Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine
Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine
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DOI：
10.1038/mp.2015.176
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发表时间：
2016-09-01
影响因子：
11
通讯作者：
Lodge, D. J.
中科院分区：
文献类型：
--
作者：
Carreno, F. R.;Donegan, J. J.;Lodge, D. J.
单次亚麻醉剂量的氯胺酮发挥快速和持续的抗抑郁作用。在这里，我们研究了腹侧海马（vHipp）-内侧前额叶皮层（mPFC）通路在氯胺酮抗抑郁反应中的作用。通过强迫游泳试验（FST）测定，利多卡因灭活vHipp可预防氯胺酮的持续但非急性抗抑郁样作用。此外，使用DREADD（设计药物专门激活的设计受体）的vHipp-mPFC途径的光遗传学和药物遗传学特异性激活模拟了对氯胺酮的抗抑郁药样反应;重要的是，这是途径特异性的，因为激活vHipp至丘脑核回路并没有做到这一点。此外，在FST时vHipp/mPFC通路的光遗传学失活完全逆转了氯胺酮的抗抑郁反应。此外，我们发现vHipp中TrkB受体磷酸化的瞬时增加有助于氯胺酮的持续抗抑郁反应。这些数据表明，vHipp-mPFC途径中的活性对于氯胺酮的抗抑郁样作用是必要且充分的。
A single sub-anesthetic dose of ketamine exerts rapid and sustained antidepressant effects. Here, we examined the role of the ventral hippocampus (vHipp)-medial prefrontal cortex (mPFC) pathway in ketamine's antidepressant response. Inactivation of the vHipp with lidocaine prevented the sustained, but not acute, antidepressant-like effect of ketamine as measured by the forced swim test (FST). Moreover, optogenetic as well as pharmacogenetic specific activation of the vHipp-mPFC pathway using DREADDs (designer receptors exclusively activated by designer drugs) mimicked the antidepressant-like response to ketamine; importantly, this was pathway specific, in that activation of a vHipp to nucleus accumbens circuit did not do this. Furthermore, optogenetic inactivation of the vHipp/mPFC pathway at the time of FST completely reversed ketamine's antidepressant response. In addition, we found that a transient increase in TrkB receptor phosphorylation in the vHipp contributes to ketamine's sustained antidepressant response. These data demonstrate that activity in the vHipp-mPFC pathway is both necessary and sufficient for the antidepressant-like effect of ketamine.