Regulation of fear expression by activity-dependent BDNF in direct hippocampal-to-prelimbic projections
活动依赖性 BDNF 在直接海马到前边缘投射中对恐惧表达的调节
基本信息
- 批准号:10220675
- 负责人:
- 金额:$ 7.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAnatomyAreaBehaviorBrainBrain regionBrain-Derived Neurotrophic FactorCalciumCell physiologyChronicDataDiseaseEnterobacteria phage P1 Cre recombinaseFrequenciesFrightFunctional disorderGeneralized Anxiety DisorderGenesGenetic TranscriptionGoalsHeadHippocampus (Brain)HumanImageImpairmentImplantIn Situ HybridizationLabelLaboratoriesLinkLiteratureMedialMediatingMembrane PotentialsMicroscopeMolecularMusNeuronsNeurotrophic Tyrosine Kinase Receptor Type 2Pathway interactionsPatternPharmacological TreatmentPopulationPopulation DynamicsPost-Traumatic Stress DisordersPrefrontal CortexProcessProductionRattusRegulationReporterResearchRestRodentRoleSignal TransductionSpecificityStructureSymptomsSynaptic PotentialsTechniquesTestingTherapeuticViralVirusWorkbehavioral phenotypingcalcium indicatorcell typeclinically relevantexperimental studyinnovationlensmolecular phenotypemutantneural circuitneuromechanismneuronal patterningneuropsychiatric disorderneurotrophic factornoveloverexpressionpatch clampprecision medicineretrograde transportside effectsingle moleculetherapeutic targettherapy developmenttreatment strategy
项目摘要
Abnormalities in hippocampal-prefrontal function are associated with impairments in fear regulation in humans,
rats, and mice. Despite the known associations between function in these brain regions and fear expression,
there is a fundamental gap in our understanding of how dysfunction in this circuit leads to expression deficits.
Continued existence of this gap represents an important problem because a thorough understanding of how
anatomically-defined neural circuits contribute to fear will likely be critical for the development of treatments for
disorders featuring dysregulation of fear expression. The long-term goal is to better understand how altered
molecular and cellular function in anatomically-connected populations of neurons contributes to fear
dysregulation in neuropsychiatric disorders, and to use this information to develop novel treatment strategies
for these disorders by selectively targeting clinically-relevant molecules within these populations. The overall
objective of this proposal, and the first step toward our long-term goal, is to establish a causal link between one
such molecule, brain-derived neurotrophic factor (BDNF), fear expression, and an anatomically-connected
neural circuit, comprised of ventral hippocampal (vHC) neurons with direct projections to the prelimbic cortex
(PrL), or vHC-PrL projectors. Our central hypothesis is that BDNF signaling impacts the ability of vHC-PrL
projectors to bi-directionally regulate fear expression. The rationale for the proposed research is that, once
causal links between hippocampal-prefrontal function, Bdnf, and fear expression are established, the selective
manipulation of Bdnf in the hippocampal-prefrontal pathway will lead to therapeutic approaches to fear
dysregulation that target only the affected neural circuitry. The central hypothesis of the proposal will be tested
by pursuing three Specific Aims: 1) Examine how altered activity-dependent BDNF signaling impacts the
structure and function of vHC-PrL projectors, 2) determine whether over-expression of BDNF in vHC-PrL
projectors reverses fear-related behavioral and molecular phenotypes in the PrL of mice with impaired
hippocampal-prefrontal function, and 3) investigate how aberrant BDNF-dependent plasticity impacts
population dynamics in the prelimbic cortex during fear expression. The approach is innovative because it
investigates the role of a selective neural circuit in fear expression with heretofore impossible anatomical
specificity; furthermore, it proposes the use of cutting edge techniques to causally link Bdnf with function of this
circuit during fear expression and fear-related population dynamics, which has never before been done. The
proposed research is significant because the results are expected to vertically advance our understanding of
the neural circuitry underlying fear expression, as well as provide potential avenues for anatomically-localized
therapeutic targeting in disorders featuring fear dysregulation. It is likely that such selective targeting of neural
circuitry in these disorders will be efficacious in reducing both the symptoms of these disorders and the side
effects associated with current pharmacological treatments, which act non-specifically in the brain.
大脑前额叶功能的缺失与人类恐惧调节的障碍有关,
大鼠和小鼠。尽管这些大脑区域的功能与恐惧表达之间存在已知的联系,
我们对这个回路的功能障碍如何导致表达缺陷的理解存在根本性的差距。
这种差距的持续存在是一个重要的问题,因为彻底了解如何
解剖学上定义的神经回路有助于恐惧可能对治疗的发展至关重要。
以恐惧表达失调为特征的疾病。长期目标是更好地了解
解剖学上相连的神经元群体中的分子和细胞功能有助于恐惧
神经精神疾病的失调,并利用这些信息来开发新的治疗策略
通过选择性靶向这些人群中的临床相关分子来治疗这些疾病。整体
这一建议的目的,也是我们实现长期目标的第一步,是在一个人和另一个人之间建立因果关系。
这些分子,脑源性神经营养因子(BDNF),恐惧表达,以及解剖学上相关
神经回路,由腹侧海马(vHC)神经元组成,直接投射到前边缘皮质
(PrL)或vHC-PrL投影仪。我们的中心假设是BDNF信号影响vHC-PrL的能力,
投射器来双向调节恐惧表达。这项研究的基本原理是,一旦
大脑前额叶功能、BDNF和恐惧表达之间的因果关系已经建立,
在大脑前额叶-前额叶通路中操纵BDNF将导致治疗恐惧的方法
仅针对受影响的神经回路的失调。该提案的核心假设将得到验证
通过追求三个具体目标:1)检查改变的活动依赖性BDNF信号传导如何影响
vHC-PrL投射器结构和功能,2)确定BDNF在vHC-PrL中是否过表达
投影仪逆转了受损小鼠PrL中与恐惧相关的行为和分子表型
海马-前额叶功能,以及3)研究异常的BDNF依赖的可塑性如何影响
恐惧表达时前边缘皮层的种群动态这种方法是创新的,因为它
研究了选择性神经回路在恐惧表达中的作用,
特异性;此外,它建议使用尖端技术将BDNF与此功能因果联系起来,
在恐惧表达和与恐惧相关的人口动态过程中,这是以前从未做过的。的
拟议的研究是重要的,因为结果预计将垂直推进我们对
恐惧表达背后的神经回路,以及提供潜在的途径,
以恐惧失调为特征的疾病的治疗靶向。很可能这种选择性靶向神经细胞的方法,
这些疾病中的电路将有效地减少这些疾病的症状和副作用。
与目前的药物治疗相关的影响,这些药物治疗在大脑中非特异性地起作用。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Phylogenomic evidence for ancient recombination between plastid genomes of the Cupressus-Juniperus-Xanthocyparis complex (Cupressaceae).
- DOI:10.1186/s12862-018-1258-2
- 发表时间:2018-09-10
- 期刊:
- 影响因子:3.4
- 作者:Zhu A;Fan W;Adams RP;Mower JP
- 通讯作者:Mower JP
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HENRY HALLOCK其他文献
HENRY HALLOCK的其他文献
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{{ truncateString('HENRY HALLOCK', 18)}}的其他基金
Molecular, cellular and physiological correlates of sustained attention in the locus coeruleus to anterior cingulate cortex circuit
蓝斑与前扣带皮层回路持续注意力的分子、细胞和生理相关性
- 批准号:
10753763 - 财政年份:2023
- 资助金额:
$ 7.26万 - 项目类别:
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