Dissecting circuits underlying loss of control relevant to binge eating
剖析与暴饮暴食相关的失控回路
基本信息
- 批准号:10722697
- 负责人:
- 金额:$ 16.25万
- 依托单位:
- 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:2023-07-01 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAcuteAnimal ModelAreaBehaviorBehavior ControlBehavior assessmentBehavioralBehavioral ParadigmBinge EatingCalciumCellsChronicClinical ResearchComplexCorpus striatum structureDataDevelopmentDiagnosticEatingEating BehaviorEnsureEventFeeding behaviorsFiberFoodFood AccessFoundationsFutureGeneral PopulationGoalsHealthHyperphagiaImageImpairmentInterventionInvestigationLearningLinkMeasurementMediatingMediationMedicalMissionMorbidity - disease rateMotor CortexMusNeuronsNon-Insulin-Dependent Diabetes MellitusObesityPathologicPatternPhotometryPhysiologicalPopulationPre-Clinical ModelProtocols documentationPublic HealthResearchResolutionRewardsRoleScientistSpecificityStatistical Data InterpretationSystemTechnical ExpertiseTechniquesTrainingWeight GainWorkbehavior measurementcareercell typefeedingfood consumptionimprovedin vivoin vivo calcium imagingloss of control over eatingmaladaptive behaviormortalityneuralneural correlateneuromechanismnovelobesity riskoptogeneticspreventprogramsskillstranslational impact
项目摘要
ABSTRACT
Obesity is a critical public health problem associated with substantial morbidity and mortality. Binge eating
(BE), a compulsive episodic overeating behavior, is associated with increased rates of obesity and weight gain.
Despite the negative impact of BE on physiological health and obesity risk, the underlying neural mechanisms
contributing to BE are largely unknown. Loss of control (LOC) over eating - i.e., being unable to control the
quantity of food consumed - is a core feature of BE and a significant predictor of obesity. However, there have
been no mechanistic investigations of in vivo neural activity patterns underlying LOC during BE, limiting
development of new treatments. LOC is associated with difficulties disengaging from eating (i.e., feeding
offset), and pre-clinical models are an optimal system to precisely measure this behavioral event. In this set of
integrated training and scientific Aims, the candidate will identify neural correlates of feeding offset using an
animal model for BE to understand the underlying neural substrates of LOC. Data in mice show that activity in
dorsolateral striatum (DLS), a key region associated with behavior cessation, is blunted at feeding offset after
chronic BE. Preliminary data also suggest that activity in secondary motor cortex (M2) to DLS projecting cells
is reduced prior to feeding offset. This project will examine the role of DLS and M2 to DLS projecting cells in
feeding offset using a robust behavioral paradigm for binge eating in mice. The overarching hypotheses are: 1)
D1 and D2 spiny projection neurons in DLS will differentially contribute to feeding offset in BE vs. non-BE mice;
2) reversing blunted DLS activity in BE mice via closed-loop stimulation will improve pathologic behavior; 3)
specific ensembles of M2 to DLS projecting cells tuned to feeding offset will be less active in BE mice; and 4)
increasing activity of M2 to DLS specific neurons will improve maladaptive feeding behavior. Cellular resolution
in vivo calcium imaging will be used to identify neural activity patterns in specific DLS cell populations during
feeding offset (Aim 1). Closed-loop optogenetics will be used determine whether manipulation of neural activity
in DLS cell populations facilitates changes in feeding offset (Aim 2). Finally, in vivo calcium imaging and
optogenetics will be used to identify, track, and manipulate M2 to DLS projecting cells at feeding offset in BE
and non-BE mice to investigate a potential cortical treatment target for non-invasive treatment of BE (Aim 3).
The integrated training plan will ensure the candidate achieves her career goal of developing an independent
program in translational BE and obesity research. The candidate will expand her training in 4 core areas: 1)
learn cellular resolution in vivo calcium imaging; 2) develop statistical analysis skills applicable to complex
neural data aligned to behavioral events; 3) apply circuit manipulation techniques to inform future treatment
interventions; and 4) refine measurement of novel BE behaviors to maximize translational impact. Completion
of this K08 will contribute to a program of research that will increase our understanding of how core circuits
underlying BE can be manipulated to minimize maladaptive feeding that contributes to obesity risk.
