Neuroimmune Mechanisms of Depressive-Like Behavior During Aging
衰老过程中抑郁样行为的神经免疫机制
基本信息
- 批准号:8049171
- 负责人:
- 金额:$ 59.78万
- 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:2007-04-01 至 2013-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdultAffectAgeAgingAging-Related ProcessAnhedoniaAnxietyAttenuatedBehaviorBehavioralBiological AvailabilityBrainC-reactive proteinCalmette-Guerin BacillusCancer PatientCardiovascular DiseasesCellsChronicClinicalDataDepressed moodDepressive disorderDesire for foodDevelopmentDioxygenasesDiseaseDisease ResistanceElderlyEncephalitisEnzymesEventExperimental ModelsFatigueFeeling suicidalGeneral PopulationGoalsHealthHeart DiseasesHepatitis CHumanImmuneImmune responseImmune systemImmunityImmunocompetenceImmunotherapyIndividualInfectionInflammationInflammatoryInjection of therapeutic agentInsulin ResistanceInterferonsInterleukin-1Interleukin-2KynurenineLaboratoriesLeadLifeMalignant NeoplasmsMediatingMediator of activation proteinMental DepressionMetabolic syndromeMetabolismMetastatic MelanomaMicrogliaMolecularMood DisordersMusNeurogliaNeuroimmunomodulationNeurotransmittersNon-Insulin-Dependent Diabetes MellitusObesityPathogenesisPatientsPatternPeripheralPlasmaPlayPopulationPrevalenceProcessPsychopathologyRecording of previous eventsRenal carcinomaResearchResearch PersonnelRheumatoid ArthritisRoleSerotoninSerumSignal TransductionSleepStagingSymptomsT-LymphocyteTestingTryptophanTryptophan Metabolism PathwayTumor Necrosis Factor-alphaage relatedagedaging brainaging populationbasecytokinedepressive symptomsfallshealthy aginghypomaniaimmune activationindoleamineinnovationmacrophagemicrobialmood regulationneurobiological mechanismneuroinflammationneuropathologyneurotransmissionnormal agingnovelnovel therapeuticsolder patientoverexpressionpreventprogramspsychologicresearch studyresponse
项目摘要
DESCRIPTION (provided by applicant): Inflammation is now recognized to be responsible for major health problems of the aging population, contributing to costly diseases such as obesity, the metabolic syndrome, heart disease and insulin resistance in type-2 diabetes. The chronic process of even healthy aging is also associated with development of low grade inflammation. However, age-related changes in inflammation have mainly been considered in relation to systemic disorders. We and others have now collected substantial evidence to show that this inflammation status, as defined by the overexpression of proinflammatory cytokines, is not restricted to the periphery but is also found in the brain. Brain inflammation causes symptoms of sickness that are usually associated with microbial infections, which is likely to make an important contribution to the comorbid behavioral and psychological disturbances that occur in the elderly. Indeed, one in five individuals over the age of 65 suffer from depressive disorders, which is more than twice the prevalence found in the general population. A likely mechanism for the increased prevalence of depressive disorders during aging is a reduction in the synthesis of serotonin, a key neurotransmitter in the regulation of mood, caused by proinflammatory cytokines acting in the brain. This action is mediated by immune-induced activation of the tryptophan-degrading enzyme, indoleamine 2,3 dioxygenase (IDO). This process decreases the bioavailability of tryptophan for the synthesis of serotonin. Our preliminary data indicate that peripheral immune activation activates IDO and induces depressive-like behavioral alterations, and these effects are exacerbated in aged compared to adult mice. Based on this evidence, we propose that peripheral immune activation precipitates the occurrence of mood disorders in aged individuals. We propose to test this hypothesis in aged mice exposed to both acute and chronic peripheral immune activation, two events that we have already shown to increase brain IDO activity. In the first objective, we will determine whether the depressive-like behavioral alterations that develop in response to both acute and chronic peripheral immune activation are exacerbated in aged mice. In the second objective, we will assess the role of increases in peripheral and brain IDO, as well as brain tryptophan and serotonin, in these behavioral changes, whereas the third objective will determine the contribution of brain glial cells to the age-associated increase in brain IDO. We will then use novel pharmacological approaches to determine if targeting brain inflammation (Objective 4) or brain IDO (Objective 5) attenuates the functional consequences of aging on development of depressive like behavior. These exciting experiments will be the first to use integrative neuroimmune approaches to evaluate IDO as the critical mediator between the age-related increase in peripheral and brain inflammation and the increased prevalence of mood disorders in aged individuals.
