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A top-down slow breathing circuit that alleviates negative affect in mice

Nature Neuroscience volume 27, pages 2455–2465 (2024)Cite this article

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Abstract

Although breathing is primarily automatic, its modulation by behavior and emotions suggests cortical inputs to brainstem respiratory networks, which hitherto have received little characterization. Here we identify in mice a top-down breathing pathway from dorsal anterior cingulate cortex (dACC) neurons to pontine reticular nucleus GABAergic inhibitory neurons (PnCGABA), which then project to the ventrolateral medulla (VLM). dACC→PnC activity correlates with slow breathing cycles and volitional orofacial behaviors and is influenced by anxiogenic conditions. Optogenetic stimulation of the dACC→PnCGABA→VLM circuit simultaneously slows breathing and suppresses anxiety-like behaviors, whereas optogenetic inhibition increases both breathing rate and anxiety-like behaviors. These findings suggest that the dACC→PnCGABA→VLM circuit has a crucial role in coordinating slow breathing and reducing negative affect. Our study elucidates a circuit basis for top-down control of breathing, which can influence emotional states.

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Fig. 1: Identification of a cortical-to-brainstem slow breathing circuit.
Fig. 2: dACC→PnC activities correlate with behaviors that alter breathing.
Fig. 3: The dACC→PnC circuit is required for voluntary drinking.
Fig. 4: dACC→PnC activities correlate with breathing changes during aversive conditions.
Fig. 5: dACC→PnC activation reduces breathing rate and anxiety-like behaviors.
Fig. 6: PnCGABA→VLM activation attenuates breathing rate and anxiety-like behavior.

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Data availability

All data are available from the corresponding author upon request. All data associated with statistical analyses are available as source data. The source data are also available at figshare repository (https://doi.org/10.6084/m9.figshare.26888749 (ref. 53)). Source data are provided with this paper.

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Acknowledgements

We thank all members of the Han Laboratory for scientific discussions and support. This work was supported by grants from the KAVLI Institute for Brain and Mind Innovative Research Grants (IRGS 2020-1710). All members of the Han Laboratory are committed to upholding principles of equity and inclusion, ensuring that no person is discriminated against based on gender, race, age, religion, sexual orientation, veteran status or disability.

Author information

Author notes

  1. Shijia Liu

    Present address: Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA

Authors and Affiliations

  1. Peptide Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA

    Jinho Jhang, Seahyung Park, Shijia Liu & Sung Han

  2. Department of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA

    Shijia Liu & Sung Han

  3. Research Development Department, The Salk Institute for Biological Studies, La Jolla, CA, USA

    David D. O’Keefe

  4. Center for Neuroscience Imaging Research, Institute for Basic Science, Suwon, Republic of Korea

    Sung Han

  5. Department of Biomedical Engineering, Sungkyunkwan University, Suwon, Republic of Korea

    Sung Han

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Contributions

S.H. and J.J. designed the study and secured funding. J.J., S.P., D.D.O. and S.H. wrote the paper. J.J. performed the experiments and analyzed the data. S.P. performed electrophysiology. S.L. helped with thermistor implantation surgeries.

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Correspondence to Sung Han.

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Extended data

Extended Data Fig. 1 Allen Brain Atlas-based search for potential top–down breathing circuits.

a, Summary of the criteria used to search candidate circuits. Axonal projection images were searched through the Mouse Brain Connectivity Atlas (Allen Brain Institute). In situ hybridization (ISH) images were searched through the Mouse Brain ISH Data Atlas (Allen Brain Institute). b, Sample images showing the projections of labeled PnC neurons observed in the ventrolateral medulla (VLM). Left, the AAV injection site (PnC). Right, the observed terminals in the VLM. c, Sample image from a Vgat ISH experiment. d, Sample images showing the projections of PFC neurons observed in the PnC. Left image shows the AAV injection site (PFC, prefrontal cortex; covering the dACC and vACC) with the expression of eGFP. Middle and right (in segmentation view) images show the eGFP-labeled axon terminals in the PnC. PnC, pontine reticular nucleus; VLM, ventrolateral medulla; PFC, prefrontal cortex. Scale bars, 200 μm in b–d. These are representative data (b–d) available from the Allen Brain Atlas.

