Differential modulation of dopamine neurons by distinct neurotensin inputs

通过不同的神经降压素输入对多巴胺神经元进行差异调节

• 批准号: 10338471
• 负责人: Marta E Soden
• 金额: $ 35.77万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10338471
• 关键词: Accounting; Action Potentials; Address; Adult; Affect; Anatomy; Behavior; Behavioral; Binding; Biological Models; Brain; Brain region; CRISPR/Cas technology; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Cues; Dependence; Dissection; Dopamine; Electrophysiology (science); Fiber; Fluorescence; Fluorescent in Situ Hybridization; Food; Genes; Genetic Techniques; Glutamates; Hypothalamic structure; Imaging Techniques; In Situ Hybridization; Individual; Label; Lateral; Learning; Link; Location; Locomotion; Maps; Measures; Medial; Methods; Modality; Monitor; Motivation; Mus; Mutagenesis; Neurons; Neuropeptides; Neurotensin; Neurotensin Receptors; Neurotransmitters; Nucleus Accumbens; Peptides; Performance; Pharmaceutical Preparations; Pharmacology Study; Photometry; Physiological; Play; Preoptic Areas; Property; Psychological reinforcement; Reporting; Rewards; Role; Second Messenger Systems; Signal Transduction; Slice; Source; Stimulus; Study models; Synapses; System; Techniques; Tracer; Ventral Tegmental Area; Viral; Virus; addiction; behavioral response; calcium indicator; cell type; combinatorial; dopamine system; dopaminergic neuron; drug of abuse; experimental study; feeding; gamma-Aminobutyric Acid; genetic manipulation; in vivo; in vivo imaging; motivated behavior; nerve supply; neurotransmitter release; optogenetics; receptor; response; retrograde transport; reward processing; tool; vesicular GABA transporter; vesicular glutamate transporter 2

Project Summary/Abstract The peptide neurotensin (NTS) is known to be a potent modulator of dopamine neuron activity, and NTS signaling has been linked to various modalities of behavioral reinforcement and reward, as well as to the behavioral response to drugs of abuse and the motivation for drug taking. Pharmacological studies have found that in the ventral tegmental area (VTA), NTS binding to its receptors depolarizes dopamine neurons through a variety of second messenger cascades, resulting in increased dopamine neuron firing and downstream dopamine release. However, much less is known about the physiological release of NTS from endogenous brain circuits and what role these circuits may play in regulating motivated behavior. Using retrograde mapping we identified 23 brain regions that send NTS input to the VTA; however, few of these inputs are well-studied for their role in NTS signaling, and little is known about what stimuli or behavioral actions may activate NTS neurons. Furthermore, though peptidergic neurons typically co-release a fast neurotransmitter, such as glutamate or GABA, current methods for circuit-specific activation fail to distinguish between downstream effects triggered by peptides versus those evoked by fast transmitters. We hypothesize that different NTS projections to the VTA may play distinct roles in modulating motivated behavior, and that NTS acts synergistically with co-released fast transmitters to govern the dynamics of downstream dopamine neuron activation. Here we propose to determine the neurotransmitter co-expression of select NTS inputs to the VTA and map their synaptic connectivity to dopamine and non-dopamine neurons. We also propose to use viral CRISPR gene mutagenesis techniques in combination with optogenetics to isolate the peptide and fast transmitter components of NTS inputs to the VTA. We will dissect the role of these components in regulating different modalities of behavioral reinforcement and will measure the response of dopamine neurons in vivo to stimulation of specific inputs. Finally, we will use fiber photometry to measure the activity profiles of NTS neurons during learning and performance of a cued reinstatement food reward task. Together, these experiments will add unprecedented circuit-specific precision to our understanding of how these critical peptidergic inputs influence the activity state of dopamine neurons and govern reward and reinforcement learning.

项目摘要/摘要 已知肽神经素（NTS）是多巴胺神经元活性的有效调节剂，NTS 信号传导与行为强化和奖励的各种方式有关，以及 对滥用药物的行为反应和吸毒动机。药理学研究发现 在腹侧对盖区域（VTA）中，NTS与其受体结合，使多巴胺神经元通过A去极化 多种信使级联 多巴胺释放。但是，关于内生的NT的生理释放知之甚少 脑电路以及这些电路在调节动机行为中可能起什么作用。使用逆行映射 我们确定了将NTS输入发送到VTA的23个大脑区域。但是，这些输入中的很少有很好的研究 它们在NTS信号传导中的作用，对哪些刺激或行为作用可能激活NTS知之甚少 神经元。此外，尽管肽能神经元通常会共同释放快速的神经递质，例如 谷氨酸或GABA，当前电路特异性激活的方法无法区分下游 肽与快速发射器引起的效果相对于肽引起的效果。我们假设不同的NTS 对VTA的预测可能在调节动机行为中起着不同的作用，而NTS行动 与共同释放的快速发射器协同结构，以控制下游多巴胺神经元的动力学 激活。在这里，我们建议确定某些NTS输入到VTA的神经递质共表达 并将其突触连通性映射到多巴胺和非阿多巴胺神经元。我们还建议使用病毒 CRISPR基因诱变技术与光遗传学结合使用，以分离肽和快速 NTS输入到VTA的发射机组件。我们将剖析这些组件在调节中的作用 行为强化的不同方式，将测量体内多巴胺神经元的反应 刺激特定输入。最后，我们将使用纤维光度法测量NTS的活性曲线 在学习和表现的恢复食品奖励任务中的神经元。在一起，这些 实验将为我们对这些关键的理解增加前所未有的电路精度 肽能输入影响多巴胺神经元的活性状态，并控制奖励和增强 学习。