspired the BRAIN initiative, such as how proteins are mobilized during learning to alter synapses, circuits and behavior. Despite great interest, decades of study, and relevance for human disease, there are still significant gaps in our understanding of habituation learning. This proposal is based on the candidate’s discovery that post-translational palmitoylation plays a critical role in habituation learning. Specifically, using the larval zebrafish, she has found that the palmitoyltransferase Hip14 targets the Shaker-like channel Kv1.1 to regulate learning. This novel learning pathway represents an entirely independent research niche from which the PI will establish her own laboratory. The Granato lab, although expert in behavioral genetics, has never systematically examined how post-translational modifications influence protein dynamics, synapses, and behavior in real time. The PI will receive training from world experts in palmitoylation (Dr. Eric Witze) and in vivo electrophysiology (Dr. Alberto Pereda), integrating these approaches into a well-rounded system to examine learning across genes, circuits, and behavior. The PI will be based in the laboratory of Dr. Michael Granato at the University of Pennsylvania for the entire K99 period. During this time, the PI will learn to perform electrophysiological recordings in vivo to identify how activity within individual neurons is dynamic during habituation learning, and how plasticity is disrupted in mutants lacking Hip14 or Kv1.1 (Aim 1). This approach will be combined with calcium imaging, unbiased whole brain activity mapping, and transgenic rescue experiments to identify new circuit loci for habituation learning. Simultaneously, the PI will perform biochemical and live imaging experiments to examine how protein palmitoylation changes during learning, and how palmitoylation affects target protein localization in vivo (Aim 2). Finally, the PI will conduct a candidate screen to identify additional learning-relevant targets for Hip14 palmitoylation (Aim 3). These efforts will establish a broad and independent foundation for the candidate’s independent career investigating how post-translational modifications influence synaptic plasticity within defined neural circuits as we learn.

习惯是一种简单的学习形式，其中动物降低了对重复刺激的反应。习惯构成正常认知的基础；没有能力过滤无关的刺激，动物将无法执行更复杂的认知任务。的确，习惯性学习受到了多种可遗传的人类疾病的损害，这些疾病患有更复杂的认知症状，包括精神分裂症，自闭症谱系障碍和亨廷顿氏病。习惯性学习也是我们先天决策的重要组成部分：特定食物或虐待药物的习惯会影响我们对这些刺激的反应以及我们寻求它们的决定。除了其与人类行为和疾病的相关性外，习惯还可以提供一个简单且可访问的模型，用于研究一些启发大脑倡议的最令人兴奋的谜团，例如如何在学习过程中动员蛋白质来改变突触，电路和行为。尽管人们非常感兴趣，数十年的研究以及与人类疾病的相关性，但我们对习惯学习的理解仍然存在很大的差距。该提议是基于候选人发现的，即翻译后棕榈酰化在习惯学习中起着至关重要的作用。具体来说，使用幼虫斑马鱼，她发现棕榈酰转移酶HIP14的靶向类似振荡器的通道KV1.1来调节学习。新颖的学习途径代表了一个完全独立的研究利基市场，PI将建立自己的实验室。尽管行为遗传学方面的专家从未系统地检查翻译后修饰如何实时影响蛋白质动力学，突触和行为。 PI将接受世界棕榈酰化专家（Eric Witze博士）和体内电生理学（Alberto Pereda博士）的培训，将这些方法整合到一个全面的系统中，以检查跨基因，电路和行为的学习。 PI将在整个K99期间的迈克尔·格拉纳托（Michael Granato）博士实验室。在此期间，PI将学习在体内进行电生理记录，以确定在习惯学习过程中单个神经元内的活动如何动态，以及在缺乏HIP14或KV1.1的突变体中如何破坏可塑性（AIM 1）。这种方法将与钙成像，无偏见的整个大脑活性映射以及转基因救援实验相结合，以确定用于习惯学习的新电路定位。同时，PI将执行生化和实时成像实验，以检查学习过程中蛋白质棕榈酰化的变化以及棕榈酰化如何影响体内目标蛋白质定位（AIM 2）。最后，PI将进行候选屏幕，以确定HIP14棕榈酰化的其他与学习相关的目标（AIM 3）。这些努力将为候选人的独立职业建立一个广泛而独立的基础，调查翻译后修改如何影响我们所学到的定义神经元电路内的突触可塑性。