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.

项目概要 伏隔核 (NAc) 代表中皮质边缘通路的一个不可或缺的功能组成部分， 规范地称为“奖励”途径。数十年的药理学研究表明，近 所有滥用药物都会引起 NAc 内多巴胺的释放，从而改变奖励处理的先天系统 急性和长期的时间尺度。长期滥用药物和成瘾被概念化为被驱动的 部分原因是奖励和厌恶处理过程中的这些适应不良的变化，以及避免的愿望 戒断药物或压力造成的烦躁不安。因此，全面的神经药理学理解 控制奖赏和厌恶的机制对于推进新的药理学目标至关重要 对于毒瘾。初级 NAc 输出神经元、中型棘神经元 (MSN) 几乎没有自发活动， 相反，更多地依赖来自基底外侧杏仁核等大脑区域的外在兴奋性输入 (BLA)、室旁丘脑 (PVT) 和前额皮质 (PFC)。 PVT，一个相对未被充分研究的大脑 区域，同样被证明在调节对奖励和奖励的行为反应方面发挥着不可或缺的作用。 厌恶的刺激。最近表明，PVT-NAc 回路活动可调节行为效应 阿片戒断、蔗糖寻求/消费以及对痛苦刺激的行为反应。 PVT 是一个 高度异质的结构，并且最近检查 PVT-NAc 电路的研究显示出相互矛盾的结果， 部分原因是 PVT 内缺乏遗传和解剖特异性。神经调节肽 神经降压素在前部 PVT 中选择性表达，我们的初步数据表明这些 神经元向 NAc 发送兴奋性投射。这种肽虽然比许多其他肽的特征较少 神经肽能信号系统已被证明可以调节对滥用药物的行为反应 和 NAc 中多巴胺的释放。该提案的首要目的是确定药理学 来自 PVT 的神经降压素输入调节 NAc 活性的机制。先前的研究有 显示纹状体中的 NTS 信号传导会动员内源性大麻素 (eCB) 的产生，这也具有类似的作用 参与调节奖励和厌恶。我们的初步数据支持 eCB 监管 PVT 输入 到国家Ac。为此，我们将确定 NTS 和 eCB 之间在调节 兴奋性 PVT-NAc 回路的活动。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节。使用状态 通过体内光度技术，我们将确定奖励和厌恶刺激如何调节神经活动 PVT-NAc 电路内的 NTS/eCB 释放。我们将进一步结合体内光遗传学技术 通过药理学来测试 PVT-NAc 活性在驱动行为反应中的必要性和充分性 奖励性和厌恶性刺激。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药物治疗方法。