Synapse-specific interactions between ethanol and opioid receptor-mediated synaptic depression in dorsal striatum

乙醇和阿片受体介导的背侧纹状体突触抑制之间的突触特异性相互作用

基本信息

批准号：
10240541
负责人：
Brady Atwood
金额：
$ 42.79万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2018-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10240541
关键词：
Address Affect Alcohol abuse Alcohol consumption Alcohols Amygdaloid structure Anterior Behavior Behavior Control Behavioral Biochemical Brain Brain region Corpus striatum structure Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Discrimination Dopamine Dorsal Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Ethanol Female Foundations Glutamates Goals In Vitro Individual Injections Interneurons Interoception Intervention Knockout Mice Laboratories Link Long-Term Depression Maintenance Maps Mediating Mental Depression Molecular Mus Opioid Opioid Receptor Pathway interactions Pharmacology Play Protein Biosynthesis Rest Role Self Administration Signal Pathway Signal Transduction Signaling Protein Slice Synapses Synaptic plasticity System Testing Thalamic structure Therapeutic Therapeutic Intervention Transgenic Mice Uncertainty United States Viral Vector Wireless Technology Work alcohol behavior alcohol effect alcohol exposure alcohol seeking behavior alcohol sensitivity alcohol use disorder brain circuitry cholinergic cognitive control delta opioid receptor drinking behavior drug discrimination experimental study frontal lobe genetic manipulation improved in vivo kappa opioid receptors male mu opioid receptors neurobehavioral new therapeutic target novel novel therapeutic intervention novel therapeutics optogenetics preference prevent receptor socioeconomics synaptic depression synaptic function targeted treatment tool

Address Affect Alcohol abuse Alcohol consumption Alcohols Amygdaloid structure Anterior Behavior Behavior Control Behavioral Biochemical Brain Brain region Corpus striatum structure Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Discrimination Dopamine Dorsal Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Ethanol Female Foundations Glutamates Goals In Vitro Individual Injections Interneurons Interoception Intervention Knockout Mice Laboratories Link Long-Term Depression Maintenance Maps Mediating Mental Depression Molecular Mus Opioid Opioid Receptor Pathway interactions Pharmacology Play Protein Biosynthesis Rest Role Self Administration Signal Pathway Signal Transduction Signaling Protein Slice Synapses Synaptic plasticity System Testing Thalamic structure Therapeutic Therapeutic Intervention Transgenic Mice Uncertainty United States Viral Vector Wireless Technology Work alcohol behavior alcohol effect alcohol exposure alcohol seeking behavior alcohol sensitivity alcohol use disorder brain circuitry cholinergic cognitive control delta opioid receptor drinking behavior drug discrimination experimental study frontal lobe genetic manipulation improved in vivo kappa opioid receptors male mu opioid receptors neurobehavioral new therapeutic target novel novel therapeutic intervention novel therapeutics optogenetics preference prevent receptor socioeconomics synaptic depression synaptic function targeted treatment tool

