Microcircuit, cellular and molecular dissection of impaired hippocampal function in a mouse model of the 22q11.2 deletion

22q11.2 缺失小鼠模型海马功能受损的微电路、细胞和分子解剖

基本信息

  • 批准号:
    10241386
  • 负责人:
  • 金额:
    $ 76.03万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

Schizophrenia is a debilitating psychiatric disorder that effects 1% of the population, with an additional 2-3% developing a schizoaffective disorder. SCZ patients exhibit a spectrum of cognitive deficits including defective episodic memory, present prior to the onset of psychosis and frequently expressed in relatives of affected individuals. Episodic memory formation is dictated in part by spatially tuned (place cell) activity of principal cells in the hippocampus. The biological mechanisms driving this learning capacity in the healthy hippocampus remain largely unknown, let alone their disruption in schizophrenia, leaving large gaps in our knowledge that need to be addressed. Using in vivo functional imaging in mouse dorsal hippocampal area CA1 during head-fixed during learning behaviors, we recently uncovered specific alterations in in vivo physiological properties of CA1 pyramidal cells in the Df(16)A+/− transgenic mouse model of 22q11.2 deletion syndrome, the largest known genetic risk to develop SCZ. Df(16)A+/− CA1 place cells exhibit reduced long-term stability, impaired context- related and lack of reward-related reorganization. A novel form of synaptic plasticity, termed behavioral time- scale synaptic plasticity (BTSP), has been found to drive rapid formation of spatially selective firing fields in CA1 pyramidal cells; notably, our preliminary studies suggest that this form of plasticity is dysregulated in Df(16)A+/− mice. We thus hypothesize that BTSP, a major form of plasticity that drives place cell-recruitment during learning, is disrupted by SCZ risk mutations. These findings at the neuronal population level provide entry points for dissecting the underlying cellular, molecular and microcircuit dysfunctions caused by schizophrenia risk mutations. To gain these mechanistic insights we will unite the complementary expertise of the Losonczy lab and the Gogos lab in etiologically valid genetic mouse models of neuropsychiatric disorders to carry out multiscale dissection of microcircuit, cellular and molecular pathophysiology of schizophrenia-related memory deficits in the adult mouse hippocampal CA1 circuitry. Aim 1 is aimed at assessing altered synaptic plasticity in CA1 pyramidal cells during episodic learning in Df(16)A+/− mice. Aim 2 deals with dissecting inhibitory microcircuit dynamics during episodic learning, while Aim 3 is focused at dissecting altered excitatory and neuromodulatory input dynamics to CA1 during episodic learning in Df(16)A+/− mice. Taken together, Aims 1-3 provide a tractable path to a deeper, mechanistic understanding of hippocampus-related cognitive memory deficits in schizophrenia.
精神分裂症是一种使人衰弱的精神疾病,影响1%的人口,另外还有2-3%的人。 患上了情感障碍SCZ患者表现出一系列的认知缺陷,包括缺陷的 情景记忆,在精神病发作之前存在,经常在受影响的亲属中表达 个体情景记忆的形成部分取决于主体的空间调谐(位置细胞)活动。 海马体中的细胞在健康的海马体中驱动这种学习能力的生物机制 仍然在很大程度上未知,更不用说他们在精神分裂症中的破坏,在我们的知识中留下了很大的空白, 需要解决的问题在体脑功能成像在小鼠头固定过程中海马CA 1区的应用 在学习行为过程中,我们最近发现了CA 1在体内生理特性的特定改变, 22q11.2缺失综合征的Df(16)A+/−转基因小鼠模型中的锥体细胞, 遗传风险发展SCZ。Df(16)A+/− CA 1位置细胞表现出长期稳定性降低,背景受损, 相关和缺乏奖励相关的重组。一种新形式的突触可塑性,被称为行为时间- 尺度突触可塑性(BTSP),已被发现驱动在CA 1的空间选择性放电场的快速形成 锥体细胞;值得注意的是,我们的初步研究表明,这种形式的可塑性在Df(16)A+/−中失调, 小鼠因此,我们假设BTSP,一种主要形式的可塑性,驱动位置细胞的招聘过程中, 学习,被SCZ风险突变破坏。这些在神经元群体水平上的发现提供了切入点 用于剖析精神分裂症风险引起的潜在细胞、分子和微电路功能障碍 突变。为了获得这些机制的见解,我们将联合Losonczy实验室的互补专业知识, Gogos实验室在神经精神疾病的病因学有效的遗传小鼠模型中进行多尺度 精神分裂症相关记忆缺陷的微电路、细胞和分子病理生理学解剖 成年小鼠海马CA 1区回路。目的1旨在评估CA 1中改变的突触可塑性 Df(16)A+/−小鼠在情景学习过程中的锥体细胞。目标2涉及解剖抑制微电路 动态在情节学习,而目标3是专注于解剖改变兴奋性和神经调节 在Df(16)A+/−小鼠的情景学习过程中对CA 1的输入动力学。总的来说,目标1-3提供了一个易于处理的 路径到一个更深层次的,机械的理解与校园相关的认知记忆缺陷, 精神分裂症

