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Alcohol-related suppression of GIRK channel activity in the basal amygdala: a link to plasticity of glutamatergic neurotransmission and withdrawal-associated behavior?

Alcohol-related suppression of GIRK channel activity in the basal amygdala: a link to plasticity of glutamatergic neurotransmission and withdrawal-associated behavior?
与酒精相关的基底杏仁核 GIRK 通道活性抑制:与谷氨酸能神经传递的可塑性和戒断相关行为的联系?
批准号:
10554284
负责人:
KEVIN D WICKMAN
金额:
$34.0万
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
项目状态:
未结题
起止时间:
2020-02-20 至 2025-01-31

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中文摘要
翻译
项目摘要 酒精中毒和戒断的反复循环促进了大脑中调节情绪的区域的适应, 学习和目标导向的行为。这些适应被认为会促进焦虑的加剧,认知能力的增强, 缺陷和渴望-酒精使用障碍(AUD)的标志,合作促进强迫性药物- 寻求行为,增加复发的易感性,并阻碍适应行为的发展, 可以支持禁欲尽管AUD的治疗选择有限,但临床前和临床数据显示, GABAB受体(GABABR)作为治疗干预的潜在靶点, 减少对酒精的渴望和减少酒精的摄入。该项目的重点是乙醇诱导的 基底杏仁核中GABABR依赖性信号的适应-焦虑的关键底物以及 与奖励和厌恶体验相关的学习。使用两种不同的乙醇暴露模型, 反复的中毒循环中,我们发现体树突GABABR依赖性信号被抑制, 小鼠BA的主要神经元,在最后一次乙醇暴露后3 - 4天测量。述适配 在外侧杏仁核的主神经元或内侧前额叶/前边缘的锥体神经元中未见 皮质,也不是由重复可卡因引起的。这种适应是由于G蛋白门控的抑制, 内向整流K+(GIRK)通道活动,一个已知的焦虑相关行为的决定因素, 学习本项目的目标是了解的显着特点和机制,以及 神经生理学和行为学的影响,乙醇诱导的GIRK通道活性的抑制, BA主要神经元。这两个相互关联的目标是:(1)阐明乙醇的潜在机制, 诱导抑制GIRK通道活性。拟议的研究将采用离体技术 电生理学、免疫电子显微镜和神经元特异性病毒操作来验证这一假设 乙醇诱导的BA主神经元GIRK通道活性抑制是由 GIRK通道的GIRK3亚基依赖性内化。(2)了解下游 GIRK通道可塑性的神经生理和行为意义。拟议的研究将探讨 GIRK通道活动的抑制在BA主要神经元的影响,测试的假设,它 足以在离散BA投射中引起突触能神经传递的适应。同时, 适应焦虑相关行为的后果,联想(恐惧)学习,和自愿 在GIRK病毒遗传抑制后,将在乙醇初治小鼠中评价乙醇消耗量 BA主神经元的通道活动。摘要:该项目利用了一个 经验丰富的团队,以及定制研究工具的可用性,以调查以前未描述的 乙醇诱导的神经适应涉及对焦虑相关行为的已知影响, 学习该项目的成功完成可能会为治疗AUD的干预措施产生新的目标。
英文摘要
PROJECT SUMMARY Repeated cycles of alcohol intoxication and withdrawal foster adaptations in brain regions that regulate mood, learning, and goal-directed behavior. These adaptations are thought to promote heightened anxiety, cognitive deficits, and craving – hallmarks of alcohol use disorder (AUD) that collaborate to promote compulsive drug- seeking behavior, increase relapse susceptibility, and impede the development of adaptive behaviors that could support abstinence. Although treatment options for AUD are limited, preclinical and clinical data have generated interest in the GABAB receptor (GABABR) as a potential target for therapeutic interventions aimed at diminishing craving and reducing alcohol intake. The focus of this project is on an ethanol-induced adaptation in GABABR-dependent signaling in the basal amygdala – a key substrate of anxiety as well as learning related to rewards and aversive experiences. Using two distinct ethanol exposure models that yield repeated cycles of intoxication, we found that somatodendritic GABABR-dependent signaling is suppressed in principal neurons of the mouse BA, as measured 3-4 days after the last ethanol exposure. The adaptation is not seen in principal neurons of the lateral amygdala or pyramidal neurons of the medial prefrontal/prelimbic cortex, nor is it evoked by repeated cocaine. The adaptation is attributable to a suppression of G protein-gated inwardly rectifying K+ (GIRK) channel activity, a known determinant of anxiety-related behavior and associative learning. The goal of this project is to understand the salient features and mechanisms, as well as neurophysiological and behavioral implications, of the ethanol-induced suppression of GIRK channel activity in BA principal neurons. The two interrelated AIMs are to: (1) Elucidate mechanisms underlying the ethanol- induced suppression of GIRK channel activity. Proposed studies will employ techniques in ex vivo electrophysiology, immunoelectron microscopy, and neuron-specific viral manipulations to test the hypothesis that the ethanol-induced suppression of GIRK channel activity in BA principal neurons is mediated by the GIRK3 subunit-dependent internalization of GIRK channels. (2) Understand the downstream neurophysiological and behavioral implications of GIRK channel plasticity. Proposed studies will probe the implications of the suppression of GIRK channel activity in BA principal neurons, testing the hypothesis that it is sufficient to provoke adaptations in glutamatergic neurotransmission in discrete BA projections. In parallel, the consequences of the adaptation to anxiety-related behavior, associative (fear) learning, and voluntary ethanol consumption will be evaluated in ethanol-naïve mice, following viral genetic suppression of GIRK channel activity in BA principal neurons. Summary: This project leverages the complementary expertise of an experienced team, and the availability of custom research tools, to investigate a previously undescribed ethanol-induced neuroadaptation involving a known influence on anxiety-related behavior and associative learning. Successful completion of this project may yield new targets for interventions designed to treat AUD.
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Alcohol-related suppression of GIRK channel activity in the basal amygdala: a link to plasticity of glutamatergic neurotransmission and withdrawal-associated behavior?
  • 批准号:
    10330020
  • 项目类别:
  • 资助金额:
    $34.0万
  • 财政年份:
    2020
  • 负责人:
    KEVIN D WICKMAN
  • 依托单位:
Viral Innovation Core
  • 批准号:
    10634615
  • 项目类别:
  • 资助金额:
    $42.67万
  • 财政年份:
    2020
  • 负责人:
    KEVIN D WICKMAN
  • 依托单位:
Viral Innovation Core
  • 批准号:
    10413184
  • 项目类别:
  • 资助金额:
    $42.76万
  • 财政年份:
    2020
  • 负责人:
    KEVIN D WICKMAN
  • 依托单位:
Viral Innovation Core
  • 批准号:
    10200731
  • 项目类别:
  • 资助金额:
    $42.73万
  • 财政年份:
    2020
  • 负责人:
    KEVIN D WICKMAN
  • 依托单位:
海外基金