Lung – Vagus Nerve - Brain Axis: A Hope for Mood and Anxiety Modulation

You haven't escaped it; the internet is brimming with various breathworks for all sorts of indications, particularly to combat stress and anxiety. Scientists have also taken up the subject. So inhale, exhale, and you're good to go!

Several studies highlight the beneficial effects of certain breathing techniques or methods that are commonly found these days. However, the underlying biological mechanisms of these effects remain unknown. Nevertheless, a study published in November 2023 in the journal Nature Communications by Dr. Andy Peng Xiang's team from Sun Yat-Sen University in China might provide some initial answers. Their work highlights the existence of a lung-vagus nerve-brain axis capable of regulating anxiety and resignation in a chronic stress model in mice.

Initially, this research team focused on mesenchymal stromal cells (MSCs). These are stem cells capable of being re-differentiated in the laboratory into another type of cell. Their interest in these cells lies in the fact that several studies have highlighted their potential antidepressant effects. Hypotheses have been formulated regarding the biological mechanisms underlying these effects, although they remain elusive. In this study, Dr. Xiang's team investigates how MSCs might produce their potential therapeutic effects.

Serotonin, Mood, and Anxiety

To do this, his team uses a chronic stress model, commonly used to induce anxiety and resignation behavior in mice, to mimic some symptoms of anxio/depressive disorders observed in humans. Using this model, they notably observed a reduction in resignation and anxiety in mice in response to MSC injection, thus confirming the results of studies reporting their antidepressant and anxiolytic effect.

Given the involvement of serotonin in the mechanism of action of antidepressants and in the pathophysiology of depression in humans, they questioned the role that serotonin might play in the therapeutic effects of MSCs. Serotonin is a neurotransmitter produced by specialized neurons in a brain area called the dorsal raphé. These neurons release serotonin in multiple brain areas where it participates in modulating a plethora of behaviors, including the regulation of emotional behavior (see figure 1).

 Figure 1. Schematic illustration of the central serotonergic system of the human brain.

Testing this hypothesis, they observe that intravenous injection of MSCs activates serotonin-producing neurons in the brain and increases their levels. Conversely, they observe that these same neurons have reduced activity in mice subjected to chronic stress and that MSC injection restores their activity to a level comparable to non-stressed mice. Finally, MSC injection also restores serotonin levels in the brain, previously reduced by chronic stress.

To prove the causal link between the observed antidepressant effects in response to MSC injection and the increased activity of serotonergic neurons, the researchers use a loss-of-function approach. They lesion the serotonergic neurons to render them non-functional. Confirming their hypothesis, they observe that when the serotonergic neurons are no longer functional, MSC injection no longer produces the previously reported antidepressant and anxiolytic effects. They conclude that the activation of serotonergic neurons is necessary for MSCs to reduce resignation and anxiety in chronically stressed mice. However, a question remains: by what mechanisms do MSCs activate the brain's serotonergic neurons to produce their therapeutic effects?

The Powers of the Lung-Vagus Nerve-Brain Axis

Initially, the researchers observe that after injection, MSCs predominantly lodge in our respiratory system. The lungs are innervated by various nerves, including the vagus nerve through its sensory endings. The vagus nerve is the most extensive cranial nerve in the human body, starting from the brainstem (base of the brain, before the spinal cord) and innervating various peripheral organs like the lungs, the digestive system, and the cardiovascular system.

Nested in the lungs, MSCs then secrete a metabolite, which is subsequently absorbed by the sensory nerves of the lungs. The absorption of this substance, still unknown at this stage of the study, by the sensory nerve induces the activation of the cells composing the vagus nerve. Finally, a so-called "tracing" method reveals a neuronal circuit allowing the pulmonary sensory endings of the vagus nerve to communicate with the brain's serotonergic neurons. The icing on the cake: they also highlight that the therapeutic effects of MSCs are mediated by the vagus nerve. Indeed, vagotomy (lesion of the vagus nerve rendering it non-functional) no longer allows inhaled MSCs to activate the brain's serotonergic neurons, resulting in the loss of the antidepressant and anxiolytic effect in stressed mice.

BDNF, the Missing Link

The final step of their work is to identify the metabolite secreted by MSCs that allows activation of serotonin neurons via the vagus nerve, reducing resignation and anxiety. Using various sequencing and molecular biology techniques, they identify the protein BDNF (Brain-Derived Neurotrophic Factor) as a potential candidate. BDNF is a neurotrophic growth factor, also naturally produced by our body, which binds to the TrkB (Tropomyosin receptor Kinase B) receptor. Through this action, it promotes neuron growth and regulates key mechanisms like neuroplasticity, which is among other things a physiological process altered in depression and restored (sometimes only partially) by antidepressant treatments.

Rather than using the BDNF protein directly, they use 7,8-DHF (7,8-Dihydroxyflavone hydrate, or tropoflavin), a molecule that, like BDNF, activates the TrkB receptor. The result is very encouraging: inhalation of this molecule activates serotonergic neurons and reproduces an antidepressant and anxiolytic effect in stressed mice.

Thus, Dr. Xiang's group's work has demonstrated that the neurotrophic growth factor BDNF, released by MSCs in the lungs, binds to the TrkB receptor and activates vagus nerve cells. This has the direct consequence of activating the brain's serotonergic neurons through the lung-vagus nerve-brain axis, ultimately supporting the antidepressant and anxiolytic effect observed in stressed mice (see figure 2).

Figure 2. Schematic illustration of the antidepressant and anxiolytic effect of MSCs mediated by

the lung–vagus nerve–brain axis.

1.Mesenchymal stromal cells (MSCs) lodge in the lungs and release the neurotrophic factor BDNF. 2. BDNF binds to its TrkB receptor. 3. BDNF binding to TrkB induces vagus nerve activation. The vagus nerve then transmits this message to the nodose ganglion neurons (4), which in turn activate the dorsal raphe serotonergic neurons (5). 6. The activation of serotonergic neurons leads to increased serotonin (5-HT) release in the brain, resulting in reduced anxiety and resignation (7).

This original study paves the way for new types of treatments for anxiety and depressive disorders. Furthermore, it clarifies the outlines of a potential underlying mechanism for the beneficial effects of breathing exercises on mood and stress. Indeed, it is just one step, or rather a few experiments, to demonstrate that breathing exercises promote BDNF secretion (which is already true for physical activity)!

Sources:

1. Huang Jing et al. Mesenchymal stromal cells alleviate depressive and anxiety-like behaviors via a lung vagal-to-brain axis in male mice. Nature Communications, 2023.

2. Ding Dah-Ching et al. Mesenchymal stem cells. Cell Transplant, 2011.

3. Cowen Philip, J. Serotonin and depression: pathophysiological mechanism or marketing myth? Trends in Pharmacological Sciences, 2008.

4. Castrén Eero & Monteggia Lisa, M. Brain-Derived Neurotrophic Factor Signaling in Depression and Antidepressant Action. Biological Psychiatry, 2021.