Parvalbumin interneurons regulate nucleus accumbens synapses and behavior

小清蛋白中间神经元调节伏隔核突触和行为

基本信息

  • 批准号:
    9174760
  • 负责人:
  • 金额:
    $ 37.61万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-08-01 至 2021-05-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Drug abuse and addiction remain a medical and societal burden with a relative paucity of prevention and treatment options. The nucleus accumbens (NAc) is an essential hub integrating cognitive, contextual, sensory and affective information into behavioral outcomes. Changes in excitatory synaptic function in the NAc is a leading molecular mechanism by which illicit drug exposure leads to the behavioral manifestations represented by addiction. While excitatory synaptic connections drive NAc neuronal firing, inhibitory synaptic transmission is important for coordinating and constraining neuronal excitability. Our work focuses on mechanisms of communication between NAc parvalbumin expressing fast-spiking interneurons (PV-FSIs) and specific medium spiny neuron subtypes (MSNs; D1 or D2 dopamine receptor expressing) in the NAc core. PV-FSIs, although limited in number, make vast inhibitory connections to MSNs thereby greatly influencing NAc output. Thus, PV- FSI synaptic activity is a putative mediator of NAc circuit adaptations. Changes in NAc excitatory and inhibitory circuit dynamics or the balance between excitation and inhibition, likely underlie addiction behaviors. Indeed, we find that manipulation of these PV-FSIs in the NAc modulate drug-related behaviors. Our data suggests that the strength of PV-FSI to MSN inhibitory synapses can be suppressed by endocannabinoid (eCB) signaling through cannabinoid receptor 1 (CB1R) and transient receptor potential vanillod 1 (TRPV1). We hypothesize that NAc PV-FSIs and MSNs communicate bi-directionally via the eCB system to regulate inhibitory synaptic function on MSNs underlying NAc-related behaviors and exposure to drugs of abuse leads to dysregulation of this process. In this grant, we will characterize the precise mechanisms by which PV-FSIs and eCB signaling at PV-FSI to MSN synapses mediate these actions. We will identify signaling mechanisms that alter synaptic strength at synapses onto NAc D1 or D2 MSNs using rigorous electrophysiological, optogenetic, and behavioral approaches in combinations of transgenic mouse lines. In turn, we will apply these protocols used to identify mechanisms of plasticity ex vivo to awake/behaving animals to determine behavioral responding. Furthermore, we will determine if manipulation of this signaling can regulate behavioral responding to drugs of abuse. The contribution of the proposed research is expected to be advancement in our knowledge of mechanisms by which PV-FSIs and more specifically, eCB signaling at PV-FSIs to MSN synapses, remodel NAc excitatory and inhibitory synaptic activity patterns and membrane firing properties, and the contribution this process likely plays in addiction-related disorders. These studies will identify mechanisms which can be exploited for the development of improved therapeutic tools for treating addiction.
项目概要 药物滥用和成瘾仍然是一个医疗和社会负担,预防和治疗相对缺乏。 治疗方案。伏隔核 (NAc) 是整合认知、情境、感觉的重要枢纽 并将情感信息转化为行为结果。 NAc 中兴奋性突触功能的变化是 非法药物暴露导致所代表的行为表现的主要分子机制 通过成瘾。兴奋性突触连接驱动 NAc 神经元放电,而抑制性突触传递 对于协调和限制神经元的兴奋性很重要。我们的工作重点是机制 表达 NAc 小清蛋白的快速尖峰中间神经元 (PV-FSIs) 与特定介质之间的通讯 NAc 核心中的多棘神经元亚型(MSN;表达 D1 或 D2 多巴胺受体)。 PV-FSI,尽管 数量有限,与 MSN 建立广泛的抑制性连接,从而极大地影响 NAc 输出。因此,PV- FSI 突触活动是 NAc 回路适应的假定介质。 NAc 兴奋性和抑制性的变化 电路动力学或兴奋与抑制之间的平衡可能是成瘾行为的基础。的确, 我们发现在 NAc 中操纵这些 PV-FSI 可以调节药物相关行为。我们的数据表明 PV-FSI 对 MSN 抑制性突触的强度可以被内源性大麻素 (eCB) 抑制 通过大麻素受体 1 (CB1R) 和瞬时受体电位 vanillod 1 (TRPV1) 发出信号。我们 假设 NAc PV-FSI 和 MSN 通过 eCB 系统进行双向通信以调节 MSN 上的抑制性突触功能是 NAc 相关行为和滥用药物导致的暴露 导致这个过程的失调。在这笔赠款中,我们将描述 PV-FSI 的精确机制 PV-FSI 到 MSN 突触的 eCB 信号传导介导这些动作。我们将确定信号机制 使用严格的电生理学方法改变​​ NAc D1 或 D2 MSN 上突触的突触强度, 转基因小鼠品系组合的光遗传学和行为方法。反过来,我们将应用这些 用于识别清醒/行为动物离体可塑性机制以确定行为的协议 回应。此外,我们将确定操纵该信号是否可以调节行为反应 滥用药物。拟议研究的贡献预计将促进我们的知识进步 PV-FSIs 的机制,更具体地说,PV-FSIs 到 MSN 突触的 eCB 信号传导,重塑 NAc 兴奋性和抑制性突触活动模式和膜放电特性及其贡献 这个过程很可能在与成瘾相关的疾病中发挥作用。这些研究将确定可 用于开发治疗成瘾的改进治疗工具。

