PACAP-Dependent Coordination of Glutamate Signaling between Neurons and Astrocytes

神经元和星形胶质细胞之间谷氨酸信号传导的 PACAP 依赖性协调

基本信息

批准号：
10612429
负责人：
DAVID A BAKER
金额：
$ 41.12万
依托单位：
MARQUETTE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612429
关键词：
Acute Astrocytes Behavior Behavioral Biotechnology Brain Cells Chronic Cocaine Cocaine Dependence Complex Corpus striatum structure Data Disease Drug Addiction Drug Targeting Drug usage Efferent Pathways Electrophysiology (science)Elements Fluorescence-Activated Cell Sorting Functional disorder Future Gene Expression Glial Fibrillary Acidic Protein Globus Pallidus Glutamate Receptor Glutamates Homeostasis Human Impairment Impulsivity Infusion procedures Lead Learning Measures Mediating Messenger RNA Microdialysis Modeling Modernization Molecular NMDA receptor antagonist Neurons Neuropeptides Neurosciences Nucleus Accumbens Output Pathologic Pathway interactions Peptides Pharmaceutical Preparations Phase II Clinical Trials Physiology Rat Transgene Rattus Receptor Signaling Regulation Research Role Severities Signal Transduction Site Site-Directed Mutagenesis Slice Substance abuse problem Substantia nigra structure Synapses Synaptic Transmission Synaptic plasticity System Testing Therapeutic Tissues Viral addiction cocaine seeking cocaine self-administration cognitive control design drug craving drug development drug seeking behavior experimental study extracellular glutamatergic signaling improved neural circuit neural network neuron component neuroregulation neurotransmission novel optical imaging pharmacologic pituitary adenylate cyclase activating polypeptide presynaptic rational design receptor receptor expression sensor tool two-photon

项目摘要

Project Summary/Abstract Dysregulation of glutamate signaling is a core component of the pathological basis of drug addiction involving cocaine and many other substances. Recent progress in neuroscience and other fields clearly establishes that the molecular and cellular basis of glutamate-encoded signaling is vastly more complex than previously recognized. In particular, it is becoming increasingly evident that astrocytes, which are among the most abundant cells in the human brain, release glutamate to produce complex regulation over neural circuit activity. This novel form of glutamate-encoded intercellular signaling may be critical to understanding the pathological glutamate produced by long-term drug use since astrocytic glutamate release mechanisms, such as system xc- (Sxc), are altered by cocaine. While these discoveries raise numerous questions that may be essential in understanding glutamate signaling in the human brain, this proposal will focus on the question, how do neurons regulate glutamate release from astrocytes to control neural network activity and behaviors relevant to cocaine addiction. We will test the hypothesis that this is achieved by the actions of the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), which we believe to be an unrecognized component of glutamate signaling in the nucleus accumbens (NAc). In support, we have found that A) PACAP mRNA is expressed in NAc afferents, B) PACAP receptors are expressed in NAc astrocytes and neurons projecting to the substantia nigra (SN) but not the ventral pallidum (VP), C) PACAP stimulates glutamate release from astrocytes by increasing the activity of system xc- (Sxc), D) PACAP application depresses eEPSCs in NAc medium spiny neurons (MSNs) projecting to the substantia nigra (SN) but not the ventral pallidum, and E) intra-NAc micro-infusion of PACAP blocks cocaine reinstatement. In this proposal, we will test the hypothesis that PACAP is a neuropeptide that regulates glutamate release from astrocytes and glutamate receptors on neurons to provide a novel form of pathway-specific regulation of NAc efferent pathways. In Aim 1, we will examine the molecular basis of PACAP-induced increases in Sxc activity and determine whether Sxc regulation is necessary for PACAP to depress eEPSCs in NAc-SN MSNs and block cocaine reinstatement. In this aim, we will also examine if PACAP increases glutamate from astrocytic release mechanisms other than Sxc. In Aim 2, we will examine the possibility that the form of astrocyte-neuron signaling triggered by PACAP require the regulation of neuronal glutamate receptors to produce the relevant changes in physiology that gate the output of NAc efferents and behavior. We will also explore whether PACAP alters presynaptic glutamate release. In Aim 3, we will investigate the role of endogenous PACAP to learn whether this neuropeptide is an unrecognized component of glutamate signaling in the NAc, and whether it is a key determinant of drug- seeking behavior.

