Norepinephrine tunes prefrontal-thalamic circuitry to modulate avoidance behavior
去甲肾上腺素调节前额丘脑回路以调节回避行为
基本信息
- 批准号:10586051
- 负责人:
- 金额:$ 18.59万
- 依托单位:
- 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:2022-03-07 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAdrenergic AgentsAffectAmygdaloid structureAnimal BehaviorAnimal ModelAnimalsAnti-Anxiety AgentsAnxietyAnxiety DisordersArousalAttentionBehaviorBehavioralBehavioral AssayBrain regionCAV2 geneCalciumCell NucleusClinicalCommunicationData AnalysesDecision MakingDetectionDopamine-beta-monooxygenaseDorsalEmotionalEnterobacteria phage P1 Cre recombinaseEnvironmentEquilibriumExhibitsFemaleFiberFrightG-Protein-Coupled ReceptorsGeneticHippocampusImageImaging DeviceInsula of ReilMajor Depressive DisorderMedialMediatingMental disordersMethodsMonitorMoodsMorphologyMotivationMusNeuronsNeurotransmittersNorepinephrinePathway interactionsPhotometryPilot ProjectsPlayPopulationPost-Traumatic Stress DisordersPosturePrefrontal CortexProcessReceptor ActivationReportingRewardsRisk TakingRodentRoleSchizophreniaSignal TransductionStressTestingThalamic structureTimeVaricosityVideo RecordingViralVirusWakefulnessaddictionanxiety-like behaviorapproach avoidance behaviorarmavoidance behaviorbrain dysfunctioncommon symptomdensitydesigner receptors exclusively activated by designer drugsdisabling symptomexecutive functionflexibilityimprovedin vivoinnovationlocus ceruleus structuremalemillisecondneuralneural circuitneuromechanismnoradrenergicoptogeneticsparticleresponsesensorspatiotemporaltemporal measurement
项目摘要
Norepinephrine tunes prefrontal-thalamic circuitry to modulate avoidance behavior
Abstract
Anxiety disorders are the most common mental illness in the U.S., affecting ~18% of the population. However,
the underlying mechanisms associated with anxiety remain elusive. Recent evidence has identified the medial
prefrontal cortex (mPFC) as a crucial regulator of anxiety and disruption of mPFC-mediated executive functions
in anxiety disorders. On the other hand, norepinephrine (NE) has long been associated with stress and anxiety.
A morphological study showed a higher density of dopamine beta-hydroxylase (DBH) varicosities in the PFC
than in other cortices. However, how the mPFC executes top-down control over other brain regions to regulate
anxiety-related approach-avoidance behavior and whether and how this is modulated by norepinephrine (NE)
remain unclear. This project will test the innovative concept that mPFC – paraventricular thalamus (mPFC-PVT)
circuit is an important previously overlooked target for anxiety and decision-making. Our pilot study suggests
that chemogenetically inhibiting mPFC-PVT pathway with DREADD viral victor significantly increased the time
spent in the open arm of the elevated plus-maze, indicating a reduction in anxiety-related avoidance behavior.
We thus hypothesize that mPFC-pPVT neurons are active during the exploration of aversive environments,
which drives avoidance behavior and elicits anxiety-dependent behaviors. We will explore the extent that
prefrontal NE signaling modulates this effect. We will investigate the communication between these two regions
by using calcium imaging, a detailed DeepLabCut analysis of animal’s behavior (Aim 1) combined with a G-
protein-coupled receptor (GPCR) Activation-Based Norepinephrine (GRAB-NE) sensor (Aim 2) for anxiety-like
behavior. The GRAB-NE will allow us to monitor prefrontal NE dynamics in real-time in free-behaving animals.
The DeepLabCut™ will provide a detailed analysis of an animal’s posture with a sub-millisecond temporal
resolution that could be used to determine an animal’s emotional state change. In summary, we address these
conceptually innovative questions using state-of-the-art methods, which allow for precise, causal interrogation
into the role of this circuit both in vivo and ex vivo in a projection-specific manner.
去甲肾上腺素调节前额叶-丘脑回路以调节回避行为
摘要
焦虑症是美国最常见的精神疾病,影响了约18%的人口。然而,在这方面,
与焦虑相关的潜在机制仍然难以捉摸。最近的证据表明,
前额叶皮层(mPFC)作为焦虑和mPFC介导的执行功能中断的关键调节器
焦虑症另一方面,去甲肾上腺素(NE)长期以来与压力和焦虑有关。
形态学研究表明,PFC中多巴胺β-羟化酶(DBH)的密度较高
比其他皮层更大。然而,mPFC如何对其他大脑区域执行自上而下的控制,
焦虑相关的接近-回避行为以及是否以及如何受去甲肾上腺素(NE)调节
仍然不清楚。该项目将测试mPFC -室旁丘脑(mPFC-PVT)
电路是一个重要的以前被忽视的目标焦虑和决策。我们的初步研究表明
用DREADD病毒维克托化学遗传学抑制mPFC-PVT途径显著增加了
花在高架十字迷宫的开放臂,表明焦虑相关的回避行为减少。
因此,我们假设mPFC-pPVT神经元在探索令人厌恶的环境时是活跃的,
从而导致回避行为和焦虑依赖行为。我们将探讨
前额叶NE信号调节这种作用。我们将调查这两个区域之间的交流
通过使用钙成像,对动物行为的详细DeepLabCut分析(目标1)结合G-
蛋白偶联受体(GPCR)基于激活的去甲肾上腺素(GRAB-NE)传感器(Aim 2)
行为GRAB-NE将使我们能够实时监测自由行为动物的前额叶NE动态。
DeepLabCut™将以亚毫秒的时间间隔提供动物姿势的详细分析,
可以用来确定动物的情绪状态变化的分辨率。总之,我们解决这些问题
使用最先进的方法提出概念上创新的问题,允许进行精确的因果询问
以投射特异性的方式在体内和离体地研究该回路的作用。
项目成果
期刊论文数量(0)
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Wen-Jun Gao其他文献
Wen-Jun Gao的其他文献
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{{ truncateString('Wen-Jun Gao', 18)}}的其他基金
Norepinephrine tunes prefrontal-thalamic circuitry to modulate avoidance behavior
去甲肾上腺素调节前额丘脑回路以调节回避行为
- 批准号:
10451927 - 财政年份:2022
- 资助金额:
$ 18.59万 - 项目类别:
Behavioral effects of igsf9b in the prefrontal cortex
igsf9b 对前额皮质的行为影响
- 批准号:
10054717 - 财政年份:2020
- 资助金额:
$ 18.59万 - 项目类别:
Role of prefrontal cortical dopamine in aggression
前额皮质多巴胺在攻击行为中的作用
- 批准号:
9281915 - 财政年份:2016
- 资助金额:
$ 18.59万 - 项目类别:
Role of prefrontal cortical dopamine in aggression
前额皮质多巴胺在攻击行为中的作用
- 批准号:
9153019 - 财政年份:2016
- 资助金额:
$ 18.59万 - 项目类别:
Antipsychotic Mechanisms of mGluR Agonists in the MK-801 Model of Schizophrenia
mGluR 激动剂在 MK-801 精神分裂症模型中的抗精神病机制
- 批准号:
8268507 - 财政年份:2009
- 资助金额:
$ 18.59万 - 项目类别:
Development of NMDAR hypofunction and cognitive deficits
NMDAR 功能减退和认知缺陷的发展
- 批准号:
8898214 - 财政年份:2009
- 资助金额:
$ 18.59万 - 项目类别:
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