precision-induction-distinction-coughing-sneezing-reflexes

Precision Induction and Distinction of Coughing and Sneezing Reflexes in Mice

Coughing and sneezing, as vital respiratory defensive reflexes, have seen research into their mechanisms constrained by the nonspecific stimulation ...

Guangzhou Medical University

Guangzhou National Laboratory

Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)

Unlike megabats, which rely on well-developed vision, microbats use ultrasonic echolocation to navigate and locate prey. To study ultrasound perception, here we compared the auditory cortices of microbats and megabats by constructing reference genomes and single-nucleus atlases for four species. We found that parvalbumin (PV) neurons exhibited evident cross-species differences and could respond to ultrasound signals, whereas their silencing severely affected ultrasound perception in the mouse auditory cortex. Moreover, megabat PV neurons expressed low levels of complexins (CPLX1-CPLX4), which can facilitate neurotransmitter release, while microbat PV neurons highly expressed CPLX1, which improves neurotransmission efficiency. Further perturbation of Cplx1 in PV neurons impaired ultrasound perception in the mouse auditory cortex. In addition, CPLX1 functioned in other parts of the auditory pathway in microbats but not megabats and exhibited convergent evolution between echolocating microbats and whales. Altogether, we conclude that CPLX1 expression throughout the entire auditory pathway can enhance mammalian ultrasound neurotransmission.

Complexin-1 enhances ultrasound neurotransmission in the mammalian auditory pathway.

After ingestion of toxin-contaminated food, the brain initiates a series of defensive responses (e.g., nausea, retching, and vomiting). How the brain detects ingested toxin and coordinates diverse defensive responses remains poorly understood. Here, we developed a mouse-based paradigm to study defensive responses induced by bacterial toxins. Using this paradigm, we identified a set of molecularly defined gut-to-brain and brain circuits that jointly mediate toxin-induced defensive responses. The gut-to-brain circuit consists of a subset of Htr3a+ vagal sensory neurons that transmit toxin-related signals from intestinal enterochromaffin cells to Tac1+ neurons in the dorsal vagal complex (DVC). Tac1+ DVC neurons drive retching-like behavior and conditioned flavor avoidance via divergent projections to the rostral ventral respiratory group and lateral parabrachial nucleus, respectively. Manipulating these circuits also interferes with defensive responses induced by the chemotherapeutic drug doxorubicin. These results suggest that food poisoning and chemotherapy recruit similar circuit modules to initiate defensive responses.

The gut-to-brain axis for toxin-induced defensive responses.

Cognitive impairment (CI) is a common neurological disease resulting from traumatic brain injury (TBI). Trigeminal nerve stimulation (TNS) is an emerging, non-invasive, and effective neuromodulation therapy especially for patients suffering from brain function disorders. However, the treatment and recovery mechanisms of TNS remain poorly understood. By using combined advanced technologies, we revealed here that the neuroprotective potential of TNS to improve CI caused by TBI. The study results found that 40 Hz TNS treatment has the ability to improve CI in TBI mice and communicates with central nervous system via the trigeminal ganglion (TG). Transsynaptic virus experiments revealed that TG is connected to the hippocampus (HPC) through the corticotropin-releasing hormone (CRH) neurons of paraventricular hypothalamic nucleus (PVN) and the dopamine transporter (DAT) neurons of substantia nigra pars compacta/ventral tegmental area (SNc/VTA). Mechanistically, the data showed that TNS can increase the release of dopamine in the HPC by activating the following neural circuit: TG→CRH+ PVN→DAT+ SNc/VTA → HPC. Bulk RNA sequencing confirmed changes in the expression of dopamine-related genes in the HPC. This work preliminarily explains the efficacy and mechanism of TNS and adds to the increasing evidence demonstrating that nerve stimulation is an effective method to treat neurological diseases.

Trigeminal nerve stimulation restores hippocampal dopamine deficiency to promote cognitive recovery in traumatic brain injury.

