The lateral preoptic area: a novel regulator of VTA activity and cocaine seeking

外侧视前区：VTA 活动和可卡因寻求的新型调节器

• 批准号: 9311742
• 负责人: Michela Marinelli
• 金额: $ 36.52万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311742
• 关键词: Anatomy; Area; Behavior; Brain; Cell Nucleus; Cocaine; Disinhibition; Dopamine; Elderly; Electrophysiology (science); Goals; Hypothalamic structure; Immunohistochemistry; Incentives; Lateral; Literature; Locomotion; Measures; Motivation; Nature; Neurons; Neurotransmitters; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Play; Positioning Attribute; Preoptic Areas; PubMed; Publications; Rattus; Regulation; Relapse; Rewards; Role; Self Administration; Self Stimulation; Sleep; Specificity; Structure; Sucrose; Synapses; System; Testing; Thirst; Ventral Tegmental Area; Work; addiction; base; dopaminergic neuron; experience; extracellular; gamma-Aminobutyric Acid; in vivo; insight; member; neurochemistry; novel; optogenetics; relapse prediction

Project Summary/Abstract The lateral preoptic area (LPO) is a hypothalamic structure whose function is largely unknown. There is evidence that stimulating the LPO elicits locomotion, and that this structure supports intracranial self- stimulation, suggesting that the LPO could be part of the “brain reward system”. The LPO also sends strong projections to the ventral tegmental area (VTA), a key member of the brain reward circuit. This further positions the LPO as a potential member of the brain reward system and, in particular, as a modulator of VTA activity. This is significant because structures that modulate VTA activity have been shown to play a critical role in cocaine seeking; increases in VTA dopamine neuron activity trigger relapse (i.e. increase drug seeking), whereas decreases reduce seeking. It is unknown if the LPO functionally regulates the activity of VTA neurons and cocaine seeking behavior. The objective of this proposal is to understand if and how the LPO regulates the activity of VTA neurons (Aim 1) and cocaine seeking behavior (Aim 2). In addition, the proposal will examine the contribution of the LPO- VTA pathway in any observed effect, and the neurotransmitters (GABA or glutamate) involved. This will be achieved by manipulating (increasing or decreasing) the activity of the LPO and LPO-VTA pathway; this will determine if this structure and pathway are sufficient and/or necessary for regulating the activity of VTA neurons and cocaine seeking behavior. Activity will be manipulated using three approaches: pharmacology, chemogenetics, and optogenetics. The activity of VTA neurons (GABA and dopamine) will be evaluated with in vivo extracellular recordings in anesthetized rats. Cocaine seeking will be evaluated after cocaine self-administration, by examining responding in the absence of cocaine. Sucrose seeking will also be tested, to examine if the role of this structure and pathway extends to seeking for natural rewards. The neurochemical nature of the LPO-VTA pathway will be probed (i) using pharmacology, (ii) by measuring synaptic currents, and (iii) by performing immunohistochemistry. We predict that stimulating the LPO increases the activity of dopamine neurons in the VTA and seeking behavior. This occurs via a GABAergic LPO-VTA pathway. Specifically, the LPO sends inhibitory GABAergic projections to the VTA. These synapse onto GABA neurons of the VTA resulting in dis-inhibition (i.e. excitation) of dopamine neurons. We expect these studies to establish a novel role for the LPO as a key modulator of VTA neuron activity and cocaine seeking behavior. This provides a significant advancement in understanding circuits and mechanisms of addiction. In addition, these studies will advance our understanding of the brain, by discovering a role of a structure whose function is largely unknown.

项目摘要/摘要 侧面前区域（LPO）是一种下刺结构，而功能是无大的。 刺激LPO引发运动的证据 刺激表明LPO可能是“大脑奖励系统”的一部分。 对脑奖励的关键成员的腹侧对接区域（VTA）的预测 LPO是大脑奖励系统的潜在苦难，尤其是作为VTA活动的模块化器。 这是调节VTA活性VTA活动的重要效果，在 可卡因寻求; 减少寻求的降低。 和可卡因寻求行为。 该提案的目的是了解LPO是否以及如何调节VTA神经元活动（AIM） 1）和可卡因寻求行为（AIM 2）。 VTA途径在任何观察到的效果中，涉及神经递质（GABA或谷氨酸）。 这将通过操纵（增加或减少）LPO和LPO-VTA活性来实现 途径；如果这种结构和通过。 VTA神经元和可卡因的活性，使用三种方法进行操纵： 药理学，化学遗传学和光遗传学。 VTA神经元（GABA和多巴胺）的活性将通过体内杂质记录进行评估 麻醉大鼠可卡因旁的可卡因自我管理后将评估 在不存在可卡因的情况下，还要测试蔗糖 结构和途径扩展到寻求自然奖励。 使用药理学，（ii）通过测量突触电流和（iii）探测途径（i）。 免疫组织化学。 我们预测，刺激LPO增加了VTA中多巴胺神经元的活性并寻求 行为。 对VTA的预测。 激发多巴胺神经元。 我们希望这些研究能够成为LPO作为VTA神经元活性的关键调节剂的新作用，并且 可卡因寻求行为。 成瘾。此外，这些研究将通过发现 其功能更大的结构未知。