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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）代表中皮质边缘通路的完整功能组分，被称为“奖赏”途径数十年的药理学研究表明，所有滥用药物都会引起NAc内多巴胺的释放，改变奖励处理的先天系统，急性和慢性时间尺度。长期滥用和吸毒成瘾被概念化为受驱动部分原因是由于奖赏和厌恶处理过程中的这些适应不良的变化，以及避免药物戒断或压力的烦躁影响。因此，全面了解神经药理学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吸毒成瘾初级NAc输出神经元，即中型棘神经元（MSN），几乎没有自发活动，而是更多地依赖于来自基底外侧杏仁核等大脑区域的外部兴奋性输入 (BLA)、室旁丘脑（PVT）和前额叶皮质（PFC）。PVT，一个相对未被充分研究的大脑区域，同样被证明在调节奖励和奖励的行为反应中起着不可或缺的作用，厌恶性刺激最近的研究表明，PVT-NAc回路活动调节了阿片戒断、蔗糖寻求/消耗和对疼痛刺激的行为反应。PVT是一个高度异质结构，最近研究PVT-NAc电路的研究显示了相互矛盾的结果，部分是由于PVT内缺乏遗传和解剖学特异性。神经降压素选择性地表达于前部PVT，我们的初步数据表明，这些神经降压素的表达可能与其在肺静脉血栓形成中的作用有关。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更少，神经肽能信号系统，已被证明可以调节滥用药物的行为反应和多巴胺的释放本建议的第一个目的是确定药理学神经降压素能输入的机制，从PVT调节NAc的活动。先前的研究显示纹状体中的NTS信号传导动员内源性大麻素（eCB）的产生，这与参与了奖赏和厌恶的调节我们的初步数据支持eCB调节PVT输入在NAC。在这个目标中，我们将确定NTS和eCBs在调节神经元功能中的相互作用。兴奋性PVT-NAc回路的活动。我们的第二个目标是确定NTS-eCB的功能作用调节PVT NTS-NAc兴奋性投射调节奖赏和厌恶。使用现有艺术在体内光度技术，我们将确定如何奖励和厌恶刺激调节神经活动和NTS/eCB在PVT-NAc回路内释放。我们将进一步利用体内光遗传学技术结合用药理学来测试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了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。