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Neurobehavioral mechanisms of a glucocorticoid-induced animal model of chronic depression.

机译：糖皮质激素诱导的慢性抑郁症动物模型的神经行为机制。

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摘要

Alterations in cellular survival and plasticity are implicated in the neurobiology of depression, based primarily on the characterization of antidepressant efficacy in naive rodents rather than on models that capture the protracted feelings of anhedonia and helplessness, behavioral inflexibility, and diminished goal-directed action that characterize depression.;A history of life stressors acts as a significant predictor for depression, so we first generated evidence that chronic exposure to the major stress-associated adrenal hormone, corticosterone, induces persistent, antidepressant-sensitive helplessness-like and anhedonic-like behavior, as well as decreased instrumental responding for food reinforcement under conditions of diminishing reinforcement availability in mice, modeling amotivation and behavioral inflexibility in depression. Several biological mechanisms of action were next implicated: First, dorsal hippocampal Brain-derived Neurotrophic Factor (BDNF) appeared to be involved in decreased hedonic sensitivity to reward via Extracellular-signal Regulated Kinase 1/2. Next, experiments using selective viral-mediated Bdnf knock-down indicated that BDNF in the medial prefrontal cortex (PFC) also regulates instrumental responding for food and its restoration by antidepressant treatment.;Based on these data, the bdnf+/- mutant mouse might be expected to be a strong candidate transgenic mouse for studying mechanisms of depressive-like behavioral responding. I show, however, that constitutive loss of Bdnf and downstream intracellular signaling relieves an inhibitory influence from the medial orbitofrontal cortex on instrumental responding, rendering the bdnf+/- mouse fundamentally insensitive to reward value.;A history of corticosterone exposure also chronically regulates rodent behavior via several glutamatergic targets: I will conclude this report with evidence that corticosterone impairs fear extinction consolidation---another learning process requiring prefrontal neural integrity---via decreased GluR2/3 and NR2B AMPA and NMDA subunit expression. Moreover, corticosterone increases GluR1 expression in the ventral hippocampus, a major regulator of the nucleus accumbens, and increased glutamatergic activity here may contribute to insensitivity to appetitive reinforcement after corticosterone.;Together, these data point to selective roles for regionally-sensitive patterns of BDNF and AMPA receptor subunit expression after chronic glucocorticoid exposure in: (1) regulating the hedonic responsiveness to, and motivation to acquire, appetitive reinforcement; and (2) interfering with the neural systems that maintain flexible responding under conditions of uncertain environmental outcomes or reward availability.
机译：细胞存活率和可塑性的改变与抑郁症的神经生物学有关，这主要是基于幼稚啮齿动物的抗抑郁药功效的表征，而不是基于捕获了长时间的快感和无助感，行为僵硬以及目标导向的行为减少的模型生活压力源的历史可以作为抑郁症的重要预测因子，因此我们首先获得证据，证明长期暴露于与压力相关的主要肾上腺激素皮质酮会导致持续，抗抑郁药敏感的无助感和无性行为感行为，以及在减少小鼠中增强物的有效性，模拟抑郁症的动机和行为僵化的条件下，减少食物增强的工具响应。接下来涉及到几种生物学作用机制：首先，背海马脑源性神经营养因子（BDNF）似乎参与了享乐主义敏感性的降低，以通过细胞外信号调节激酶1/2进行奖励。接下来，使用选择性病毒介导的Bdnf敲除的实验表明，内侧前额叶皮层（PFC）中的BDNF还调节食物对食物的反应以及通过抗抑郁药治疗对其的恢复。基于这些数据，bdnf +/-突变小鼠可能是有望成为研究抑郁样行为反应机制的强大候选转基因小鼠。然而，我发现Bdnf的组成性丧失和下游细胞内信号转导缓解了眶额叶内侧皮质对工具性反应的抑制作用，使bdnf +/-小鼠对奖励价值基本上不敏感。;皮质酮的暴露史也长期调节着啮齿动物的行为通过一些谷氨酸能靶点：我将以证据证明皮质酮通过减少GluR2 / 3和NR2B AMPA和NMDA亚基的表达来削弱恐惧的消退巩固-这是另一个需要前额神经完整性的学习过程。此外，皮质酮会增加腹伏海马（伏隔核的主要调节剂）中GluR1的表达，并且增加的谷氨酸能活性可能会导致皮质酮后对食欲增强的不敏感性。在一起，这些数据共同表明了BDNF区域敏感型的选择性作用慢性糖皮质激素暴露后的AMPA受体亚基表达：（1）调节享乐对食欲增强的反应性和获得性的动机； （2）干扰在不确定的环境结果或奖励可用性条件下保持灵活响应的神经系统。

著录项

  • 作者

    Gourley, Shannon Leigh.;

  • 作者单位

    Yale University.;

  • 授予单位 Yale University.;
  • 学科 Psychobiology.;Neurosciences.;Pharmacology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 264 p.
  • 总页数 264
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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