描述(由申请人提供):炎症现在被认为是老龄化人口的主要健康问题的原因,导致昂贵的疾病,如肥胖症、代谢综合征、心脏病和2型糖尿病中的胰岛素抵抗。即使是健康衰老的慢性过程也与低度炎症的发展有关。然而,年龄相关的炎症变化主要被认为与全身性疾病有关。我们和其他人现在已经收集了大量的证据表明,这种炎症状态,定义为促炎细胞因子的过度表达,不仅限于外周,而且也存在于大脑中。脑炎症引起通常与微生物感染相关的疾病症状,这可能对老年人发生的共病行为和心理障碍做出重要贡献。事实上,65岁以上的人中有五分之一患有抑郁症,这是普通人群患病率的两倍多。衰老过程中抑郁症患病率增加的一个可能机制是血清素合成减少,血清素是调节情绪的关键神经递质,由大脑中的促炎细胞因子引起。这种作用是由免疫诱导的对葡聚糖降解酶吲哚胺2,3双加氧酶(IDO)的激活介导的。这个过程降低了色氨酸合成血清素的生物利用度。我们的初步数据表明,外周免疫激活激活IDO并诱导抑郁样行为改变,并且与成年小鼠相比,这些影响在老年小鼠中加剧。基于这一证据,我们提出,外周免疫激活沉淀情绪障碍的发生在老年人。我们建议在暴露于急性和慢性外周免疫激活的老年小鼠中测试这一假设,这两个事件我们已经证明会增加大脑IDO活性。在第一个目标中,我们将确定在急性和慢性外周免疫激活中发展的抑郁样行为改变是否在老年小鼠中加剧。在第二个目标中,我们将评估外周和脑IDO以及脑色氨酸和血清素增加在这些行为变化中的作用,而第三个目标将确定脑胶质细胞对脑IDO年龄相关性增加的贡献。然后,我们将使用新的药理学方法来确定靶向脑炎症(目标4)或脑IDO(目标5)是否减弱了衰老对抑郁样行为发展的功能后果。这些令人兴奋的实验将是第一个使用综合神经免疫方法来评估IDO作为与年龄相关的外周和大脑炎症增加与老年人情绪障碍患病率增加之间的关键介导因素。
项目成果
期刊论文数量(15)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Voluntary wheel running does not affect lipopolysaccharide-induced depressive-like behavior in young adult and aged mice.
- DOI:10.1159/000356144
- 发表时间:2014
- 期刊:
- 影响因子:2.4
- 作者:Martin SA;Dantzer R;Kelley KW;Woods JA
- 通讯作者:Woods JA
Aging leads to prolonged duration of inflammation-induced depression-like behavior caused by Bacillus Calmette-Guérin.
- DOI:10.1016/j.bbi.2013.02.003
- 发表时间:2013-08
- 期刊:
- 影响因子:15.1
- 作者:Kelley, Keith W.;O'Connor, Jason C.;Lawson, Marcus A.;Dantzer, Robert;Rodriguez-Zas, Sandra L.;McCusker, Robert H.
- 通讯作者:McCusker, Robert H.
Interleukin-1 beta converting enzyme is necessary for development of depression-like behavior following intracerebroventricular administration of lipopolysaccharide to mice.
- DOI:10.1186/1742-2094-10-54
- 发表时间:2013-05-01
- 期刊:
- 影响因子:9.3
- 作者:Lawson MA;McCusker RH;Kelley KW
- 通讯作者:Kelley KW
Effects of voluntary wheel running on LPS-induced sickness behavior in aged mice.
- DOI:10.1016/j.bbi.2012.12.014
- 发表时间:2013-03
- 期刊:
- 影响因子:0
- 作者:Martin SA;Pence BD;Greene RM;Johnson SJ;Dantzer R;Kelley KW;Woods JA
- 通讯作者:Woods JA
Forced treadmill exercise training exacerbates inflammation and causes mortality while voluntary wheel training is protective in a mouse model of colitis.
- DOI:10.1016/j.bbi.2013.05.005
- 发表时间:2013-10
- 期刊:
- 影响因子:0
- 作者:Cook MD;Martin SA;Williams C;Whitlock K;Wallig MA;Pence BD;Woods JA
- 通讯作者:Woods JA
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Keith W Kelley其他文献
Keith W Kelley的其他文献
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{{ truncateString('Keith W Kelley', 18)}}的其他基金
Neuroimmune Mechanisms of Depressive-Like Behavior During Aging
衰老过程中抑郁样行为的神经免疫机制
- 批准号:
7588876 - 财政年份:2007
- 资助金额:
$ 59.78万 - 项目类别:
Neuroimmune Mechanisms of Depressive-Like Behavior During Aging
衰老过程中抑郁样行为的神经免疫机制
- 批准号:
7986896 - 财政年份:2007
- 资助金额:
$ 59.78万 - 项目类别:
Neuroimmune Mechanisms of Depressive-Like Behavior During Aging
衰老过程中抑郁样行为的神经免疫机制
- 批准号:
7795124 - 财政年份:2007
- 资助金额:
$ 59.78万 - 项目类别:
Neuroimmune Mechanisms of Depressive-Like Behavior During Aging
衰老过程中抑郁样行为的神经免疫机制
- 批准号:
7174006 - 财政年份:2007
- 资助金额:
$ 59.78万 - 项目类别:
Neuroimmune Mechanisms of Depressive-Like Behavior During Aging
衰老过程中抑郁样行为的神经免疫机制
- 批准号:
7391645 - 财政年份:2007
- 资助金额:
$ 59.78万 - 项目类别:
CYTOKINE AND HORMONE INTERACTIONS IN COMORBIDITY OF AIDS
艾滋病合并症中细胞因子和激素的相互作用
- 批准号:
6604731 - 财政年份:2002
- 资助金额:
$ 59.78万 - 项目类别:
CYTOKINE AND HORMONE INTERACTIONS IN COMORBIDITY OF AIDS
艾滋病合并症中细胞因子和激素的相互作用
- 批准号:
6789383 - 财政年份:2002
- 资助金额:
$ 59.78万 - 项目类别:
CYTOKINE AND HORMONE INTERACTIONS IN COMORBIDITY OF AIDS
艾滋病合并症中细胞因子和激素的相互作用
- 批准号:
6930551 - 财政年份:2002
- 资助金额:
$ 59.78万 - 项目类别:
CYTOKINE AND HORMONE INTERACTIONS IN COMORBIDITY OF AIDS
艾滋病合并症中细胞因子和激素的相互作用
- 批准号:
6495926 - 财政年份:2002
- 资助金额:
$ 59.78万 - 项目类别:
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