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

基本信息

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
项目类别：
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

项目摘要

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，几十年的药理学研究已经证明，这种途径被称为“奖励”途径。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严重且长期的药物滥用和成瘾被概念化为被驱动。部分原因是奖赏和厌恶处理过程中的这些适应不良的变化，以及避免这种情况的愿望。药物戒断或应激的烦躁影响因此，需要全面的神经药理学了解。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初级 NAc 输出神经元，中型多棘神经元 (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 是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。最近表明，PVT-NAc 回路活动可调节厌恶刺激的行为效应。阿片戒断、蔗糖寻求/消费以及对疼痛刺激的行为反应。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，但与许多其他肽相比，其特征较少。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 中的多巴胺释放该提案的首要目的是确定药理学。先前的研究表明，PVT 的神经降压素输入调节 NAc 活性的机制。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我们的初步数据支持 eCB 监管 PVT 输入。为了实现这一目标，我们将确定 NTS 和 eCB 在监管方面的功能相互作用。我们的第二个目标是确定 NTS-eCB 的功能作用。 PVT NTS-NAc 兴奋性投射在调节奖赏和厌恶使用状态中的调节。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我们将进一步使用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。