Jhang Jinho, Liu Shijia, O'Keefe David D, Han Sung
Peptide Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
Department of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
bioRxiv. 2023 Feb 27:2023.02.25.529925. doi: 10.1101/2023.02.25.529925.
Breathing is profoundly influenced by both behavior and emotion and is the only physiological parameter that can be volitionally controlled. This indicates the presence of cortical-to-brainstem pathways that directly control brainstem breathing centers, but the neural circuit mechanisms of top-down breathing control remain poorly understood. Here, we identify neurons in the dorsal anterior cingulate cortex (dACC) that project to the pontine reticular nucleus caudalis (PnC) and function to slow breathing rates. Optogenetic activation of this corticopontine pathway (dACC→PnC neurons) in mice slows breathing and alleviates behaviors associated with negative emotions without altering valence. Calcium responses of dACC→PnC neurons are tightly correlated with changes in breathing patterns entrained by behaviors, such as drinking. Activity is also elevated when mice find relief from an anxiety-provoking environment and slow their breathing pattern. Further, GABAergic inhibitory neurons within the PnC that receive direct input from dACC neurons decrease breathing rate by projecting to pontomedullary breathing centers. They also send collateral projections to anxiety-related structures in the forebrain, thus comprising a neural network that modulates breathing and negative affect in parallel. These analyses greatly expand our understanding of top-down breathing control and reveal circuit-based mechanisms by which slow breathing and anxiety relief are regulated together.
呼吸受到行为和情绪的深刻影响，并且是唯一可以自主控制的生理参数。这表明存在直接控制脑干呼吸中枢的皮质到脑干通路，但自上而下呼吸控制的神经回路机制仍知之甚少。在这里，我们识别出背侧前扣带回皮质（dACC）中投射到脑桥尾侧网状核（PnC）并具有减慢呼吸频率功能的神经元。在小鼠中对这条皮质脑桥通路（dACC→PnC神经元）进行光遗传学激活可减慢呼吸，并减轻与负面情绪相关的行为，而不改变情绪效价。dACC→PnC神经元的钙反应与由行为（如饮水）带动的呼吸模式变化紧密相关。当小鼠从引发焦虑的环境中解脱并减慢其呼吸模式时，其活动也会增强。此外，PnC内接受dACC神经元直接输入的GABA能抑制性神经元通过投射到脑桥延髓呼吸中枢来降低呼吸频率。它们还向前脑与焦虑相关的结构发出侧支投射，从而构成一个并行调节呼吸和负面影响的神经网络。这些分析极大地扩展了我们对自上而下呼吸控制的理解，并揭示了共同调节慢呼吸和缓解焦虑的基于回路的机制。