项目摘要/摘要谷氨酸信号传导的失调是涉及药物成瘾病理基础的核心组成部分可卡因和许多其他物质。神经科学和其他领域的最新进展清楚地表明了谷氨酸编码信号的分子和细胞基础比以前更为复杂认可。特别是，越来越明显的是，星形胶质细胞是最多的人脑中的丰富细胞，释放谷氨酸以在神经回路活性上产生复杂的调节。谷氨酸编码的这种新型形式的细胞间信号对于理解病理可能至关重要由于星形细胞谷氨酸释放机制（例如系统），由长期使用药物产生的谷氨酸 XC-（SXC）通过可卡因改变。尽管这些发现提出了许多可能至关重要的问题了解人脑中的谷氨酸信号传导，该建议将重点放在问题上，如何神经元调节谷氨酸从星形胶质细胞释放，以控制与与可卡因成瘾。我们将检验以下假设，即这是通过神经肽垂体的作用来实现的腺苷酸环化酶激活多肽（PACAP），我们认为这是未识别的成分伏隔核中的谷氨酸信号传导（NAC）。为了支持，我们发现a）pacap mRNA是 B）在NAC传入中表达，PACAP受体在NAC星形胶质细胞和神经元中表达，投影到黑质（SN），但不是腹侧粒子（VP），c）PACAP刺激谷氨酸从通过增加系统XC-（SXC）的活性，d）PACAP应用使NAC中的EEPSC降低EEPSC，投射到黑质Nigra（SN）的中刺神经元（MSN），而不是腹侧pallidum，E） PACAP的NAC内微传输可卡因恢复可卡因。在此提案中，我们将检验假设 PACAP是一种神经肽，可调节从星形胶质细胞和谷氨酸受体释放的神经肽神经元提供了一种新型的NAC传出途径的途径特异性调节形式。在AIM 1中，我们将检查PACAP诱导的SXC活性增加的分子基础，并确定SXC是否是否 PACAP在NAC-SN MSN中降低EEPSC并阻止可卡因恢复原状是必要的。在这个目的，我们还将检查PACAP是否增加了来自星形胶质细胞释放机制的谷氨酸 SXC。在AIM 2中，我们将研究由PACAP触发的星形胶质细胞神经元信号的形式需要调节神经元谷氨酸受体，以产生栅极的生理学变化 NAC发出和行为的输出。我们还将探索PACAP是否会改变突触前谷氨酸发布。在AIM 3中，我们将研究内源性PACAP在了解该神经肽是否是一种 NAC中谷氨酸信号传导的未识别成分，以及它是否是药物的关键决定因素寻求行为。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pituitary adenylate cyclase-activating polypeptide receptor activation in the hypothalamus recruits unique signaling pathways involved in energy homeostasis.

下丘脑中垂体腺苷酸环化酶激活多肽受体的激活会招募参与能量稳态的独特信号通路。

DOI：
10.1152/ajpendo.00320.2021
发表时间：
2022
期刊：
American journal of physiology. Endocrinology and metabolism
影响因子：
0
作者：
Maunze,Brian;Bruckner,KatherineWood;Desai,NikhilNilesh;Chen,Christopher;Chen,Fanghong;Baker,David;Choi,SuJean
通讯作者：
Choi,SuJean

Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via enhancement of dopamine release.

DOI：
10.7554/elife.80747
发表时间：
2022-08-22
期刊：
ELIFE
影响因子：
7.7
作者：
Liu, Xiaojie;Vickstrom, Casey R.;Yu, Hao;Liu, Shuai;Snarrenberg, Shana Terai;Friedman, Vladislav;Mu, Lianwei;Chen, Bixuan;Kelly, Thomas J.;Baker, David A.;Liu, Qing-song
通讯作者：
Liu, Qing-song

Role of endocannabinoid signaling in a septohabenular pathway in the regulation of anxiety- and depressive-like behavior.