Leibniz Institute for Neurobiology, Magdeburg, D-39118, Germany.
Graduate School of Life Science, Julius Maximilians University, Würzburg, D-97074, Germany.
J Physiol. 2020 Jul;598(13):2741-2755. doi: 10.1113/JP279705. Epub 2020 May 20.
Ketamine is a common anaesthetic agent used in research and more recently as medication in treatment of depression. It has known effects on inhibition of interneurons and cortical stimulus-locked responses, but the underlying functional network mechanisms are still elusive. Analysing population activity across all layers within the auditory cortex, we found that doses of this anaesthetic induce a stronger activation and stimulus-locked response to pure-tone stimuli. This cortical response is driven by gain enhancement of thalamocortical input processing selectively within granular layers due to an increased recurrent excitation. Time-frequency analysis indicates a higher broadband magnitude response and prolonged phase coherence in granular layers, possibly pointing to disinhibition of this recurrent excitation. These results further the understanding of ketamine's functional mechanisms, which will improve the ability to interpret physiological studies moving from anaesthetized to awake paradigms and may lead to the development of better ketamine-based depression treatments with lower side effects.
Ketamine is commonly used as an anaesthetic agent and has more recently gained attention as an antidepressant. It has been linked to increased stimulus-locked excitability, inhibition of interneurons and modulation of intrinsic neuronal oscillations. However, the functional network mechanisms are still elusive. A better understanding of these anaesthetic network effects may improve upon previous interpretations of seminal studies conducted under anaesthesia and have widespread relevance for neuroscience with awake and anaesthetized subjects as well as in medicine. Here, we investigated the effects of anaesthetic doses of ketamine (15 mg kg h i.p.) on the network activity after pure-tone stimulation within the auditory cortex of male Mongolian gerbils (Meriones unguiculatus). We used laminar current source density (CSD) analysis and subsequent layer-specific continuous wavelet analysis to investigate spatiotemporal response dynamics on cortical columnar processing in awake and ketamine-anaesthetized animals. We found thalamocortical input processing within granular layers III/IV to be significantly increased under ketamine. This layer-dependent gain enhancement under ketamine was not due to changes in cross-trial phase coherence but was rather attributed to a broadband increase in magnitude reflecting an increase in recurrent excitation. A time-frequency analysis was indicative of a prolonged period of stimulus-induced excitation possibly due to a reduced coupling of excitation and inhibition in granular input circuits - in line with the common hypothesis of cortical disinhibition via suppression of GABAergic interneurons.
氯胺酮是一种常见的麻醉剂，用于研究，最近也被用作治疗抑郁症的药物。它对抑制中间神经元和皮质刺激锁响应有已知的影响，但潜在的功能网络机制仍难以捉摸。通过分析听觉皮层内所有层的群体活动，我们发现这种麻醉剂的剂量会导致对纯音刺激的更强激活和刺激锁响应。这种皮质响应是由颗粒层中海马皮层输入处理的增益增强驱动的，这是由于反复兴奋的增加而选择性发生的。时频分析表明，在颗粒层中存在更高的宽带幅度响应和更长的相位相干性，这可能指向这种反复兴奋的去抑制。这些结果进一步了解了氯胺酮的功能机制，这将提高从麻醉到清醒范式解释生理研究的能力，并可能导致开发副作用更低的更好的基于氯胺酮的抑郁症治疗方法。
氯胺酮通常用作麻醉剂，最近作为抗抑郁药引起了人们的关注。它与刺激锁兴奋性增加、中间神经元抑制和内在神经元振荡调制有关。然而，功能网络机制仍难以捉摸。对这些麻醉网络效应的更好理解可能会改进以前在麻醉下进行的开创性研究的解释，并对神经科学具有广泛的意义，包括清醒和麻醉的受试者以及医学。在这里，我们研究了麻醉剂量的氯胺酮（15mgkg 皮下注射 h）对雄性蒙古沙鼠（Meriones unguiculatus）听觉皮层内纯音刺激后的网络活动的影响。我们使用层电流源密度（CSD）分析和随后的层特异性连续小波分析来研究清醒和氯胺酮麻醉动物的皮质柱状处理的时空响应动力学。我们发现，在氯胺酮下，颗粒层 III/IV 中海马皮层输入处理显著增加。氯胺酮下的这种层依赖性增益增强不是由于跨试验相位相干性的变化，而是归因于宽带幅度的增加，反映了反复兴奋的增加。时频分析表明，刺激诱导的兴奋期延长，可能是由于颗粒输入电路中兴奋和抑制的耦合减少，这与皮质去抑制的常见假设一致，即通过抑制 GABA 能中间神经元来实现。
