Central control of breathing and breathing-associated behaviors by brainstem premotor neurons

• Applicant: Luis R. Hernandez-Miranda, Ph.D.
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450241946

Breathing (or respiration) is a complex and unconscious motor behavior, the neuronal drive for which originates in the brainstem. Respiratory disorders are common in humans and a leading cause of death and disability in the world. Frequently, individuals with respiratory disorders have difficulties when swallowing or attempting speech production. Failure to coordinate swallowing or speech with breathing oftentimes results in aspiration pneumonia, a primary cause of death in Alzheimer’s disease, Parkinson’s disease and many other neurodegenerative disorders. Breathing, swallowing and speech are known to overlap, but the brain center in charge of coordinating such activities is yet to be defined. Using intersectional mouse genetics, electrophysiology and optogenetics, I have recently identified novel elements of the neuronal circuit controlling respiration and respiratory reflexes (Hernandez-Miranda et al., 2017b in PNAS and Hernandez-Miranda et al., 2018 in PNAS). My preliminary data show that some of these neurons are essential for vocalization and the regulation of laryngeal and expiratory motor neurons. These previously unknown premotor neurons reside in the nucleus tractus solitarius (nTS, in the dorsal brainstem). My preliminary data also reveal that the nTS contains additional premotor neurons, and the absence of the nTS completely abolishes vocalization, swallowing and ventilatory responses to changes in blood gases. In humans and mice, the nTS receives all visceral information from our internal organs and it relays this information to other brain centers. Here, I propose to define the molecular and functional signatures of premotor neurons existing in the nTS that coordinate breathing with vocalization, swallowing and the response to blood gas changes in the body. I envision this proposal will increase our comprehension on the neuronal drive that allows for the coordination of distinct orofacial behaviors with breathing and pave the way towards therapeutic intervention in patients with respiratory and other neurodegenerative disorders.The applicant, Dr. Hernandez-Miranda, is currently associated with the Institute for Cell Biology and Neurobiology at the Charité Universitätsmedizin Berlin, where he is establishing his first independent group and working towards obtaining a Habilitation in Anatomy (expected by Winter of 2020). Furthermore, Dr. Hernandez-Miranda has extensive experience in the fields of breathing, congenital hypoventilation and neurological disorders and has published four recent first-author research papers in Science (2017), PNAS (2017 and 2018) and Journal of Medical Genetics (2017). This proposal represents Dr. Hernandez-Miranda’s first-time application for funding to the Deutsche Forschungsgemeinschaft.

• DFG Programme: Research Grants
• Major Instrumentation: plethysmograph for small animals
• Instrumentation Group: 3460 Kymographen, Plethysmographen, Muskelkraft-Messung