Afferents modulating VTA activity and their plasticity after self-administration

自我给药后调节 VTA 活性及其可塑性的传入神经

基本信息

批准号：
8266368
负责人：
Michela Marinelli
金额：
$ 19.25万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8266368
关键词：
Addictive Behavior Adult Affect Algae Area Behavior Behavioral Brain Brain region Cell Nucleus Cells Characteristics Cocaine Data Dependovirus Depressed mood Distal Dopamine Drug Addiction Event Exhibits Exposure to Fire - disasters Future Glutamates Goals Immunohistochemistry In Vitro Ion Channel Light Link Measures Mediating Motivation Nature Neuromodulator Neurons Pathway interactions Pattern Pedunculopontine Tegmental Nucleus Pharmaceutical Preparations Physiologic pulse Play Population Positioning Attribute Presynaptic Terminals Prevention strategy Property Proteins Public Health Qualifying Rattus Relapse Research Rewards Role Self Administration Self-Administered Stimulus Structure Synapses Synaptic Potentials Synaptic plasticity System Techniques Technology Testing Time Ventral Tegmental Area Withdrawal Work addiction brain cell cholinergic dopaminergic neuron experience hindbrain in vivo innovation insight neural circuit neuronal cell body novel optogenetics research study tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The activity of dopamine cells of the ventral tegmental area (VTA) plays a critical role in reward and motivation. In vivo, these cells fire irregularly, with interspersed "burst" events; this pattern of activity is the consequence of excitatory and inhibitory inputs arising locally and from distal structures. In addition, plasticity of these inputs occurs after exposure and withdrawal from addictive drugs. However, understanding the functional role of specific afferents to the VTA, both in baseline conditions and after exposure to drugs, has been limited by current technology. These studies will establish how the activity of the VTA is modulated by specific afferents, before or after cocaine self-administration in rats. To dissect the role of specific afferents, we will use the technique of optogenetics whereby the activity of selective pathways can be increased with pulses of light applied to the terminals that express the algae protein channelrhodopsin 2 (ChR2). Specific brain regions of adult rats will be infected with an adeno-associated virus for ChR2 expression in neurons. We will then determine the functional role of specific pathways by applying light pulses in the VTA, to stimulate the afferents from each of these regions. We will examine inputs to the VTA from (i) the pedunculopontine tegmental nucleus (PPTg), a mixed glutamatergic/cholinergic population that responds to salient stimuli; (ii) local VTA glutamate cells, which have recently been described but whose functional role is unclear; and (iii) the rostromedial tegmental nucleus (RMTg), a hindbrain structure recently identified that sends important GABAergic projections to the VTA but whose functional role is unknown. We will evaluate the consequence of pathway-specific stimulation on cell activity (firing rates and patterns) measured in vivo in anesthetized rats. Then, we will determine the nature of these inputs in vitro, by measuring synaptic potentials generated upon stimulation of these pathways. We will also determine the manner in which such synaptic input is integrated. Finally, we will further test the nature of the pathways by performing immunohistochemistry studies. Aim 1 will examine the role of these pathways in drug-naove rats. Aim 2 will examine it in rats that have self-administered cocaine. These studies will be the first to determine the functional role of unexplored and novel afferents to the VTA. They will also determine how cocaine self-administration modifies the way dopamine cells are excited by specific afferents. This will provide important information on the manner in which brain reward pathways function in baseline conditions, and their plasticity after self-administration. These studies will provide novel insights on neural circuits that control addictive behavior.

描述（由申请人提供）：腹侧盖区域（VTA）的多巴胺细胞的活性在奖励和动机中起着至关重要的作用。在体内，这些细胞不规则地发射，散布着“爆发”事件。这种活性模式是局部和远端结构引起的兴奋性和抑制投入的结果。此外，这些投入的可塑性是在暴露并从成瘾性药物中退出后发生的。但是，在基线条件下和暴露于药物后，了解特定传入的VTA的功能作用受到当前技术的限制。这些研究将确定在可卡因自我管理大鼠之前或之后，VTA的活性如何受到特定传入的调节。为了剖析特定传入的作用，我们将使用光遗传学技术，从而通过施加到表达藻类蛋白通道旋转2（CHR2）的末端的光脉冲来增加选择性途径的活性。成年大鼠的特定大脑区域将被神经元中CHR2表达的腺相关病毒感染。然后，我们将通过在VTA中应用光脉冲来确定特定途径的功能作用，从而刺激每个区域的传入。我们将从（i）pedunculopontine temental核（PPTG）对VTA进行输入，这是一种对显着刺激的反应的混合谷氨酸能/胆碱能种群；（ii）局部VTA谷氨酸细胞，这些细胞最近被描述了，但其功能作用尚不清楚；（iii）鼻膜细胞核（RMTG），一种后部脑结构最近识别出向VTA发送重要的GABA能投影，但其功能作用尚不清楚。我们将评估途径特异性刺激对麻醉大鼠体内测量的细胞活性（发射速率和模式）的后果。然后，我们将通过测量刺激这些途径产生的突触电位来确定这些输入的性质。我们还将确定集成此类突触输入的方式。最后，我们将通过进行免疫组织化学研究进一步测试途径的性质。 AIM 1将检查这些途径在药物诺夫大鼠中的作用。 AIM 2将在具有自我管理可卡因的大鼠中检查它。这些研究将是第一个确定未开发和新颖传入VTA的功能作用的研究。他们还将确定可卡因自我给药如何修饰多巴胺细胞被特定传入的激发方式。这将提供有关大脑奖励在基线条件下运行及其在自我管理后的可塑性的方式的重要信息。这些研究将为控制成瘾行为的神经回路提供新的见解。