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：
10631062
负责人：
David J. Marcus
金额：
$ 7.45万
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/10631062
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 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 design drug of abuse drug withdrawal endocannabinoid signaling foot glutamatergic signaling hindbrain in vivo insight neural neuromechanism neuronal circuitry neuroregulation neurotransmission novel novel strategies opioid withdrawal optogenetics pharmacologic preference presynaptic psychiatric comorbidity psychostimulant recruit 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.

项目摘要伏隔核（NAC）代表中皮质胶质途径的整体功能成分，即在规范上被称为“奖励”途径。数十年的药物研究表明，几乎所有滥用药物都会在NAC内部释放多巴胺，改变了先天系统以奖励处理急性和慢性时间尺度。长期虐待和对药物的成瘾被概念化为被驱动部分是由于这些不良适应性的奖励和厌恶处理的变化，以及避免避免的愿望药物戒断或压力的烦躁不安。因此，全面的神经药理理解控制奖励和厌恶的机制对于促进新的药物目标至关重要原发性NAC输出神经元，中棘神经元（MSN）的发起活动几乎没有，相反，更严重地依靠来自大脑区域的外部兴奋性输入（BLA），室室丘脑（PVT）和额叶皮层（PFC）。 PVT，相对理解的大脑同样，地区，在将行为响应调节以奖励和厌恶刺激。最近已经显示，PVT-NAC电路活性调节利用戒断，寻求/消费的蔗糖以及对痛苦刺激的行为反应。 Pvt是高度异源结构，最近检查PVT-NAC电路的研究显示出冲突的结果，部分原因是PVT中缺乏遗传和解剖学特异性。神经调节肽神经素在前PVT中有选择地表达，我们的初步数据表明这些神经元将兴奋性项目发送给NAC。这种肽，虽然比许多其他肽的特征较少已证明神经肽的信号系统可以调节对滥用药物的行为反应和多巴胺在NAC中释放。该提案的第一个目的是确定药物来自PVT的神经增生输入的机制调节NAC活性。先前的研究已有在纹状体中显示的NTS信号传导动员了内源性大麻素（ECB）的产生，该产量类似我们与调节奖励和厌恶有关。我们的初步数据支持ECB调节PVT输入到NAC。在此目标中，我们将确定NTS和ECB之间的功能相互作用在确定兴奋PVT-NAC电路的活性。我们的第二个目标是确定NTS-ECB的功能作用调节PVT NTS-NAC兴奋性项目，以确定奖励和厌恶。使用状态在体内光度计技术中，我们将确定如何调节和厌恶刺激调节神经活动 PVT-NAC电路中的NTS/ECB释放。我们将进一步使用体内光遗传技术使用药理学来测试PVT-NAC活性在驱动行为反应中的必要和充分性有益和厌恶刺激。这些数据将有助于更好地理解先天机制调节奖励和厌恶开放潜在的药物滥用药物。