项目成果

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Brad Alan Grueter其他文献

Brad Alan Grueter的其他文献

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{{ truncateString('Brad Alan Grueter', 18)}}的其他基金

Photoperiodic Programming of Monoamine Brain Circuits
单胺脑回路的光周期编程
  • 批准号:
    10735447
  • 财政年份:
    2023
  • 资助金额:
    $ 37.61万
  • 项目类别:
Parvalbumin interneurons regulate nucleus accumbens synapses and behavior
小白蛋白中间神经元调节伏隔核突触和行为
  • 批准号:
    10487428
  • 财政年份:
    2016
  • 资助金额:
    $ 37.61万
  • 项目类别:
Parvalbumin interneurons regulate nucleus accumbens synapses and behavior
小清蛋白中间神经元调节伏隔核突触和行为
  • 批准号:
    10298824
  • 财政年份:
    2016
  • 资助金额:
    $ 37.61万
  • 项目类别:
Parvalbumin interneurons regulate nucleus accumbens synapses and behavior
小白蛋白中间神经元调节伏隔核突触和行为
  • 批准号:
    10161984
  • 财政年份:
    2016
  • 资助金额:
    $ 37.61万
  • 项目类别:
Parvalbumin interneurons regulate nucleus accumbens synapses and behavior
小清蛋白中间神经元调节伏隔核突触和行为
  • 批准号:
    9923260
  • 财政年份:
    2016
  • 资助金额:
    $ 37.61万
  • 项目类别:
Parvalbumin interneurons regulate nucleus accumbens synapses and behavior
小清蛋白中间神经元调节伏隔核突触和行为
  • 批准号:
    10675558
  • 财政年份:
    2016
  • 资助金额:
    $ 37.61万
  • 项目类别:
Parvalbumin interneurons regulate nucleus accumbens synapses and behavior
小白蛋白中间神经元调节伏隔核突触和行为
  • 批准号:
    9698739
  • 财政年份:
    2016
  • 资助金额:
    $ 37.61万
  • 项目类别:
Synaptic Mechanisms of Addiction-Related Behaviors in the Nucleus Accumbens
伏核成瘾相关行为的突触机制
  • 批准号:
    8585390
  • 财政年份:
    2013
  • 资助金额:
    $ 37.61万
  • 项目类别:
Synaptic Mechanisms of Addiction-Related Behaviors in the Nucleus Accumbens
伏核成瘾相关行为的突触机制
  • 批准号:
    8637959
  • 财政年份:
    2013
  • 资助金额:
    $ 37.61万
  • 项目类别:
Synaptic Mechanisms of Addiction-Related Behaviors in the Nucleus Accumbens
伏核成瘾相关行为的突触机制
  • 批准号:
    8825475
  • 财政年份:
    2013
  • 资助金额:
    $ 37.61万
  • 项目类别:

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