摘要
肥胖是一个严重的公共卫生问题,与相当大的发病率和死亡率有关。暴饮暴食
(BE),一种强制性的间歇性暴食行为,与肥胖率和体重增加有关。
尽管BE对生理健康和肥胖风险有负面影响,但潜在的神经机制
对BE的贡献在很大程度上是未知的。对进食失去控制(LOC)--即无法控制
食物消耗量-是BE的核心特征,也是肥胖的重要预测指标。然而,有一些
在BE期间,没有对LOC潜在的体内神经活动模式进行机制研究,限制了
开发新的治疗方法。LOC与脱离进食(即进食)的困难有关
偏移量),临床前模型是精确测量这种行为事件的最佳系统。在这套
综合培训和科学目标,候选人将识别神经相关的喂养补偿使用
BE的动物模型以了解LOC的潜在神经基础。在老鼠身上的数据显示,在
背外侧纹状体(DLS)是与行为停止相关的关键区域,在行为停止后的摄食偏移时变钝
慢性病就是。初步数据还表明,次级运动皮质(M2)对DLS投射细胞的活动
在进给偏移量之前减少。本项目将研究DLS和M2在DLS投射细胞中的作用
在老鼠暴饮暴食中使用健壮的行为范式进行摄食补偿。主要假设如下:1)
DLS内的D1和D2棘突投射神经元对BE小鼠和非BE小鼠的摄食补偿有不同的贡献;
2)通过闭环刺激逆转BE小鼠迟钝的DLS活性将改善病理行为;3)
调节到摄食偏移的M2到DLS投射细胞的特定集合在BE小鼠中将不那么活跃;以及4)
增加M2对DLS特异性神经元的活动将改善不良适应的摄食行为。细胞分辨率
体内钙成像将用于识别特定DLS细胞群中的神经活动模式
进给偏移(目标1)。将使用闭环光遗传学来确定是否操纵神经活动
DLS细胞种群的变化有助于改变摄食补偿(目标2)。最后,体内钙成像和
光遗传学将被用来识别、跟踪和操纵BE中饲养偏移的M2到DLS投射细胞
和非BE小鼠研究非侵入性治疗BE的潜在皮质治疗靶点(目标3)。
综合培训计划将确保应聘者实现她的职业目标,即发展独立的
翻译BE和肥胖症研究计划。候选人将在4个核心领域扩大她的培训:1)
学习体内细胞分辨率钙成像;2)开发适用于复合体的统计分析技能
神经数据与行为事件一致;3)应用电路操作技术,为未来的治疗提供信息
干预措施;以及4)改进对新的商务英语行为的测量,以最大限度地提高翻译效果。完成
将有助于一个研究计划,该计划将增加我们对核心电路如何
潜在的BE可以被操纵,以最大限度地减少导致肥胖风险的不适应喂养。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Britny Hildebrandt其他文献
Britny Hildebrandt的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Britny Hildebrandt', 18)}}的其他基金
Dissecting corticostriatal circuitry underlying chronic binge eating
剖析慢性暴饮暴食背后的皮质纹状体回路
- 批准号:
10226723 - 财政年份:2021
- 资助金额:
$ 16.25万 - 项目类别:
Dissecting corticostriatal circuitry underlying chronic binge eating
剖析慢性暴饮暴食背后的皮质纹状体回路
- 批准号:
9795363 - 财政年份:2018
- 资助金额:
$ 16.25万 - 项目类别:
相似海外基金
Research on the pathophysiology of acute transient psychosis using animal model
急性短暂性精神病动物模型病理生理学研究
- 批准号:
22K07589 - 财政年份:2022
- 资助金额:
$ 16.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A new monitoring method using transpulmonary thermodilution in an animal model of acute respiratory distress syndrome.
在急性呼吸窘迫综合征动物模型中使用经肺热稀释的新监测方法。
- 批准号:
21K16596 - 财政年份:2021
- 资助金额:
$ 16.25万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Testing existing and new therapeutic interventions in a novel animal model of acute Spot Positive intracranial hemorrhage
在急性斑点阳性颅内出血的新型动物模型中测试现有和新的治疗干预措施
- 批准号:
342058 - 财政年份:2016
- 资助金额:
$ 16.25万 - 项目类别:
Operating Grants
Development of a gene therapy approach to treat acute lung injury using a preclinical, large animal model
使用临床前大型动物模型开发治疗急性肺损伤的基因治疗方法
- 批准号:
9044084 - 财政年份:2016
- 资助金额:
$ 16.25万 - 项目类别:
Effect of Stem Cells derived from Human Exfoliated Decidious Teeth in animal model of acute liver failure-correlation between inflammation and regeneration in liver
人脱落乳牙干细胞在急性肝功能衰竭动物模型中的作用——肝脏炎症与再生的相关性
- 批准号:
15K08996 - 财政年份:2015
- 资助金额:
$ 16.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The search of the drug for the acute severe HBV hepatitis using animal model
动物模型寻找治疗急性重型乙型肝炎药物
- 批准号:
15K09003 - 财政年份:2015
- 资助金额:
$ 16.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A new animal model for stress-induced transition from acute to chronic pain
压力引起的急性疼痛向慢性疼痛转变的新动物模型
- 批准号:
9081225 - 财政年份:2014
- 资助金额:
$ 16.25万 - 项目类别:
A new animal model for stress-induced transition from acute to chronic pain
压力引起的急性疼痛向慢性疼痛转变的新动物模型
- 批准号:
8862455 - 财政年份:2014
- 资助金额:
$ 16.25万 - 项目类别:
Development of a animal model of acute encephalopathy and an antibody therapy
急性脑病动物模型的开发和抗体治疗
- 批准号:
26670500 - 财政年份:2014
- 资助金额:
$ 16.25万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
A new animal model for stress-induced transition from acute to chronic pain
压力引起的急性疼痛向慢性疼痛转变的新动物模型
- 批准号:
8976522 - 财政年份:2014
- 资助金额:
$ 16.25万 - 项目类别: