Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Neurosci. 2013 Jan 16;33(3):1116-29. doi: 10.1523/JNEUROSCI.0092-12.2013.
Transcranial magnetic stimulation and deep brain stimulation have emerged as therapeutic modalities for treatment refractory depression; however, little remains known regarding the circuitry that mediates the therapeutic effect of these approaches. Here we show that direct optogenetic stimulation of prefrontal cortex (PFC) descending projection neurons in mice engineered to express Chr2 in layer V pyramidal neurons (Thy1-Chr2 mice) models an antidepressant-like effect in mice subjected to a forced-swim test. Furthermore, we show that this PFC stimulation induces a long-lasting suppression of anxiety-like behavior (but not conditioned social avoidance) in socially stressed Thy1-Chr2 mice: an effect that is observed >10 d after the last stimulation. Finally, we use optogenetic stimulation and multicircuit recording techniques concurrently in Thy1-Chr2 mice to demonstrate that activation of cortical projection neurons entrains neural oscillatory activity and drives synchrony across limbic brain areas that regulate affect. Importantly, these neural oscillatory changes directly correlate with the temporally precise activation and suppression of limbic unit activity. Together, our findings show that the direct activation of cortical projection systems is sufficient to modulate activity across networks underlying affective regulation. They also suggest that optogenetic stimulation of cortical projection systems may serve as a viable therapeutic strategy for treating affective disorders.
经颅磁刺激和深部脑刺激已成为治疗难治性抑郁症的治疗方法；然而，对于这些方法介导治疗效果的回路知之甚少。在这里，我们展示了在表达 Chr2 的层 V 锥体神经元（Thy1-Chr2 小鼠）中设计的小鼠中，直接光遗传刺激前额叶皮层（PFC）的下行投射神经元模拟了强迫游泳试验中老鼠的抗抑郁样作用。此外，我们还表明，这种 PFC 刺激会导致社交应激性 Thy1-Chr2 小鼠的焦虑样行为（但不是条件性社会回避）长期抑制：这种作用在最后一次刺激后 10 天以上观察到。最后，我们在 Thy1-Chr2 小鼠中同时使用光遗传刺激和多回路记录技术证明，皮质投射神经元的激活会引起神经振荡活动，并驱动调节情感的边缘脑区之间的同步。重要的是，这些神经振荡变化与边缘单元活动的精确时间激活和抑制直接相关。总之，我们的研究结果表明，皮质投射系统的直接激活足以调节情感调节网络中的活动。它们还表明，皮质投射系统的光遗传刺激可能是治疗情感障碍的可行治疗策略。
