Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
Neuropsychopharmacology. 2023 Mar;48(4):642-652. doi: 10.1038/s41386-022-01506-y. Epub 2022 Nov 19.
Anxious, depressive, traumatic, and other stress-related disorders are associated with large scale brain network functional connectivity changes, yet the relationship between acute stress effects and the emergence of persistent large scale network reorganization is unclear. Using male Thy 1-jRGECO1a transgenic mice, we repeatedly sampled mesoscale cortical calcium activity across dorsal neocortex. First, mice were imaged in a homecage control condition, followed by an acute foot-shock stress, a chronic variable stress protocol, an acute on chronic foot-shock stress, and finally treatment with the prototype rapid acting antidepressant ketamine or vehicle. We derived functional connectivity metrics and network efficiency in two activity bands, namely slow cortical activity (0.3-4 Hz) and theta-alpha cortical activity (4-15 Hz). Compared to homecage control, an acute foot-shock stress induced widespread increases in cortical functional connectivity and network efficiency in the 4-15 Hz temporal band before normalizing after 24 h. Conversely, chronic stress produced a selective increase in between-module functional connectivity and network efficiency in the 0.3-4 Hz band, which was reversed after treatment with the rapid acting antidepressant ketamine. The functional connectivity changes induced by acute stress in the 4-15 Hz band were strongly related to those in the slow band after chronic stress, as well as the selective effects of subanesthetic ketamine. Together, this data indicates that stress induces functional connectivity changes with spatiotemporal features that link acute stress, persistent network reorganization after chronic stress, and treatment effects.
焦虑、抑郁、创伤和其他与应激相关的障碍与大脑网络功能连接的大规模变化有关，但急性应激效应与持续的大规模网络重组的出现之间的关系尚不清楚。使用雄性 Thy1-jRGECO1a 转基因小鼠，我们反复在背侧新皮层采集介观皮层钙活动。首先，在笼内对照条件下对小鼠进行成像，然后进行急性足底电击应激、慢性可变应激方案、急性慢性足底电击应激，最后用原型快速作用抗抑郁药氯胺酮或载体进行治疗。我们在两个活动频段（即慢皮层活动（0.3-4 Hz）和θ-α皮层活动（4-15 Hz））中得出功能连接度量和网络效率。与笼内对照相比，急性足底电击应激在 4-15 Hz 时间频段中诱导广泛的皮层功能连接和网络效率增加，在 24 小时后恢复正常。相反，慢性应激导致 0.3-4 Hz 频段中模块间功能连接和网络效率的选择性增加，在用快速作用抗抑郁药氯胺酮治疗后得到逆转。急性应激在 4-15 Hz 频段中引起的功能连接变化与慢性应激后慢频段中的变化以及亚麻醉剂量氯胺酮的选择性作用密切相关。总之，这些数据表明，应激诱导的功能连接变化具有时空特征，将急性应激、慢性应激后持续的网络重组和治疗效果联系起来。
