Functional role of Gastrin Releasing Peptide (GRP) and GRP expressing neurons in the gustatory cortex

胃泌素释放肽 (GRP) 和味觉皮层中 GRP 表达神经元的功能作用

基本信息

批准号：
10733764
负责人：
Alfredo Fontanini
金额：
$ 58.76万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-09 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733764
关键词：
Acute Address Affect Amygdaloid structure Anatomy Animals Appetitive Behavior Area Automobile Driving Behavior Behavior Control Behavioral Behavioral Paradigm Calcium Cell Nucleus Cells Consumption Cues Data Desire for food Electrophysiology (science)Feeding behaviors Gastrin releasing peptide Glutamates Head Hunger Image In Vitro Infusion procedures Interoception Knowledge Learning Location LoxP-flanked allele Measures Mediating Methods Modeling Monitor Mus Nature Neurons Neuropeptides Neurotransmitters Nutrient Output Pattern Peptides Pharmacology Pharmacology Study Play Population Process Property Reporter Research Rodent Role Satiation Sensory Shapes Signal Transduction Stimulus Study models Synapses System Taste Perception Testing Thirst Time Tracer Transgenic Mice Viral Visualization Work base behavioral response cellular imaging drinking excitatory neuron expectation experimental study feeding imaging study neural neurochemistry neurotransmission novel optogenetics patch clamp pharmacologic response restraint sensory integration transmission process two-photon

项目摘要

PROJECT SUMMARY It is well-established that neural activity in the rodent gustatory cortex (GC) encodes taste, taste-predictive cues and taste-guided decisions. These neural signals play an important role in guiding behaviors related to taste and consumption. Recent electrophysiological and imaging studies demonstrated that GC can also process interoceptive information pertaining to the homeostatic control of feeding and drinking, with hunger/satiety and thirst/quenching affecting neural activity on both the slow time scale of ongoing activity and the fast time scale of taste- and cue-evoked activity. The GC circuits and neurochemicals involved in processing interoceptive signals as well as their role in driving specific behavioral responses are not fully understood yet. We propose to address this gap by focusing on a neuropeptide, the gastrin-releasing peptide, (GRP), and a GC population of neurons producing GRP. As GRP is a feeding-suppressing peptide, neurons expressing GRP (GRP+) are ideal candidates to sense homeostatic states and mediate the effects of GC on consumption. Our preliminary data show that GC GRP+ neurons project to the basolateral nucleus of the amygdala (BLA) – a nucleus known for its role in mediating aversive and appetitive behaviors – corroborating the idea that this population of cells may indeed control behavior and lead to meal termination. The experiments in this proposal we will test the overarching hypothesis that GC GRP+ neurons process interoceptive homeostatic signals at both the slow and fast temporal scales of ongoing and taste/cue- evoked activity, and are capable of inhibiting consumption. Anatomical and immunohistological methods, in vitro patch clamp electrophysiology, 2-photon (2P) calcium imaging in behaving mice, and optogenetic/pharmacological manipulations will be used to address the following specific aims: Aim #1 will rely on anatomical methods, patch clamp and optogenetics to establish neurochemical identity, electrophysiological properties, laminar distribution and connectivity of GC GRP+ neurons. The studies will test the hypothesis that GC GRP+ neurons are excitatory neurons sending projections to BLA and that GRP released by these neurons modulates the activity of BLA circuits. Aim #2 will use 2P calcium imaging to study the activity patterns of GRP+ and GRP- neurons in mice engaged in behavioral tasks probing taste and anticipatory-cues processing under distinct homeostatic conditions. These experiments will test the hypothesis that activity of GC GRP+ neurons, and specifically those projecting to BLA, integrate sensory signals related to nutrients (taste and cues) with homeostatic signals related to meal termination. Finally, Aim #3 will rely on optogenetic activation at different time scales to establish the behavioral contribution of GC GRP+ neurons and investigate the neurochemical bases of this effect. The experiments will test the hypothesis that GC GRP+ neurons provide a meal termination signal, and that their projection to BLA mediates, at least in part, the control of feeding behavior. Altogether, the proposed experiments will establish a new research avenue on the GC and GCBLA circuits involved in representing interoceptive signals and guiding homeostatic behaviors. If successful, these study will i) enhance our understanding of the function of the gustatory cortex; ii) unveil a new role for cortical GRP within the GRPBLA axis; iii) establish a model for studying peptidergic transmission in cortico-amygalar circuits. The results will have important consequences for our understanding of the role of GC in ingestive behaviors.

项目概要众所周知，啮齿动物味觉皮层 (GC) 的神经活动编码味觉、味觉预测这些神经信号在指导相关行为方面发挥着重要作用。最近的电生理学和成像研究表明，GC 还可以处理味道和消耗。与进食和饮水的稳态控制有关的内感受信息，包括饥饿/饱腹感和口渴/解渴在正在进行的活动的慢时间尺度和快时间尺度上影响神经活动味觉和提示诱发的活动的 GC 回路和神经化学物质参与处理内感受。信号及其在驱动特定行为反应中的作用尚未完全了解。我们建议通过关注神经肽、胃泌素释放肽（GRP）和产生 GRP 的神经元 GC 群体由于 GRP 是一种摄食抑制肽，因此神经元表达 GRP。 (GRP+) 是感知稳态并调节 GC 对消耗影响的理想候选者。初步数据显示 GC GRP+ 神经元投射到杏仁核 (BLA) 的基底外侧核 – 核以其在调节厌恶和食欲行为中的作用而闻名——证实了这一观点细胞群确实可以控制行为并导致进餐终止。在本提案中的实验中，我们将测试 GC GRP+ 神经元处理的总体假设持续和味觉/提示的慢速和快速时间尺度的内感受稳态信号诱发活动，并能够抑制消耗。体外膜片钳电生理学、行为小鼠的 2 光子 (2P) 钙成像，以及光遗传学/药理学操作将用于实现以下具体目标：目标#1将依赖于解剖学方法、膜片钳和光遗传学以建立神经化学特性、电生理学这些研究将检验 GC GRP+ 神经元的特性、层状分布和连接性。 GC GRP+ 神经元是兴奋性神经元，向 BLA 发送投射，并且这些神经元释放 GRP 调节 BLA 回路的活动目标 #2 将使用 2P 钙成像来研究 GRP+ 的活动模式。小鼠中的 GRP- 神经元参与探索味觉和预期线索处理的行为任务这些实验将检验 GC GRP+ 神经元活性的假设。特别是那些投射到 BLA 的信号，将与营养物质（味道和线索）相关的感官信号与最后，目标#3将依赖于不同时间的光遗传学激活。时间尺度来确定 GC GRP+ 神经元的行为贡献并研究神经化学该实验将检验 GC GRP+ 神经元提供进餐终止的假设。信号，并且它们对 BLA 的投射至少部分介导了进食行为的控制。总之，所提出的实验将为 GC 和 GCBLA 电路建立新的研究途径如果成功的话，这些研究将参与代表内感受信号和指导稳态行为。 i) 增强我们对味觉皮层功能的理解；ii) 揭示皮质 GRP 的新作用； GRPBLA 轴；iii) 建立研究皮质杏仁核回路中肽能传递的模型。结果将对我们理解 GC 在摄取行为中的作用产生重要影响。