Reverse Translation of Psychosis - associated Hippocampal Hyperactivity in the mouse
精神病相关的小鼠海马过度活跃的反向翻译
基本信息
- 批准号:10670252
- 负责人:
- 金额:$ 41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdolescenceAdolescentAdultAffectAgeAmygdaloid structureAnatomyAnimal BehaviorAnimal TestingAnimalsAreaAttenuatedAutopsyBackBehaviorBehavioralBrainBrain DiseasesBrain PathologyBrain imagingBrain-Derived Neurotrophic FactorCell Culture TechniquesCharacteristicsCognitiveDLG4 geneDevelopmentDiseaseElectrophysiology (science)Functional disorderGene ExpressionGenerationsGeneticGlutamate ReceptorGoalsGolgi ApparatusHippocampusHumanHyperactivityImage AnalysisKnock-outKnockout MiceMedialMediatingMemoryModelingMolecularMusNMDA receptor A1NeurobiologyNeuronsNucleus AccumbensOutcomePathologyPathway interactionsPatternPhasePhenotypePrefrontal CortexPreparationProteinsPsychosesPyramidal CellsReportingSamplingSchizophreniaSignal TransductionSiteStructureSynapsesTechniquesTestingTimeTissuesTranslationsWorkbehavioral outcomebrain tissuecomparison controlcritical perioddentate gyrusdesigner receptors exclusively activated by designer drugsexperimental studyhuman tissueknockout animalmolecular markermolecular pathologymossy fiberpsychotictranscriptometransmission process
项目摘要
ABSTRACT
The hippocampus has been implicated in numerous functions related to normal memory and its dysfunction in
several diseases. Our lab has investigated the hippocampus in relation to schizophrenia (SZ) pathophysiology
using cognitive and behavioral outcomes(1-3) and brain image analyses(4-6). These consistently show that
hippocampal (Hipp) activity is elevated in schizophrenic psychosis (SZ), especially in early illness. To test the
molecular basis of this hyperactivity, we examined human postmortem hippocampal tissue by subfield,
contrasting healthy and schizophrenia cases, using excitatory and inhibitory synaptic markers and Golgi. We
found a reduction in GluN1 limited to dentate gyrus (DG) and an increase in markers of synaptic strength in CA3
in the SZ tissue; these changes are consistent with the observations that Lee et al(7) reported in hippocampal
cell cultures (see A.1). Lee showed that CA3 pyramidal cell sensitivity is inversely and powerfully controlled by
afferent input from DG, with decreased afferent input associated with increased pyramidal cell activity. We have
been able to recapitulate this human-specific SZ pathology in a mouse using a DG-selective GluN1 knock out
(KO)(8). This back-translation mouse KO demonstrated Hipp hyperactivity and alterations in Hipp-mediated
behaviors (8). We are piloting an inhibitory DREADD technique in DG to mimic the DG-selective GluN1 KO
mouse and saw evidence of a sensitive period during ‘adolescence’, when reduced DG activity could stimulate
hyperactivity in CA3/CA1. This time phase cannot be resolved in the KO animal, so we had not seen it before
and can only study it using DREADDs. The goal of these experiments are to causally define the mechanisms
underlying the neurobiological outcomes of temporary DG hypofunction in mouse using DREADD constructs,
and to show the extent, development, and critical periods of vulnerability of brain-wide changes. Having found
a discrete circuit of Hipp projection regions hyperactive in the KO mouse, we will test human SZ vs HC tissue in
these regions for evidence of hyperactivity and coherence with Hipp. The goal is to build a model of how
hippocampal hyperactivity affects behavior and brain pathology, and specifically how this tissue pathology could
support aberrant memories with psychotic content.
摘要
海马体与许多与正常记忆相关的功能有关,
几种疾病。本实验室研究了海马与精神分裂症(SZ)病理生理学的关系
使用认知和行为结果(1-3)和大脑图像分析(4-6)。这些一致表明,
海马(Hipp)活性在精神分裂症性精神病(SZ)中升高,特别是在早期疾病中。测试
这种活动过度的分子基础,我们检查了人死后海马组织的亚区,
对照健康和精神分裂症病例,使用兴奋性和抑制性突触标记和高尔基体。我们
发现仅限于齿状回(DG)的GluN 1减少,CA 3中突触强度标记物增加
这些变化与Lee等人(7)在海马组织中报告的观察结果一致。
细胞培养物(见A.1)。Lee表明,CA 3锥体细胞敏感性是由
来自DG的传入输入,传入输入减少与锥体细胞活动增加相关。我们有
我能够使用DG选择性GluN 1敲除在小鼠中重现这种人类特异性SZ病理
(KO)(8).这种反向翻译小鼠KO证明了Hipp的过度活跃和Hipp介导的细胞凋亡的改变。
行为(8)。我们正在DG中试验抑制性DREADD技术,以模拟DG选择性GluN 1 KO
小鼠和看到的证据,一个敏感的时期,在'中毒',当减少DG活动可以刺激
CA 3/CA 1过度活跃。在KO动物中无法分辨该时间相,因此我们之前未发现
只能用DREADDs来研究这些实验的目的是因果定义的机制
作为使用DREADD构建体的小鼠中暂时DG功能减退的神经生物学结果的基础,
并显示全脑变化的程度、发展和脆弱性的关键时期。找到了
在KO小鼠中Hipp投射区域过度活跃的离散回路中,我们将测试人类SZ与HC组织,
这些地区的证据多动症和连贯性与Hipp。目标是建立一个模型,
海马过度活跃影响行为和大脑病理学,特别是这种组织病理学如何能够
支持异常记忆的精神病内容
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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Carol A Tamminga其他文献
842. Changes in Hippocampal Subfield Activity Contribute to Psychosis-Like Behaviors in Mice
- DOI:
10.1016/j.biopsych.2017.02.567 - 发表时间:
2017-05-15 - 期刊:
- 影响因子:
- 作者:
Daniel Scott;Carol A Tamminga - 通讯作者:
Carol A Tamminga
The human brain.
