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

基本信息

批准号：
10617254
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
项目类别：
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/10617254
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 behavioral sensitization 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

项目摘要

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.

项目概要/摘要已知肽神经降压素 (NTS) 是多巴胺神经元活性的有效调节剂，NTS 信号传导与各种行为强化和奖励方式以及对滥用药物的行为反应和吸毒动机。药理研究发现在腹侧被盖区 (VTA)，NTS 与其受体结合，通过各种第二信使级联，导致多巴胺神经元放电和下游增加多巴胺释放。然而，人们对内源性 NTS 的生理释放知之甚少。大脑回路以及这些回路在调节动机行为中可能发挥的作用。使用逆行测绘我们确定了 23 个将 NTS 输入发送到 VTA 的大脑区域；然而，这些输入中很少有经过充分研究的它们在 NTS 信号传导中的作用，但对于哪些刺激或行为动作可能激活 NTS 知之甚少神经元。此外，尽管肽能神经元通常共同释放快速神经递质，例如谷氨酸或 GABA，目前的电路特异性激活方法无法区分下游肽触发的效应与快速递质引起的效应。我们假设不同的 NTS 对 VTA 的预测可能在调节动机行为方面发挥独特的作用，并且 NTS 的作用与共同释放的快速递质协同控制下游多巴胺神经元的动态激活。在这里，我们建议确定 VTA 的选定 NTS 输入的神经递质共表达并将它们的突触连接映射到多巴胺和非多巴胺神经元。我们还建议使用病毒式 CRISPR基因诱变技术结合光遗传学快速分离肽 NTS 输入到 VTA 的发射器组件。我们将剖析这些成分在调节中的作用行为强化的不同方式，并将测量体内多巴胺神经元的反应刺激特定的投入。最后，我们将使用光纤光度法来测量 NTS 的活性曲线神经元在学习和执行提示恢复食物奖励任务期间。在一起，这些实验将为我们理解这些关键的电路如何提供前所未有的特定电路精度肽能输入影响多巴胺神经元的活动状态并控制奖励和强化学习。