Dissecting the Role of Infralimbic Circuitry in Dysfunctional Alcohol Seeking

剖析边缘下回路在功能失调的酒精寻求中的作用

• 批准号: 9147465
• 负责人: Colby Renee Keistler
• 金额: $ 2.24万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-02 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9147465
• 关键词: Ablation; Affect; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Attenuated; Behavior; Behavior Therapy; Behavioral; Chronic; Cocaine; Contralateral; Corpus striatum structure; Coupled; Cues; Data; Diphtheria Toxin; Disease; Extinction (Psychology); Human; Knowledge; Lesion; Medial; Mediating; Neurons; Nucleus Accumbens; Pathway interactions; Pharmacogenetics; Pharmacological Treatment; Play; Predisposition; Prefrontal Cortex; Rattus; Recovery; Regulation; Relapse; Research; Resistance; Rodent; Role; Self Administration; Structure; Techniques; Testing; Therapeutic; Time; Training; Translating; Viral; alcohol behavior; alcohol cue; alcohol seeking behavior; alcohol use disorder; base; conditioned fear; designer receptors exclusively activated by designer drugs; diphtheria toxin receptor; drinking; driving behavior; gain of function; improved; insight; loss of function; neural circuit; novel; public health relevance; research study; selective expression; treatment program

 DESCRIPTION (provided by applicant): Recovering from alcohol use disorders is made exceedingly difficult by both an initial inability to quit drinking and a chronic susceptibility to relapse. Improving behavioral and pharmacological treatments for alcoholism will require a better understanding of the neural circuitry that mediates these behaviors. Recent studies highlight the importance of the ventral portion of medial prefrontal cortex, the infralimbic cortex (ilPFC), in regulating alcohol seeking. However, the role of ilPFC projections to specific subcortical targets in these behaviors is still largely unknown. Our preliminary data suggest that ilPFC may bi-directionally regulate alcohol-related behaviors via its connectivity with nucleus accumbens shell (NAcS) and basolateral amygdala (BLA). Specifically, we have seen that functionally disconnecting ilPFC from NAcS increases self- administration and cue-induced reinstatement of alcohol seeking, while disconnecting ilPFC from BLA decreases cue-induced reinstatement. It is unclear whether these effects result from a disruption of infralimbic afferent or efferents, and whether the circuits are specifically necessary for reinstatement or play a more general role in alcohol seeking overall. Here we propose to use a novel combination of viral and behavioral techniques to selectively manipulate ilPFC projections to both NAc and BLA to determine their precise roles in these behaviors. Aim 1 will test the hypothesis that the ilPFC � NAcS projection inhibits alcohol seeking during extinction and reinstatement. Experiment 1a will utilize a novel, target-specific ablation strategy to test the effects of loss of function in this projection during extinction and reinstatement. Experiment 1b will use excitatory DREADDs to test the effects of activating the projection during these same behaviors. Aim 2 will test the hypothesis that the ilPFC à BLA projection drives alcohol seeking during extinction and reinstatement. Using the same strategies as in Aim 1, we will decrease (Experiment 2a) and increase (Experiment 2b) the activity of this pathway to test its role in alcohol extinction and reinstatement. While ilPFC projections to NAcS and BLA are known to regulate other behaviors (e.g., fear conditioning and cocaine seeking), their role in alcohol-related behaviors is unclear. The proposed research will therefore provide novel insight into the circuit-level regulation of alcohol seeking, and highlight how circuit dysregulation may underlie an inability to quit drinking We believe that the knowledge gained from these experiments will ultimately be translated into improved therapeutic strategies for alcohol use disorders in humans.

 描述（由应用程序提供）：从酒精使用障碍中恢复到最初的戒酒和长期对 复发。改善酒精中毒的行为和药物治疗方法将需要更好地了解介导这些行为的神经元回路。最近的研究强调了内侧前额叶皮层的腹侧部分的重要性 （ILPFC），控制饮酒。但是，ILPFC项目在这些行为中特定皮层靶标的作用仍然很大程度上是未知的。我们的初步数据表明，ILPFC可以通过与伏隔核（NACS）和基底外侧杏仁核（BLA）的连通性来调节酒精相关的行为。具体而言，我们已经看到，在功能上与NACS断开ILPFC会增加自我给药和提示诱导的寻求酒精的恢复，同时将ILPFC与BLA断开，从而减少了提示引起的恢复。目前尚不清楚这些影响是由于侵入性传入或有效性的破坏以及这些电路是否是恢复原状或在整体寻求酒精中起着更一般作用所必需的。在这里，我们建议使用病毒和行为技术的新型组合来选择性地操纵ILPFC项目，以确定它们在这些行为中的精确作用。 AIM 1将检验ILPFC NACS投影在扩展和恢复期间抑制酒精寻求的假设。实验1A将利用一种新颖的，特定目标的消融策略来测试在扩展和恢复期间该投影中功能丧失的影响。实验1b将使用兴奋性恐怖分来测试在这些相同行为中激活投影的效果。目的2尽管ILPFC向NACS和BLA项目项目却众所周知会调节其他行为（例如，恐惧调节和可卡因寻求），但它们在与酒精相关的行为中的作用尚不清楚。因此，拟议的研究将为寻求酒精的电路级调节提供新的见解，并强调电路失调如何在无法戒烟的基础上我们认为，从这些实验中获得的知识最终将被转化为人类中酒精饮酒障碍的治疗策略。