Source data

Extended Data Fig. 2 Photoactivation of dACC→PnC neurons with breathing measurement.

a, Representative raw breathing trace measured by inductance plethysmography experiment under anesthesia from a mouse expressing ChR2 in dACC→PnC neurons. b–f, Analyses of breathing rates and inspiratory/expiratory durations during photoactivation of dACC→PnC neurons with reduced light intensity (b–f; ChR2, N = 6; eGFP, N = 5 mice). b,c, Percent change of normalized breathing rates during the photoactivation with ~6 mW (b) and ~3 mW (c) intensity. d, Correlation between the change of breathing rate and intensity of light stimulation. e,f, Correlation between the change of inspiratory (e) or expiratory (f) duration and intensity of light stimulation. g, Photaoactivation of dACC→PnC neurons decreases breathing rates (shown in breath per minute; BPM). h, Schematic of breathing monitoring using a nasal thermistor sensor. i,j, Photoactivation of dACC→PnC neurons led to a decrease in breathing rate in awake mice (ChR2, N = 6; eGFP N = 6 mice). Average breathing rate (5-s window smoothed; i); light-induced changes (ON– OFF) in breathing rates (j). N.SP > 0.05, *P < 0.05, **P < 0.01, ***P < 0.001. Line graphs are shown as mean ± s.e.m. Box-whisker plot is shown as median and interquartile range with minimum and maximum.

Extended Data Fig. 3 Retrograde tracing from the dACC does not label neurons in the PnC.

a, Schematic of CTB-555 injection into the dACC (left) and representative image showing the injection site (right). Scale bar, 500 μm. b, Known afferent regions of the dACC (claustrum and basolateral amygdala) and the PnC. No retrograde labeling occurred in the PnC (N = 4 mice). CLA, claustrum; LA, lateral nucleus of amygdala; BLA, basolateral nucleus of amygdala. Scale bar, 200 μm.

Extended Data Fig. 4 Raw breathing traces and jaw movement recording during optogenetic stimulation of PnCGABA neurons.

a, Raw breathing trace recorded during ChR2-mediated photoactivation of PnCGABA neurons. Scale bar, 10 s. b, Raw breathing trace recorded during eNpHR3.0-mediated photoinhibition of PnCGABA neurons. Scale bar, 10 s. c,d, Schematic of simultaneous recording of jaw movement and breathing signals using inductance plethysmography under anesthesia (c, left) or using nasal thermistor sensor in awake state (d, left). No instance of jaw opening or mastication was observed throughout the duration of photostimulation (right; c, N = 4 mice; d, N = 5 mice).

Extended Data Fig. 5 Response of PnCGABA neurons to drinking and swimming.

a, Surgical procedure for expressing jGCaMP7s in PnCGABA neurons, and image showing jGCaMP7s expression (right). Scale bar, 200 μm. b, Schematic showing observation of voluntary drinking behavior. c, Representative traces showing breathing cycles and PnCGABA activity during drinking behavior. d, Average PnCGABA activity during drinking behavior (N = 5 mice). Dashed line shows the moment that a water droplet was taken into oral cavity. e, Schematic of submersion experiments in which mice were removed after 1–2 s (withdrawal). f, Representative traces showing breathing cycles and PnCGABA activity during withdrawal experiments. g, Average PnCGABA neuronal activity during withdrawal experiments (N = 5 mice). h, Schematic of submersion experiments in which mice were released. i, Representative traces showing breathing cycles and PnCGABA activity during release/swim experiments. j, Average PnCGABA neuronal activity during release/swim experiments (N = 5 mice). Data are shown as mean ± s.e.m. or individual value from each subject.

