Neuroanatomy and neuropathophysiology of volitional control of breathing

Abstract

Patients with neurodegenerative diseases, such as Parkinson’s, Alzheimer’s, and frontotemporal dementia may present laryngeal motor dysfunction even during the early stages of the disease progression. The larynx, also called the glottis, is the main valve that regulates respiratory airflow. Moreover, the muscles of the glottis are critically involved in the mediation of orofacial behaviours, such as vocalisation and swallowing. For example, glottis prevents the aspiration of foods into the lungs during swallowing. Furthermore, during speech, the vocal folds located within the glottis are vibrated by the expiratory airflow to produce sound.

Post-mortem studies in patients with neurodegenerative diseases indicate that neuronal degeneration within the brainstem respiratory network may be the cause of laryngeal motor dysfunction. Not surprisingly, patients often present respiratory, vocalisation, and swallowing malfunction. These clinical reports motivated my research group to study a transgenic mouse model of neurodegeneration (i.e., tauopathy) in the brainstem respiratory network. Data from the respiratory neurobiology team at the Florey found that similarly to clinical observations, this mouse model presents laryngeal motor dysfunction, leading to respiratory and swallowing impairments. Thus, the next step was to investigate whether tauopathy in the brainstem can also be linked to impaired ultrasonic vocalisation (USV).

This working hypothesis was part of my first experimental study of my PhD (chapter 2). I found that the transgenic mouse model presented USV patterns similar to the wild-type mice (control group), even during the late stage of diseases progression, when many brainstem circuits have degenerated. However, it is crucial to note that orofacial behaviours, including vocalisation, can be volitionally controlled by supra-pontine brains regions, such as the cortex and the limbic system in the forebrain, and I speculated that these control circuits for vocalisation might be able to compensate for brainstem neurodegeneration. Surprisingly, the neuroanatomical pathways that might be involved with volitional control of respiration during orofacial behaviours were poorly defined.

Thus, the following experimental study (Chapter 3) examined the anatomical projections from the forebrain to the brainstem respiratory network using a retrograde tracing approach. I reported for the first time widespread descending cortical and subcortical descending projections to a subset of primary respiratory control nuclei. Functionally, this neuroanatomical framework suggests that volitional information is sent to the brainstem respiratory network to adapt breathing with orofacial behaviours, such as vocalisation. Moreover, I found a highly redundant network connectome within the brainstem respiratory network that could be implicated in the compensation of local brainstem tauopathy (Chapter 4). Collectively, data from my thesis suggest the presence of numerous pathways in the brain that may compensate for localised neurodegeneration in the respiratory network of patients with neurodegenerative diseases. In summary, my PhD thesis proposes a new neuroanatomical framework to study behavioural adaptation of breathing in healthy and neurological diseases.