Brainstem Dopamine Beta-Hydroxylase Positive Neurons Control Allergen-Induced Airway Hyperreactivity in Asthma

Core Concepts

Brainstem Dbh+ neurons are a key node in the neural circuit controlling allergen-induced airway hyperreactivity, a hallmark of asthma.

Abstract

The article investigates the neural mechanisms underlying allergen-induced airway hyperreactivity, a characteristic feature of asthma. The researchers mapped the full allergen response circuit from the lung to the brainstem and back to the lung. Key findings: Repeated allergen exposure activated neurons in the nucleus of the solitary tract (nTS) in the brainstem in a mast cell-, IL-4-, and vagal nerve-dependent manner. Single-nucleus RNA sequencing and RNAscope assays showed that a specific population of Dbh+ (dopamine beta-hydroxylase positive) nTS neurons is preferentially activated by allergen exposure. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted airway hyperreactivity, while chemogenetic activation promoted it. Viral tracing revealed that Dbh+ nTS neurons project to the nucleus ambiguus (NA), and NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that directly drive airway constriction. Delivery of noradrenaline antagonists to the NA blunted hyperreactivity, suggesting noradrenaline as the key neurotransmitter between Dbh+ nTS and NA neurons. The study provides a comprehensive understanding of the neural circuit underlying allergen-induced airway hyperreactivity, with Dbh+ brainstem neurons as a critical node. This knowledge could inform the development of neural modulation strategies to control asthma symptoms.

Stats

Repeated exposure of mice to inhaled allergen activated the nuclei of solitary tract (nTS) neurons in a mast cell-, interleukin-4 (IL-4)- and vagal nerve-dependent manner. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted hyperreactivity, whereas chemogenetic activation promoted it. Delivery of noradrenaline antagonists to the nucleus ambiguus (NA) blunted hyperreactivity.

Quotes

"Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted hyperreactivity whereas chemogenetic activation promoted it." "Viral tracing indicated that Dbh+ nTS neurons project to the nucleus ambiguus (NA) and that NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that directly drive airway constriction." "Delivery of noradrenaline antagonists to the NA blunted hyperreactivity, suggesting noradrenaline as the transmitter between Dbh+ nTS and NA."

Key Insights Distilled From

Brainstem Dbh+ neurons control allergen-induced airway hyperreactivity - Nature

by Yujuan Su,Ji... at www.nature.com 07-10-2024

https://www.nature.com/articles/s41586-024-07608-5

Deeper Inquiries

What other neurotransmitters or neuromodulators might be involved in the brainstem circuit regulating allergen-induced airway hyperreactivity?

In addition to noradrenaline, other neurotransmitters or neuromodulators that could be involved in the brainstem circuit regulating allergen-induced airway hyperreactivity include acetylcholine, substance P, and glutamate. Acetylcholine is known to play a role in bronchoconstriction and airway hyperreactivity, while substance P is involved in neurogenic inflammation and modulation of airway smooth muscle tone. Glutamate, as an excitatory neurotransmitter, may also contribute to the regulation of airway responses. Further research is needed to elucidate the specific roles of these neurotransmitters in the context of allergen-induced airway hyperreactivity.

How might genetic or environmental factors influence the activity of the Dbh+ brainstem neurons and their role in asthma pathogenesis?

Genetic factors can influence the activity of Dbh+ brainstem neurons and their role in asthma pathogenesis through variations in gene expression, receptor sensitivity, or signaling pathways. Polymorphisms in genes related to neurotransmitter synthesis, release, or receptor function could impact the activity of Dbh+ neurons and their ability to modulate airway responses. Environmental factors such as exposure to allergens, pollutants, or stressors can also affect the function of Dbh+ neurons by altering their activation patterns or neurotransmitter release. These interactions between genetic and environmental factors may contribute to the development and exacerbation of asthma symptoms.

Could targeting the Dbh+ brainstem neurons or the NA-mediated neural pathway lead to the development of novel therapeutic approaches for asthma management?

Targeting the Dbh+ brainstem neurons or the NA-mediated neural pathway holds promise for the development of novel therapeutic approaches for asthma management. By modulating the activity of Dbh+ neurons or the transmission of noradrenaline to the nucleus ambiguus (NA), it may be possible to regulate airway hyperreactivity and bronchoconstriction in asthma. Strategies such as pharmacological interventions, gene therapy, or neuromodulation techniques could be explored to specifically target these neural pathways. By understanding the molecular and anatomical basis of the allergen response circuit, researchers can potentially design more targeted and effective therapies for asthma that focus on neural modulation.