Salvi Sonali S, Pati Sthitapranjya, Chaudhari Pratik R, Tiwari Praachi, Banerjee Toshali, Vaidya Vidita A
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
Front Behav Neurosci. 2019 Oct 29;13:249. doi: 10.3389/fnbeh.2019.00249. eCollection 2019.
Anxiety disorders are amongst the most prevalent mental health disorders. Several lines of evidence have implicated cortical regions such as the medial prefrontal cortex, orbitofrontal cortex, and insular cortex along with the hippocampus in the top-down modulation of anxiety-like behaviour in animal models. Both rodent models of anxiety, as well as treatment with anxiolytic drugs, result in the concomitant activation of multiple forebrain regions. Here, we sought to examine the effects of chemogenetic activation or inhibition of forebrain principal neurons on anxiety and despair-like behaviour. We acutely activated or inhibited Ca/calmodulin-dependent protein kinase II α (CamKIIα)-positive forebrain excitatory neurons using the hM3Dq or the hM4Di Designer Receptor Exclusively Activated by Designer Drug (DREADD) respectively. Circuit activation was confirmed via an increase in expression of the immediate early gene, c-Fos, within both the hippocampus and the neocortex. We then examined the influence of DREADD-mediated activation of forebrain excitatory neurons on behavioural tests for anxiety and despair-like behaviour. Our results indicate that acute hM3Dq DREADD activation of forebrain excitatory neurons resulted in a significant decline in anxiety-like behaviour on the open field, light-dark avoidance, and the elevated plus maze test. In contrast, hM3Dq DREADD activation of forebrain excitatory neurons did not alter despair-like behaviour on either the tail suspension or forced swim tests. Acute hM4Di DREADD inhibition of CamKIIα-positive forebrain excitatory neurons did not modify either anxiety or despair-like behaviour. Taken together, our results demonstrate that chemogenetic activation of excitatory neurons in the forebrain decreases anxiety-like behaviour in mice.
焦虑症是最常见的精神健康障碍之一。多条证据表明，在动物模型中，内侧前额叶皮质、眶额皮质和岛叶皮质等皮质区域以及海马体参与了对焦虑样行为的自上而下的调节。焦虑症的啮齿动物模型以及使用抗焦虑药物进行治疗，都会导致多个前脑区域同时被激活。在这里，我们试图研究对前脑主神经元进行化学遗传激活或抑制对焦虑和绝望样行为的影响。我们分别使用hM3Dq或hM4Di仅由设计药物激活的设计受体（DREADD），急性激活或抑制钙/钙调蛋白依赖性蛋白激酶IIα（CamKIIα）阳性的前脑兴奋性神经元。通过海马体和新皮质中即时早期基因c-Fos表达的增加，证实了回路激活。然后，我们研究了DREADD介导的前脑兴奋性神经元激活对焦虑和绝望样行为的行为测试的影响。我们的结果表明，前脑兴奋性神经元的急性hM3Dq DREADD激活导致旷场试验、明暗回避试验和高架十字迷宫试验中的焦虑样行为显著下降。相比之下，前脑兴奋性神经元的hM3Dq DREADD激活在悬尾试验或强迫游泳试验中均未改变绝望样行为。急性hM4Di DREADD抑制CamKIIα阳性的前脑兴奋性神经元对焦虑或绝望样行为均无影响。综上所述，我们的结果表明，前脑兴奋性神经元的化学遗传激活可降低小鼠的焦虑样行为。
