Through the Microscope is a reoccurring Helix column that poses questions to members of the RFU community. Kaiwen Kam, PhD, was asked for an overview of his work identifying nerve cells in the brainstem that connect breathing to states of mind.

“Take a deep breath in, and let it out …”

Anyone who has practiced mindfulness, meditation, yoga or similar exercises would recognize the instruction to breathe as an integral aspect of their routines. Indeed, for millennia, breathing exercises have been recognized to produce calming and stress-relieving effects and can even help pain control during labor. While the effects of breathing on emotion and pain are well-known, up until recently a biological mechanism evaded discovery.

Breathing is controlled by the brain. The diaphragm and upper airway muscles that generate and regulate airflow contract in response to activity from nerve cells or neurons in the brain and spinal cord. In fact, a small network of neurons in your brainstem is responsible for generating the rhythm of breathing. This small network is called the preBötzinger Complex. Despite the seeming simplicity of breathing, the preBötzinger Complex actually has a very difficult task. It needs to sustain breathing for the lifespan — in humans, half a billion breaths over the average 76-year lifespan. The preBötzinger Complex also has to regulate breathing frequency and tidal volume to accommodate changes in metabolic demand, such as during exercise, and to coordinate regular breathing with behaviors that share the airway like sighing, swallowing, crying and speaking.

To manage this task, groups of preBötzinger Complex neurons play different roles in processing the information that comes in and determining how and where respiratory activity is sent out. In collaboration with investigators at UCLA and Stanford University, we discovered a particular subgroup of preBötzinger Complex neurons that expressed a protein called cadherin-9. Inactivating these cadherin-9-expressing neurons in mice models caused the models to spend more time sitting or engaged in calm, resting behaviors, such as grooming, but did not otherwise appear to affect breathing. Interestingly, these neurons sent their signals to the locus coeruleus, a brain region known to regulate brainwide arousal and attention. We suggested that these cadherin-9-expressing preBötzinger Complex neurons therefore link breathing with arousal and attention.

Because breathing responds faithfully to physiological state, we speculate that this connection naturally functions to ensure heightened brain arousal and attention in stressful situations where breathing rate is increased. A weakened connection between breathing and arousal may underlie Sudden Infant Death Syndrome, whereas an overactive connection may produce a vulnerability to anxiety or panic disorders. On the other hand, we suggest that this link can be co-opted to produce calm and relaxation through volitional slowing of breathing that may be useful for relieving stress, fear, anxiety, panic, depression and pain. The discovery of these preBötzinger Complex cadherin-9 neurons thus fills a major gap in the complex interplay of breathing, emotion and cognition and opens up new avenues for exploring pathological and healthful links between breathing and complex behavior.

Cadherin-9 neurons are only one subpopulation of preBötzinger Complex neurons. My group continues to uncover roles for other neuronal subtypes in preBötzinger Complex and dissect the surprisingly complex circuitry controlling breathing. Through our study of this fundamental rhythm of life, we hope to understand how the simple act of breathing in and breathing out affects behavior, mood, and cognition in health and disease.

Dr. Kaiwen Kam is an associate professor of Cell Biology and Anatomy in the Stanson Toshok Center for Brain Function and Repair at RFU. He received his PhD from the University of California, San Francisco, and did his postdoctoral studies at the University of California, Los Angeles.

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