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项目摘要

Project Summary There is no doubt that the alcohol use disorders (AUDs) have a significant socioeconomic toll on the United States and the rest of the world. Many current therapeutics are not sufficiently effective, as they do not target the neurobehavioral underpinnings contributing to the development and maintenance of alcohol abuse in many individuals. There is a critical need for novel therapeutic interventions that can undo the negative effects of ethanol on brain circuitry, restoring cognitive control over drinking behavior. A barrier to progress is a lack of understanding of the specific effects that ethanol has on select synapses within parts of the brain known to control alcohol-related behaviors and even the behavioral role of many of these select synapses in the context of the larger function of each brain region. Our preliminary data indicate that ethanol only affects certain forms of opioid receptor-mediated synaptic plasticity at very specific synapses within the dorsal striatum while leaving plasticity at nearby synapses unaffected. One of these synapses is the inputs from the anterior insular cortex (AIC) to the dorsolateral striatum (DLS). The AIC is involved in ethanol interoception and the DLS controls habitual responding for ethanol drinking and seeking behavior. In vivo ethanol exposure in mice disrupts mu opioid long-term synaptic depression (LTD) at this synapse while leaving mu opioid signaling at other synapses unaffected. LTD mediated by kappa and delta opioid receptors occur at unidentified dorsal striatal synapses and ethanol could have similar differential effects on these forms of LTD. Our data also show that LTD at AIC-DLS synapses is likely mediated by altered cAMP signaling and de novo protein synthesis. The objective of this proposal is to determine synapse-specific opioid LTD mechanisms and how ethanol selectively affects some synapses, while leaving others unaffected and to determine the behavioral relevance of opioid LTD at AIC-DLS synapses. Our central hypothesis is that alcohol disrupts dorsal striatal opioid plasticity at specific synapses due to distinct alcohol-sensitive signaling pathways at synapses that modulate alcohol consumption, seeking, and interoception. In Aim 1, we will identify the impact of in vivo ethanol exposure on mu, delta, and kappa opioid receptor-mediated synaptic depression at specific types of dorsal striatal glutamatergic synapses. In Aim 2 we will determine the mechanisms of ethanol-sensitive and insensitive forms of dorsal striatal opioid plasticity to decipher the impact of ethanol on these signaling pathways. In Aim 3 we will decipher the role of mu opioid LTD at AIC-DLS synapses in ethanol consumption, seeking, and interoception. We will use brain slice electrophysiology, in vitro and in vivo optogenetics, transgenic mice, viral vectors, and pharmacological tools to address these three aims. By understanding the synapse-specific effects of ethanol on plasticity mechanisms at behaviorally-defined synapses in the dorsal striatum, we will identify novel therapeutic targets for treating AUDs. This will be a leap forward towards improving the lives of those that suffer from the effects of AUDs.

项目摘要毫无疑问，酒精使用障碍（AUDS）对联合会造成了重大的社会经济损失国家和世界其他地方。许多当前的治疗剂没有足够的有效性，因为它们没有针对神经行为的基础，有助于许多人在许多人中开发和维持酒精滥用个人。对新型治疗干预措施的迫切需要，可以消除脑电路上的乙醇，恢复对饮酒行为的认知控制。进步的障碍是缺乏了解乙醇对已知大脑部分中某些突触的特定影响控制与酒精相关的行为，甚至在上下文中许多选择突触的行为作用每个大脑区域的较大功能。我们的初步数据表明乙醇仅影响某些形式离开后纹状体内非常特异的突触时阿片受体介导的突触可塑性附近突触的可塑性不受影响。这些突触之一是从前岛皮层的输入（AIC）到背外侧纹状体（DLS）。 AIC参与乙醇互认为和DLS控制习惯对乙醇饮酒和寻求行为的反应。小鼠的体内乙醇暴露会破坏MU 阿片类药物长期突触抑郁症（LTD）在该突触处，同时在其他突触处留下mu阿片类信号传导不受影响。由Kappa和Delta阿片受体介导的LTD发生在身份不明的背纹状体突触和乙醇可能会对这些形式的有限公司产生类似的差异影响。我们的数据还表明，AIC-DLS的LTD 突触可能是通过改变的cAMP信号传导和从头蛋白质的合成介导的。这个目的建议是确定突触特异性阿片类药物有限公司的机制以及乙醇如何选择性影响某些突触，使其他人不受影响，并确定AIC-DLS上阿片类药物有限公司的行为相关性突触。我们的中心假设是，酒精在应得在调节酒精消耗，寻求和互感。在AIM 1中，我们将确定体内乙醇暴露对MU，Delta和Kappa阿片类药物的影响受体介导的突触抑制在特定类型的背纹状体谷氨酸能突触上。在目标2中，我们将确定乙醇敏感和不敏感形式的背纹状性阿片类药物的机制破译乙醇对这些信号通路的影响。在AIM 3中，我们将破译MU阿片类药物有限公司的作用在AIC-DLS乙醇消耗，寻求和互认为中的突触。我们将使用大脑切片电生理学，体外和体内光遗传学，转基因小鼠，病毒载体和药理学工具解决这三个目标。通过了解乙醇对塑性机制的突触特异性影响在背纹状体中，行为定义的突触，我们将确定治疗AUDS的新型治疗靶标。这将是迈向改善遭受声音影响的人的生活的飞跃。