Neural Mechanisms of Cognitive Decline in Aging
衰老过程中认知能力下降的神经机制
基本信息
- 批准号:9250037
- 负责人:
- 金额:$ 30.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-08-01 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:Adaptive BehaviorsAffectAgingAnatomyAttentionAttenuatedBehaviorBehavioralBehavioral AssayCognitionCognitiveComplexDataDecision MakingElectrophysiology (science)EvaluationExecutive DysfunctionFoundationsGene ExpressionGoalsImmediate-Early GenesImpaired cognitionImpairmentInbred F344 RatsIndividualIndividual DifferencesInterneuronsInterventionKnowledgeLinkLongevityMethodologyMolecularNeuronsPathologicPatternPharmacologyPharmacology StudyPlayPopulationPositioning AttributePrefrontal CortexProcessProsencephalonPublishingQuality of lifeRattusRegulationResearchRoleSchizophreniaShort-Term MemorySignal TransductionSignaling ProteinSystemTechniquesTestingWorkage relatedagedbasal forebraincognitive abilitycognitive disabilitycognitive testingexecutive functionexperimental studyflexibilitygamma-Aminobutyric Acidimprovedindividualized medicineinnovationneuromechanismnormal agingnovelprogramspublic health relevanceresponsetherapeutic target
项目摘要
DESCRIPTION (provided by applicant): Accumulating evidence indicates that during normal aging, executive functions supported by the prefrontal cortex are among the earliest and most severely impaired cognitive abilities. Executive functions, which include attention, working memory, and cognitive flexibility, are essential to the successful guidance of adaptive behavior and to higher-order aspects of cognition such as decision making. Disruption of corticolimbic g- aminobutyric acid (GABA)ergic inhibitory circuits can have profound consequences for executive function, and preliminary data indicate that prefrontal cortical GABAergic systems are dysregulated in normal aging. Our long term goal is to understand how age-related alterations in forebrain inhibitory circuitry affect executive functions, and to identify potential therapeutic targets that can be exploited to improve cognition in aged individuals. Important to this goal, we have found that there are robust individual differences in the effects of normal aging on executive function, such that some aged subjects are impaired on an attentional set shifting test of cognitive flexibility whereas others are impaired on a delayed response test of working memory. Moreover, our preliminary data suggest that these distinct forms of executive dysfunction are linked to differences in patterns of GABAergic signaling. Building on our extensive preliminary data, the objective of this proposal is to determine how altered GABAergic signaling within the prefrontal cortex affects executive function and whether this signaling can be manipulated to attenuate age-related executive impairments. Our central hypothesis is that individual differences in prefrontal cortical GABAergic signaling underlie distinct forms of executive dysfunction within aging populations. The rationale for the proposed work is that by understanding how altered inhibitory signaling in prefrontal cortex contributes to different forms of executive dysfunction, we will be well-positioned to begin to develop intervention strategies that will allow tailored and more efficacious treatments for executive decline that accompanies aging. Using an integrative approach in which we combine behavioral assays with molecular, electrophysiological, anatomical, and pharmacological studies in Fischer 344 rats, we will test our central hypothesis by: 1) determining if individual differences in prefrontal cortical GABAergic signaling contribute to different forms of age-related executive dysfunction; 2) determining if compromised regulation and activation of prefrontal cortical interneurons contributes to age-related executive dysfunction; and 3) determining if altered GABAergic signaling and executive dysfunction in aging contribute to impairments in decision making. We will employ an innovative approach which both considers individual differences and employs the evaluation of multiple subcomponents of executive function. The findings from the proposed studies will be significant because the information gained will provide foundational knowledge necessary to develop tailored treatments for remediating executive decline and promoting quality of life and independence across the full lifespan.
DESCRIPTION (provided by applicant): Accumulating evidence indicates that during normal aging, executive functions supported by the prefrontal cortex are among the earliest and most severely impaired cognitive abilities. Executive functions, which include attention, working memory, and cognitive flexibility, are essential to the successful guidance of adaptive behavior and to higher-order aspects of cognition such as decision making. Disruption of corticolimbic g- aminobutyric acid (GABA)ergic inhibitory circuits can have profound consequences for executive function, and preliminary data indicate that prefrontal cortical GABAergic systems are dysregulated in normal aging. Our long term goal is to understand how age-related alterations in forebrain inhibitory circuitry affect executive functions, and to identify potential therapeutic targets that can be exploited to improve cognition in aged individuals. Important to this goal, we have found that there are robust individual differences in the effects of normal aging on executive function, such that some aged subjects are impaired on an attentional set shifting test of cognitive flexibility whereas others are impaired on a delayed response test of working memory. Moreover, our preliminary data suggest that these distinct forms of executive dysfunction are linked to differences in patterns of GABAergic signaling. Building on our extensive preliminary data, the objective of this proposal is to determine how altered GABAergic signaling within the prefrontal cortex affects executive function and whether this signaling can be manipulated to attenuate age-related executive impairments. Our central hypothesis is that individual differences in prefrontal cortical GABAergic signaling underlie distinct forms of executive dysfunction within aging populations. The rationale for the proposed work is that by understanding how altered inhibitory signaling in prefrontal cortex contributes to different forms of executive dysfunction, we will be well-positioned to begin to develop intervention strategies that will allow tailored and more efficacious treatments for executive decline that accompanies aging. Using an integrative approach in which we combine behavioral assays with molecular, electrophysiological, anatomical, and pharmacological studies in Fischer 344 rats, we will test our central hypothesis by: 1) determining if individual differences in prefrontal cortical GABAergic signaling contribute to different forms of age-related executive dysfunction; 2) determining if compromised regulation and activation of prefrontal cortical interneurons contributes to age-related executive dysfunction; and 3) determining if altered GABAergic signaling and executive dysfunction in aging contribute to impairments in decision making. We will employ an innovative approach which both considers individual differences and employs the evaluation of multiple subcomponents of executive function. The findings from the proposed studies will be significant because the information gained will provide foundational knowledge necessary to develop tailored treatments for remediating executive decline and promoting quality of life and independence across the full lifespan.
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)
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JENNIFER Lynn BIZON其他文献
JENNIFER Lynn BIZON的其他文献
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10633300 - 财政年份:2021
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$ 30.36万 - 项目类别:
Effects of cannabis on age-related cognitive decline and Alzheimers disease pathology
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10469575 - 财政年份:2021
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Immunotherapy targeting the HPA axis in Alzheimer's disease
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10846355 - 财政年份:2019
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Clinical and Translational Pre-doctoral training in Alzheimer's Disease and Related Dementias
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10475693 - 财政年份:2018
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Clinical and Translational Pre-doctoral training in Alzheimer's Disease and Related Dementias
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- 批准号:
10228736 - 财政年份:2018
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$ 30.36万 - 项目类别:
2RO1AG029421 Neural Mechanisms of Age-related cognitive decline
2RO1AG029421 与年龄相关的认知能力下降的神经机制
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8852384 - 财政年份:2014
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Basal forebrain and cognitive aging: Novel experimental and theraptutic avenues
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8180233 - 财政年份:2007
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$ 30.36万 - 项目类别:
Basal forebrain and cognitive aging: Novel experimental and theraptutic avenues
基底前脑和认知衰老:新的实验和治疗途径
- 批准号:
7627219 - 财政年份:2007
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