Nausea and vomiting are important defensive responses to cope with pathogens and toxins that invade the body. The nucleus of the solitary tract (NTS) is important for initiating these responses. However, the molecular heterogeneities and cellular diversities of the NTS occlude a better understanding of these defensive responses. Here, we constructed the single-nucleus transcriptomic atlas of NTS cells and found multiple populations of NTS neurons that may be involved in these defensive responses. Among these, we identified Calbindin1-positive (Calb1) NTS neurons that are molecularly distinct from Tac1 neurons. These Calb1 neurons are critical for nausea and retching induced by cereulide; an emetic toxin secreted by . Strikingly, we found that cereulide can directly modulate vagal sensory neurons that innervate Calb1 NTS neurons, a novel mechanism distinct from that for nausea and retching induced by Staphylococcal enterotoxin A. Together, our transcriptomic atlas of NTS neurons and the functional analyses revealed the neural mechanism for cereulide-induced retching-like behavior. These results demonstrate the molecular and cellular complexities in the brain that underlie defensive responses to the diversities of pathogens and toxins.

Brain circuits for retching-like behavior.

Cough is a vital defensive reflex for expelling harmful substances from the airway. The sensory afferents for the cough reflex have been intensively studied. However, the brain mechanisms underlying the cough reflex remain poorly understood. Here, we developed a paradigm to quantitatively measure cough-like reflexes in mice. Using this paradigm, we found that -expressing (+) neurons in the nucleus of the solitary tract (NTS) are critical for capsaicin-induced cough-like reflexes. These neurons receive cough-related neural signals from + vagal sensory neurons. The activation of + NTS neurons triggered respiratory responses resembling cough-like reflexes. Among the divergent projections of + NTS neurons, a glutamatergic pathway projecting to the caudal ventral respiratory group (cVRG), the canonical cough center, was necessary and sufficient for capsaicin-induced cough-like reflexes. These results reveal that + NTS neurons, as a key neuronal population at the entry point of the vagus nerve to the brainstem, initiate cough-like reflexes in mice.

Brainstem opioid peptidergic neurons regulate cough reflexes in mice.

The arousal state is defined as the degree to which an individual is aware of themselves and their surroundings, and is a crucial component of consciousness. Trigeminal nerve stimulation (TNS), a non-invasive clinical neuromodulation technique, has shown potential in aiding the functional recovery of patients with impaired consciousness. Understanding the specific neuronal subpopulations and circuits through which TNS improves arousal states is essential for advancing its clinical application.  A mouse model of traumatic brain injury (TBI) was established using a weight-drop technique to induce neurological dysfunction, and the arousal state was assessed through visual and auditory defensive responses. Techniques such as viral tracing, chemogenetics, patch-clamp recordings, calcium signaling, and neurotransmitter probes were employed to investigate the relevant subpopulations of trigeminal ganglion (TG) neurons and the underlying mechanisms in the central nervous system.  Neuronal subgroups involved in TNS therapy at the key peripheral nucleus, the TG, were identified. Two distinct types of neurons were found to contribute differently: The Tac1+TG-locus coeruleus (LC)-superior colliculus (SC) pathway elevated noradrenaline levels in the SC, enhancing receptive field sensitivity recovery in TBI mice; the Piezo2+TG-paraventricular hypothalamic nucleus (PVN)-substantia nigra pars compacta (SNc)-dorsal striatum (DS) pathway initiated dopamine (DA) release in the DS, ameliorating motor disorders in TBI mice.  These pathways contribute to the improvement of defensive arousal responses from different perspectives. The findings from this study imply that TNS effectively restores defensive arousal responses to visual and auditory threats in mice suffering from TBI, offering insights that may facilitate the implementation of TNS therapy in clinical settings.

Article	Year
Complexin-1 enhances ultrasound neurotransmission in the mammalian auditory pathway. Nature genetics\| PubMed ID: 38834904	2024
The gut-to-brain axis for toxin-induced defensive responses. Cell\| PubMed ID: 36323317	2022
Trigeminal nerve stimulation restores hippocampal dopamine deficiency to promote cognitive recovery in traumatic brain injury. Progress in neurobiology\| PubMed ID: 37270025	2023
Brain circuits for retching-like behavior. National science review\| PubMed ID: 38288368	2024
Brainstem opioid peptidergic neurons regulate cough reflexes in mice. Innovation (Cambridge (Mass.))\| PubMed ID: 39529953	2024
Neural mechanism of trigeminal nerve stimulation recovering defensive arousal responses in traumatic brain injury. Theranostics\| PubMed ID: 39990219	2025

Congping Shang

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