Adolescent intermittent ethanol induction of neuroimmune signaling disrupts the mature phenotype of surviving hippocampal neuroprogenitors

青少年间歇性乙醇诱导神经免疫信号破坏存活海马神经祖细胞的成熟表型

基本信息

项目摘要

PROJECT SUMMARY Adolescent binge drinking hijacks the developing brain, resulting in long-lasting increases in neuroinflammation which are paralleled by decreases in hippocampal neurogenesis and deficits in learning and memory-related tasks. Unlike adult alcohol exposure, the cellular and behavioral effects of adolescent binge drinking do not recover following periods of abstinence, suggesting that alcohol exposure across adolescence permanently disrupts the brain’s developmental trajectory. However, while prior research has focused on the underlying mechanisms driving this loss and restoration of newborn hippocampal neurons, no research has investigated how adolescent intermittent ethanol (AIE) impacts the ability of surviving hippocampal neuroprogenitor cells (NPCs) to appropriately integrate into adult hippocampal circuitry. Newborn neurons assimilate into dentate circuitry in an activity dependent manner which is sensitive to shifts in the balance between neuronal excitation and inhibition as well as neuroinflammatory signaling. Any disruption in this integration could have profound consequences on learning and memory functions as granular cells are a gatekeeper for downstream activation of hippocampal circuitry. To test the impact of adolescent alcohol on network integration of developing neurons, we will use a reporter mouse line (DCX-CreERT2/tdtomato) which was developed to specifically tag and then fate-map NPCs across their lifespan. This technique will allow us to track how alcohol impacts the ability of adolescent maturing neurons to effectively integrate into mature dentate circuitry. By combining this transgenic model with 5-ethynyl-2'-deoxyuridine, we will test whether adolescent alcohol exposure induces adult innate immune gene expression preferentially in adolescent-maturing NPCs and glia, and we will also test whether AIE impairs formation of dendritic arborization in adolescent-maturing NPCs (AIM 1/K99). We will then test whether adolescent alcohol impairs the electrophysiological properties of these adolescent-maturing NPCs in adulthood (AIM 2/K99). As it remains unclear whether maturational changes in adolescent maturing neurons mediate cognitive-behavioral deficits, we will test whether AIE disrupts immediate early gene expression in adolescent-maturing NPCs following reversal learning in the Morris water maze, novel object recognition memory, and social dominance behaviors in adulthood (AIM 3/K99). Finally, while preliminary data suggest that anti-inflammatory interventions can reverse neurogenic and behavioral deficits after AIE in both sexes, whether anti-inflammatory pharmacological interventions (e.g., indomethacin) can similarly restore morphological and physiological maturation, circuit integration, and innate immune gene expression in adolescent-maturing NPCs in adulthood is unknown (AIM 4/R00). Collectively, these experiments will provide critical insight into the impact of adolescent alcohol on the resulting phenotypic fate and circuit regulation of surviving NPCs in both sexes.
项目摘要 青少年酗酒劫持了发育中的大脑,导致神经炎症的长期增加 这是由海马神经发生减少和学习和记忆相关的缺陷引起的。 任务与成人酒精暴露不同,青少年酗酒对细胞和行为的影响并不 在禁欲期后恢复,这表明青春期的酒精暴露 会扰乱大脑的发育轨迹然而,虽然先前的研究集中在潜在的 驱动新生海马神经元丢失和恢复的机制,没有研究调查 青少年间歇性乙醇(AIE)如何影响海马神经祖细胞存活的能力 (NPC)适当整合到成人海马电路。新生神经元同化成齿状核 以活动依赖的方式,其对神经元兴奋之间的平衡的变化敏感 和抑制以及神经炎症信号。这种整合的任何中断都可能产生深远的影响。 颗粒细胞是下游激活的看门人, 海马体回路。测试青少年饮酒对发展中国家网络整合的影响, 神经元,我们将使用报告小鼠系(DCX-CreERT 2/tdtomato),其被开发用于特异性标记 然后绘制NPC的一生命运图这项技术将使我们能够跟踪酒精如何影响 青少年成熟神经元有效整合到成熟齿状回的能力。通过组合该 转基因模型与5-乙炔基-2 '-脱氧尿苷,我们将测试是否青少年酒精暴露诱导 成人先天性免疫基因表达优先在发育成熟的NPC和神经胶质细胞,我们还将 测试AIE是否损害在促分化成熟的NPC(AIM 1/K99)中树突状分支的形成。我们将 然后测试青少年饮酒是否会损害这些神经元的电生理特性, 成年期的NPC(AIM 2/K99)。由于尚不清楚青少年成熟过程中的成熟变化 神经元介导认知行为缺陷,我们将测试AIE是否破坏了即刻早期基因, 在Morris水迷宫中逆转学习后, 再认记忆和成年期社会优势行为(AIM 3/K99)。虽然初步数据显示 提示抗炎干预可以逆转AIE后的神经和行为缺陷, 性别,是否抗炎药物干预(例如,吲哚美辛)可以类似地恢复 形态和生理成熟,电路整合和先天免疫基因表达, 成年期的NPC是否会发育成熟尚不清楚(AIM 4/R 00)。总的来说,这些实验将提供 关键洞察到青少年酒精对由此产生的表型命运和电路调节的影响, 两种性别的幸存NPC。

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 }}

Victoria Alice Macht其他文献

Victoria Alice Macht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 }}

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:
    $ 12.55万
  • 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:
    $ 12.55万
  • 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:
    $ 12.55万
  • 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:
    $ 12.55万
  • 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:
    $ 12.55万
  • 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:
    $ 12.55万
  • 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:
    $ 12.55万
  • 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:
    $ 12.55万
  • 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:
    $ 12.55万
  • 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:
    $ 12.55万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了