Neurotensinergic-eCB modulation of reward and aversion via a PVT-NAc circuit

通过 PVT-NAc 回路进行奖赏和厌恶的神经降压 eCB 调节

• 批准号: 10311839
• 负责人: David J. Marcus
• 金额: $ 6.87万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311839
• 关键词: Acute; Amygdaloid structure; Anatomy; Anterior; Antisocial Personality Disorder; Area; Attention; Automobile Driving; Aversive Stimulus; Behavior; Behavioral; Binding; Brain; Brain Stem; Brain region; CNR1 gene; Calcium; Chronic; Communication; Complex; Conflict (Psychology); Consumption; Corpus striatum structure; Coupled; Data; Dopamine; Dopamine Receptor; Drug Addiction; Drug Targeting; Dynorphins; Electrophysiology (science); Endocannabinoids; Enkephalins; Feedback; Fiber; Freezing; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genetic; Glutamates; Goals; In Situ Hybridization; Intervention; Investigation; Measures; Mediating; Mental Depression; Mental disorders; Messenger RNA; Mus; Neurobiology; Neuromodulator; Neurons; Neuropeptides; Neurotensin; Neurotensin Receptors; Nucleus Accumbens; Opioid; Output; Pain; Pathologic; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacology Study; Photometry; Physiological; Play; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Production; Regulation; Research Training; Rewards; Role; Scientist; Sensory; Shock; Signal Transduction; Specificity; Stimulus; Stress; Structure; Structure of paraventricular nucleus of thalamus; Substance abuse problem; Sucrose; System; Techniques; Testing; Thalamic structure; Time; Training; Visceral; addiction; behavioral response; career; chronic pain; comorbidity; design; drug of abuse; drug withdrawal; endocannabinoid signaling; foot; glutamatergic signaling; hindbrain; in vivo; insight; neuromechanism; neuronal circuitry; neuroregulation; novel; novel strategies; opioid withdrawal; optogenetics; preference; presynaptic; recruit; relating to nervous system; response; reward processing; selective expression; sensor; substance abuse treatment

PROJECT SUMMARY The Nucleus Accumbens (NAc) represents an integral functional component of the mesocorticolimbic pathway, canonically known as the “reward” pathway. Decades of pharmacological studies have demonstrated that nearly all drugs of abuse elicit dopamine release within the NAc, altering innate systems for reward processing both acutely and over chronic time scales. Long-term abuse and addiction to drugs is conceptualized as being driven in part by these maladaptive changes in reward and aversion processing alongside a desire to avoid the dysphoric effects of drug withdrawal or stress. Therefore, a comprehensive neuropharmacological understanding of the mechanisms that govern reward and aversion are crucial towards advancing new pharmacological targets for drug addiction. Primary NAc output neurons, medium spiny neurons (MSNs), have little spontaneous activity, and instead rely more heavily on extrinsic excitatory input from brain regions such as the basolateral amygdala (BLA), paraventricular thalamus (PVT), and prefrontal cortex (PFC). The PVT, a relatively understudied brain region, has similarly been shown to play an integral role in regulating behavioral responses to rewarding and aversive stimuli. It has been recently shown that PVT-NAc circuit activity regulates the behavioral effects of opiate withdrawal, sucrose seeking/consumption, and behavioral responses to painful stimuli. The PVT is a highly heterogenous structure, and recent studies examining the PVT-NAc circuit have shown conflicting results, partially driven by a lack of genetic and anatomical specificity within the PVT. The neuromodulatory peptide neurotensin is selectively expressed in the anterior PVT and our preliminary data demonstrates that these neurons send excitatory projections to the NAc. This peptide, while less characterized than many other neuropeptidergic signaling systems, has been shown to regulate the behavioral responses to drugs of abuse and dopamine release in the NAc. The first aim of this proposal is to determine the pharmacological mechanism by which neurotensinergic input from the PVT regulates NAc activity. Prior studies have shown NTS signaling in the striatum mobilizes endogenous cannabinoid (eCB) production, which has similarly been implicated in regulating reward and aversion. Our preliminary data supports that eCBs regulate PVT input to the NAc. In this aim, we will determine the functional interaction between NTS and eCBs in regulating the activity of the excitatory PVT-NAc circuit. Our second aim will be to determine the functional role of NTS-eCB modulation of PVT NTS-NAc excitatory projections in regulating reward and aversion. Using state of the art in vivo photometric techniques, we will determine how rewarding and aversive stimuli modulate neural activity and NTS/eCB release within the PVT-NAc circuit. We will further use in vivo optogenetic techniques combined with pharmacology to test the necessity and sufficiency of PVT-NAc activity in driving behavioral responses to rewarding and aversive stimuli. These data will facilitate a better understanding of the innate mechanisms regulating reward and aversion opening up potential new pharmacological treatments for substance abuse.

项目总结 伏隔核(NAC)代表了中皮质边缘通路的一个完整的功能成分， 通常被称为“奖励”途径。数十年的药理研究表明，几乎 所有滥用药物都会在NAC内引起多巴胺的释放，改变了奖赏处理的固有系统 尖锐且超过长期的时间尺度。长期滥用和吸毒成瘾被认为是由 部分是由于奖励和厌恶加工中的这些不适应的变化，以及避免 停药或压力引起的烦躁不安的影响。因此，全面了解神经药理学 控制奖赏和厌恶的机制对推进新的药物靶点至关重要 因为吸毒成瘾。初级NAC输出神经元，中棘神经元(MSN)，自发活动很少， 取而代之的是更多地依赖来自杏仁基底外侧核等脑区的外在兴奋性输入 丘脑(BLA)、室旁丘脑(PVT)和前额叶皮质(PFC)。PVT，一个相对研究较少的大脑 类似地，也被证明在调节对奖励和 厌恶的刺激。最近的研究表明，PVT-NAC回路活动调节大鼠的行为效应。 鸦片类药物戒断，寻求/消耗蔗糖，以及对疼痛刺激的行为反应。PVT是一种 高度不均匀的结构，并且最近对PVT-NAC电路的研究显示出相互矛盾的结果， 部分原因是PVT缺乏遗传和解剖学上的特异性。神经调节肽 神经降压素选择性地在前部PVT中表达，我们的初步数据表明，这些 神经元向NAC发送兴奋性投射。这种多肽虽然不像许多其他多肽那样具有特征性 神经肽能信号系统，已被证明调节滥用药物的行为反应 以及NAC中的多巴胺释放。这项建议的第一个目标是确定药理作用 下丘脑室旁核神经降压素能输入调节NAC活动的机制。先前的研究已经 显示纹状体中的NTS信号动员内源性大麻素(ECB)的产生，这与 牵涉到调节奖赏和厌恶。我们的初步数据支持ECB调节PVT输入 送到南汽。为此，我们将确定非关税壁垒和欧洲央行之间在调节 兴奋性PVT-NAC环路的活动。我们的第二个目标是确定NTS-ECB的职能作用 PVT、NTS-NAC兴奋性投射在调节奖赏和厌恶中的调制。的使用状态 在活体光度学技术中，我们将确定奖赏和厌恶刺激如何调节神经活动 和NTS/ECB在PVT-NAC电路内释放。我们将进一步利用体内光遗传技术相结合 用药理学测试PVT-NAC活性在驱动行为反应中的必要性和充分性 奖赏和厌恶的刺激。这些数据将有助于更好地理解先天机制。 调节奖赏和厌恶，为药物滥用开辟了潜在的新的药物治疗方法。