Slow Outward Currents and Learning In Aging Hippocampus
Slow Outward Currents and Learning In Aging Hippocampus
批准号:
10205720
负责人:
JOHN F DISTERHOFT
金额:
$36.69万
依托单位国家:
美国
项目类别:
财政年份:
1990
资助国家:
美国
项目状态:
已结题
起止时间:
1990-03-01 至 2022-01-31
关键词:
Action PotentialsAgeAge-associated memory impairmentAgingAlzheimer&aposs DiseaseAnimalsAwardBehavioralBinding ProteinsBiological AssayBiological MarkersBiophysicsBuffersCREB1 geneCalciumCognitiveCyclic AMP-Dependent Protein KinasesCyclic AMP-Responsive DNA-Binding ProteinCytosolDorsalEndoplasmic ReticulumFosteringFoundationsGene ProteinsGenesGoalsHippocampus (Brain)HumanImageImaging TechniquesImpairmentInstructionInterventionKnock-inLaser Scanning MicroscopyLearningMeasurementMeasuresMediatingMethodsMolecularMolecular GeneticsMolecular TargetNerve DegenerationNeurodegenerative DisordersNeuronsPathway interactionsProgress ReportsPropertyProtein BiosynthesisProtein MicrochipsProteinsProxyPublishingRattusRecombinantsReportingResearchReview LiteratureRisk FactorsRoleSignal PathwaySolidSourceSurfaceTherapeuticTherapeutic InterventionTrainingTransgenic MiceViral VectorWestern BlottingWorkadeno-associated viral vectorage relatedagedaging hippocampusbaseclassical conditioningdesignexperimental studyeyeblink conditioninggene therapygenetic approachgenetic manipulationhippocampal pyramidal neuronimaging studynormal agingprogramsprotein activationsuccesstherapeutic targettranscription factortranslation to humanstwo-photonvoltageyoung adult
中文摘要
海马体在陈述性学习的早期阶段至关重要,它的功能和
英文摘要
The hippocampus is critically involved in the early stages of declarative learning, and its function and
capacity are degraded during normal aging that causes age-associated learning impairments. It has been
repeatedly demonstrated that a cellular biomarker of this age-associated learning deficit is the enlarged
Ca2+-dependent postburst afterhyperpolarization (AHP) that reduces the intrinsic excitability of CA1
pyramidal neurons in aged subjects. Thus, we have hypothesized that restoring intrinsic excitability of aged
CAI neurons to a young-like state by reducing the AHP using genetic manipulations would rescue the age-
related learning deficits. Hence we have designed a research program to identify the candidate proteins for
genetic manipulation with the use of recombinant adeno-associated viral (AAV) vectors. In the initial 3.5
years of this MERIT award, we have determined that 1) Ca2+ accumulation in the cytosol evoked with trains
of action potentials is greatly elevated in aged CA1 neurons and may underlie the enlarged AHP in these
neurons; 2) Ca2+ buffer capacity is increased in aged CAI neurons, potentially as a cellular mechanism to
counteract the increased Ca2+ accumulation; 3) CREB activation (an important cellular mechanism for
protein synthesis necessary for learning and for AHP reduction) is impaired in hippocampus of aged rats;
and 4) L-type Ca2+ channel (LTCC) expression on the surface of CAI neurons is elevated in aged rats,
which provides a molecular mechanism for the reported increased Ca2+ influx through LTCC in aged CAI
neurons. Based on these findings, we have identified Ca2+ binding proteins, CREB, and LTCC as
candidates to rescue the age-related deficits by manipulating their function with AAV vectors. We have
created AAV vectors targeting CREB and LTCC, and will continue the systematic characterization of their
potential as therapeutics for restoring the age-related deficits. The candidate Ca2+ binding protein genes to
manipulate will be determined from protein microarray experiments (a new powerful method to screen
expression level changes in hundreds of proteins), and confirmed through literature review and further
molecular (e.g., western blot) assays. In addition, we will identify the source(s) ofthe elevated Ca2+
accumulation in aged CAI neurons using Ca2+ imaging with two-photon laser scanning microscopy; and
thus, reveal additional potential therapeutic targets for intervention. Our goals remain unchanged: to confirm
that the AHP is the key regulator of intrinsic excitability and that targeted molecular methods to reduce the
AHP in CAI neurons in aged subjects will lead to successful learning. Continued success will indicate that
the protein being manipulated is a viable candidate to target as a therapeutic intervention point for age-
associated learning impairments. This research program has clear relevance to understanding and treating
neurodegenerative diseases such as Alzheimer's Disease, in which aging is the principal risk factor.
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Sex-Dependent Effects of Chronic Microdrive Implantation on Acquisition of Trace Eyeblink Conditioning.
慢性微驱动器植入对微量眨眼条件获得的性别依赖性影响。
DOI:
10.1016/j.nlm.2022.107649
发表时间:
2022
期刊:
Neurobiology of learning and memory
影响因子:
2.7
作者:
[Rapp,AmyP, Hark,TimothyJ, Power,JohnM, Savas,JefferyN, MatthewOh,M, Disterhoft,JohnF]
通讯作者:
Disterhoft,JohnF
Aging-related alterations in the distribution of Ca(2+)-dependent PKC isoforms in rabbit hippocampus.
兔海马中 Ca(2) 依赖性 PKC 异构体分布的衰老相关变化。
DOI:
10.1002/hipo.20000
发表时间:
2004
期刊:
Hippocampus
影响因子:
3.5
作者:
[VanderZee,EA, Palm,IF, O'Connor,M, Maizels,ET, Hunzicker-Dunn,M, Disterhoft,JF]
通讯作者:
Disterhoft,JF
Differential effects of alphaCaMKII mutation on hippocampal learning and changes in intrinsic neuronal excitability.
αCaMKII 突变对海马学习和内在神经元兴奋性变化的不同影响。
DOI:
10.1111/j.1460-9568.2006.04746.x
发表时间:
2006
期刊:
The European journal of neuroscience
影响因子:
--
作者:
[Ohno,Masuo, Sametsky,EvgenyA, Silva,AlcinoJ, Disterhoft,JohnF]
通讯作者:
Disterhoft,JohnF
DOI:
10.1002/hipo.23468
发表时间:
2022-10
期刊:
HIPPOCAMPUS
影响因子:
3.5
作者:
[Miller, Lisa N., Weiss, Craig, Disterhoft, John F.]
通讯作者:
Disterhoft, John F.
DOI:
10.1016/j.nlm.2019.107133
发表时间:
2020-01
期刊:
Neurobiology of learning and memory
影响因子:
2.7
作者:
[Oh MM, Disterhoft JF]
通讯作者:
Disterhoft JF
共 7 条
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Northwestern University Interdepartmental Neuroscience Postbaccalaureate Research Education Program
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依托单位:
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Predoctoral and postdoctoral training program in aging and dementia
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资助金额:$43.31万
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资助金额:$35.8万
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财政年份:2002
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负责人:JOHN F DISTERHOFT
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依托单位:
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