Source data

Extended Data Fig. 6 Extended data related to breathing and dACC→PnC activity measurements during EPM exposure.

a, Illustrations showing GCaMP7s injection sites and fiber placement targeting dACC area, in mice used for elevated plus maze, elevated platform and foot shock exposure experiments (N = 6 mice). b, Representative traces of dACC→PnC neuronal activity (top) and breathing rate (bottom) during the elevated plus maze exposure. c, Representative raw breathing signals observed during an exit episode. d, Analysis of the length of inspiratory and expiratory phases before and after exit (N = 6 mice). e, Breathing rates during exploration of an exposed area classified by episodes with refrained behavior (n = 43 episodes) and full exploration (n = 10 episodes). ***P < 0.001. Data are shown as mean ± s.e.m. or individual value from each subject.

Source data

Extended Data Fig. 7 Axon collaterals of dACC→PnC neurons and behavioral tests with photoactivation or photoinhibition of the dACC→PnC pathway.

a, Axon collaterals of dACC→PnC neurons observed in regions other than the PnC. Scale bar, 200 μm. b,c, Photoactivation of dACC→PnC neurons (ChR2, N = 6; eGFP, N = 7 male mice) did not change approach response to female odor (b) but reduced avoidance response to TMT (c). d–f, Photoactivation of dACC→PnC neurons during light/dark choice test (d, ChR2, N = 9 and eGFP control, N = 8 mice). Photoactivation of dACC→PnC neurons reduces ΔBPM (light–dark; e) and increases time spent in the light zone (f). g,h, Photoinhibition of dACC→PnC projections (eNpHR3.0, N = 7; eGFP control, N = 8 male mice) did not change approach response to female odor (g) or avoidance response to TMT (h). LV, lateral ventricle; CPu, caudate putamen; cc, corpus callosum; D3V, dorsal third ventricle; PVT, paraventricular thalamic nucleus; MD, mediodorsal thalamic nucleus; VMT, ventromedial thalamic nucleus; DpME, deep mesencephalic nucleus; RMC, red nucleus, magnocellular; ZI, zona incerta; LH, lateral hypothalamus; mt, mammillothalamic tract; ic, internal capsule. N.SP > 0.05, *P < 0.05, **P < 0.01. Bar graphs are shown as mean ± s.e.m. Box-whisker plots are shown as median and interquartile range with minimum and maximum.

Source data

Extended Data Fig. 8 Efferent projections of PnCGABA neurons.

a, Efferent projections of PnCGABA neurons. Right, quantification of projection density of eYFP-labeled axons (N = 5 mice, Vgat-ires-Cre). Scale bar, 200 μm. b, Images showing the viral injection site in the PnC, and brainstem regions receiving efferent fibers expressing ChR2-eYFP. Scale bar, 200 μm. BST, bed nucleus of stria terminalis; LHb, lateral habenula; PVT, paraventricular nucleus of thalamus; PB, parabrachial nucleus; VLM, ventrolateral medulla. Data are shown as mean ± s.e.m.

Source data

Extended Data Fig. 9 Measurement of breathing rate during photoactivation of PnCGABA terminals.

a, Inductance plethysmography experiments performed with photoactivation of PnCGABA→VLM terminals (ChR2, N = 7; eGFP, N = 7 mice), tested with different frequencies. b, Changes in breathing rates (% of baseline) induced by stimulation of PnCGABA→VLM terminals (ChR2, N = 7; eGFP, N = 7 mice). c, Inductance plethysmography experiments performed with photoactivation of PnCGABA→LHb/PVT terminals (ChR2, N = 7; eGFP, N = 8 mice), tested with different frequencies. d, Changes in breathing rates (% of baseline) induced by stimulation of PnCGABA→LHb/PVT terminals (ChR2, N = 7; eGFP, N = 8 mice). e–g, Breathing rates shown as breaths per minute (BPM) during photoactivation experiments (15-Hz stimulation; e, PnCGABA→VLM; f, PnCGABA→LHb/PVT; g, AAV1-based labeling). ***P < 0.001. Line graphs are shown as mean ± s.e.m. Box-whisker plots are shown as median and interquartile range with minimum and maximum.

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Jhang, J., Park, S., Liu, S. et al. A top-down slow breathing circuit that alleviates negative affect in mice. Nat Neurosci 27, 2455–2465 (2024). https://doi.org/10.1038/s41593-024-01799-w

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