- DOI:
10.1176/appi.ajp.161.7.1169 - 发表时间:
2004-07 - 期刊:
- 影响因子:0
- 作者:
Carol A Tamminga - 通讯作者:
Carol A Tamminga
ΔFosB in brain reward circuits mediates resilience to stress and antidepressant responses
大脑奖赏回路中的ΔFosB 介导对应激的恢复力和抗抑郁反应
- DOI:
10.1038/nn.2551 - 发表时间:
2010-05-16 - 期刊:
- 影响因子:20.000
- 作者:
Vincent Vialou;Alfred J Robison;Quincey C LaPlant;Herbert E Covington;David M Dietz;Yoshinori N Ohnishi;Ezekiell Mouzon;Augustus J Rush;Emily L Watts;Deanna L Wallace;Sergio D Iñiguez;Yoko H Ohnishi;Michel A Steiner;Brandon L Warren;Vaishnav Krishnan;Carlos A Bolaños;Rachael L Neve;Subroto Ghose;Olivier Berton;Carol A Tamminga;Eric J Nestler - 通讯作者:
Eric J Nestler
The Texas child mental health network: A child and adolescent research registry
德克萨斯州儿童心理健康网络:儿童和青少年研究登记处
- DOI:
10.1016/j.pmip.2024.100124 - 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Carol A Tamminga;Madhukar H. Trivedi;K. D. Wagner;S. Wakefield;D. Jeffrey Newport;James Norcross;David L. Lakey;Charlie Nemeroff - 通讯作者:
Charlie Nemeroff
62. Acoustic Startle Latency is Prolonged in Schizophrenia in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) Cohort
- DOI:
10.1016/j.biopsych.2017.02.073 - 发表时间:
2017-05-15 - 期刊:
- 影响因子:
- 作者:
Nicholas Massa;Arpita Bhattacharya;John A Sweeney;Godfrey D Pearlson;Matcheri S Keshavan;Carol A Tamminga;Brett A Clementz;Erica Duncan - 通讯作者:
Erica Duncan
Carol A Tamminga的其他文献
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{{ truncateString('Carol A Tamminga', 18)}}的其他基金
1/5 - Biomarkers/Biotypes, Course of Early Psychosis and Specialty Services (BICEPS)
1/5 - 生物标志物/生物型、早期精神病课程和专业服务 (BICEPS)
- 批准号:
10683302 - 财政年份:2022
- 资助金额:
$ 41万 - 项目类别:
Reverse Translation of Psychosis - associated Hippocampal Hyperactivity in the mouse
精神病相关的小鼠海马过度活跃的反向翻译
- 批准号:
10473803 - 财政年份:2021
- 资助金额:
$ 41万 - 项目类别:
1/5 - Selective Antipsychotic Response to Clozapine in B-SNIP Biotype-1 (Clozapine)
1/5 - B-SNIP Biotype-1(氯氮平)中对氯氮平的选择性抗精神病反应
- 批准号:
10397393 - 财政年份:2021
- 资助金额:
$ 41万 - 项目类别:
1/5 - Selective Antipsychotic Response to Clozapine in B-SNIP Biotype-1 (Clozapine)
1/5 - B-SNIP Biotype-1(氯氮平)中对氯氮平的选择性抗精神病反应
- 批准号:
10097226 - 财政年份:2021
- 资助金额:
$ 41万 - 项目类别:
1/5 - Selective Antipsychotic Response to Clozapine in B-SNIP Biotype-1 (Clozapine)
1/5 - B-SNIP Biotype-1(氯氮平)中对氯氮平的选择性抗精神病反应
- 批准号:
10614443 - 财政年份:2021
- 资助金额:
$ 41万 - 项目类别:
Psychosis and Affective Research Domains and Intermediate Phenotypes (PARDIP)
精神病和情感研究领域和中间表型(PARDIP)
- 批准号:
8920187 - 财政年份:2013
- 资助金额:
$ 41万 - 项目类别:
Psychosis and Affective Research Domains and Intermediate Phenotypes (PARDIP)
精神病和情感研究领域和中间表型(PARDIP)
- 批准号:
8706964 - 财政年份:2013
- 资助金额:
$ 41万 - 项目类别:
Psychosis and Affective Research Domains and Intermediate Phenotypes (PARDIP)
精神病和情感研究领域和中间表型(PARDIP)
- 批准号:
8507371 - 财政年份:2013
- 资助金额:
$ 41万 - 项目类别:
Epigenetic Mechanisms of Depression in Human Limbic Circuits
人类边缘回路抑郁的表观遗传机制
- 批准号:
9279582 - 财政年份:2012
- 资助金额:
$ 41万 - 项目类别:
Project 5-CREB and the other targets in Projects 1-4 in reward regions in depress
项目 5-CREB 和项目 1-4 中奖励地区的其他目标位于抑郁症地区
- 批准号:
8114145 - 财政年份:2010
- 资助金额:
$ 41万 - 项目类别:
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