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 }}

JOSEPH A GOGOS其他文献

JOSEPH A GOGOS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('JOSEPH A GOGOS', 18)}}的其他基金

Microcircuit, cellular and molecular dissection of impaired hippocampal function in a mouse model of the 22q11.2 deletion
22q11.2 缺失小鼠模型海马功能受损的微电路、细胞和分子解剖
  • 批准号:
    10441594
  • 财政年份:
    2020
  • 资助金额:
    $ 76.03万
  • 项目类别:
Discovery and analysis of brain circuits and cell types affected in autism and schizophrenia
发现和分析受自闭症和精神分裂症影响的大脑回路和细胞类型
  • 批准号:
    10673200
  • 财政年份:
    2020
  • 资助金额:
    $ 76.03万
  • 项目类别:
Discovery and analysis of brain circuits and cell types affected in autism and schizophrenia
发现和分析受自闭症和精神分裂症影响的大脑回路和细胞类型
  • 批准号:
    10100970
  • 财政年份:
    2020
  • 资助金额:
    $ 76.03万
  • 项目类别:
Microcircuit, cellular and molecular dissection of impaired hippocampal function in a mouse model of the 22q11.2 deletion
22q11.2 缺失小鼠模型海马功能受损的微电路、细胞和分子解剖
  • 批准号:
    10643829
  • 财政年份:
    2020
  • 资助金额:
    $ 76.03万
  • 项目类别:
Microcircuit, cellular and molecular dissection of impaired hippocampal function in a mouse model of the 22q11.2 deletion
22q11.2 缺失小鼠模型海马功能受损的微电路、细胞和分子解剖
  • 批准号:
    10044137
  • 财政年份:
    2020
  • 资助金额:
    $ 76.03万
  • 项目类别:
Discovery and analysis of brain circuits and cell types affected in autism and schizophrenia
发现和分析受自闭症和精神分裂症影响的大脑回路和细胞类型
  • 批准号:
    10264058
  • 财政年份:
    2020
  • 资助金额:
    $ 76.03万
  • 项目类别:
Deciphering the role of histone methyltransferase SETD1A in schizophrenia susceptibility
破译组蛋白甲基转移酶 SETD1A 在精神分裂症易感性中的作用
  • 批准号:
    9288683
  • 财政年份:
    2017
  • 资助金额:
    $ 76.03万
  • 项目类别:
The role of GABA-mimetic metabolites in neurodevelopmental and neuropsychiatric d
GABA 模拟代谢物在神经发育和神经精神疾病中的作用
  • 批准号:
    8675291
  • 财政年份:
    2013
  • 资助金额:
    $ 76.03万
  • 项目类别:
The role of GABA-mimetic metabolites in neurodevelopmental and neuropsychiatric d
GABA 模拟代谢物在神经发育和神经精神疾病中的作用
  • 批准号:
    8492293
  • 财政年份:
    2013
  • 资助金额:
    $ 76.03万
  • 项目类别:
Mechanisms underlying the functional connectivity deficit in the 22q11 microdelet
22q11 微缺失功能连接缺陷的潜在机制
  • 批准号:
    8881316
  • 财政年份:
    2012
  • 资助金额:
    $ 76.03万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 76.03万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 76.03万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 76.03万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 76.03万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 76.03万
  • 项目类别:
    Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 76.03万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 76.03万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 76.03万
  • 项目类别:
    EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 76.03万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 76.03万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了