Antidepressant-like cognitive and behavioral effects of acute ketamine administration associated with plasticity in the ventral hippocampus to medial prefrontal cortex pathway.
Antidepressant-like cognitive and behavioral effects of acute ketamine administration associated with plasticity in the ventral hippocampus to medial prefrontal cortex pathway.
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DOI：
10.1007/s00213-015-3957-3
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发表时间：
2015-09
影响因子：
3.4
通讯作者：
Morilak DA
中科院分区：
文献类型：
--
作者：
Jett JD;Boley AM;Girotti M;Shah A;Lodge DJ;Morilak DA
急性低剂量给予NMDA受体拮抗剂氯胺酮，在人类和啮齿动物中产生快速和持续的抗抑郁样作用。最近，我们发现氯胺酮对强迫游泳试验的持久作用需要给药时腹侧海马（vHipp）的活动。内侧前额叶皮层（mPFC）是vHipp在抑郁症中失调的靶点，对认知灵活性和反应策略选择具有重要作用。认知灵活性的缺陷，即根据环境变化改变思想和行为的能力，与抑郁症有关。我们已经证明，慢性应激损害认知灵活性的注意定势转换测试（AST），并诱导从主动到被动的反应策略的冲击探头防御性掩埋测试（SPDB）。在这项研究中，我们测试了氯胺酮对慢性应激引起的认知灵活性和应对行为的变化的影响，分别对AST和SPDB。随后，我们研究了vHipp-mPFC可塑性作为氯胺酮治疗作用的潜在机制。氯胺酮逆转了认知灵活性的缺陷，并恢复了慢性应激大鼠的积极应对行为。此外，vHipp中的高频刺激复制了氯胺酮对强迫游泳试验和AST的抗抑郁样作用，但对SPDB没有。这些结果表明，氯胺酮恢复认知灵活性和应对策略受到压力的影响。vHipp-mPFC通路中的活性可能代表氯胺酮的一些抗抑郁样行为效应（包括认知灵活性）的神经底物，但其他回路可能介导氯胺酮对应对反应策略的影响。
Acute low-dose administration of the NMDA receptor antagonist, ketamine, produces rapid and sustained antidepressant-like effects in humans and rodents. Recently, we found that the long-lasting effect of ketamine on the forced swim test requires ventral hippocampal (vHipp) activity at the time of drug administration. The medial prefrontal cortex (mPFC), a target of the vHipp dysregulated in depression, is important for cognitive flexibility and response strategy selection. Deficits in cognitive flexibility, the ability to modify thoughts and behaviors in response to changes in the environment, are associated with depression. We have shown that chronic stress impairs cognitive flexibility on the attentional set-shifting test (AST), and induces a shift from active to passive response strategies on the shock-probe defensive burying test (SPDB). In this study, we tested the effects of ketamine on chronic stress-induced changes in cognitive flexibility and coping behavior on the AST and SPDB, respectively. Subsequently, we investigated vHipp-mPFC plasticity as a potential mechanism of ketamine’s therapeutic action. Ketamine reversed deficits in cognitive flexibility and restored active coping behavior in chronically stressed rats. Further, high frequency stimulation in the vHipp replicated ketamine’s antidepressant-like effects on the forced swim test and AST, but not on the SPDB. These results show that ketamine restores cognitive flexibility and coping response strategy compromised by stress. Activity in the vHipp-mPFC pathway may represent a neural substrate for some of the antidepressant-like behavioral effects of ketamine, including cognitive flexibility, but other circuits may mediate the effects of ketamine on coping response strategy.