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

• 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
• 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

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）：腹侧被盖区（VTA）的多巴胺细胞的活性在奖励和动机中发挥着关键作用。在体内，这些细胞不规则地放电，并散布着“爆发”事件；这种活动模式是局部和远端结构产生的兴奋性和抑制性输入的结果。此外，这些输入的可塑性发生在接触和戒断成瘾药物之后。然而，了解特定传入神经对 VTA 的功能作用（无论是在基线条件下还是在接触药物后）受到当前技术的限制。这些研究将确定在大鼠自我施用可卡因之前或之后，特定传入神经如何调节 VTA 的活性。为了剖析特定传入的作用，我们将使用光遗传学技术，通过将光脉冲施加到表达藻类蛋白通道视紫红质 2 (ChR2) 的末端，可以增加选择性途径的活性。成年大鼠的特定大脑区域将被腺相关病毒感染，以在神经元中表达 ChR2。然后，我们将通过在 VTA 中应用光脉冲来刺激来自每个区域的传入神经，从而确定特定通路的功能作用。我们将检查来自 (i) 脚桥被盖核 (PPTg) 的 VTA 输入，这是一个对显着刺激做出反应的混合谷氨酸能/胆碱能群体； (ii) 局部 VTA 谷氨酸细胞，最近已被描述，但其功能作用尚不清楚； (iii) 喙内侧被盖核 (RMTg)，这是最近发现的一种后脑结构，可向 VTA 发送重要的 GABA 能投射，但其功能作用尚不清楚。我们将评估通路特异性刺激对麻醉大鼠体内测量的细胞活性（放电速率和模式）的影响。然后，我们将通过测量刺激这些通路时产生的突触电位来确定这些体外输入的性质。我们还将确定这种突触输入的整合方式。最后，我们将通过进行免疫组织化学研究进一步测试该途径的性质。目标 1 将检查这些途径在未接触药物的大鼠中的作用。目标 2 将在自我注射可卡因的老鼠身上进行检查。这些研究将首次确定未探索的新型传入神经对 VTA 的功能作用。他们还将确定可卡因自我给药如何改变多巴胺细胞被特定传入刺激的方式。这将为大脑奖励通路在基线条件下的运作方式及其自我管理后的可塑性提供重要信息。这些研究将为控制成瘾行为的神经回路提供新的见解。