[F31] Cellular and circuit mechanisms of volitional breath-holding
Ente: National Heart Lung and Blood Institute
Scadenza: 2029-08-31
Importo max: $43,101
Paese: US
Descrizione
PROJECT SUMMARY
The breathing and heart rhythms are both essential for life, but unlike the incessant beating of the heart,
breathing has the unique capacity to be stopped at will. From our first breath, innate protective reflexes can
pause breathing, needed in instances like a sudden immersion into water. Eventually, we learn to volitionally
stop or modify our breathing for various purposes. This includes learning to preemptively hold our breath, as in
preparation for a dive, or to avoid noxious odors rather than depending upon reflexes. Another is the capacity to
use our breath to express emotions, like a sigh of frustration, or adopting a slow breathing pattern to alleviate
stress. This ability to control such a vital behavior epitomizes volition. Despite this evident importance, the
mechanisms that allow us to override this autonomous behavior remain elusive. Here, we aim to determine
whether a volitional breath hold is executed by engaging conserved reflex pathways that stop breathing, or
whether the brain employs an entirely new approach.
We have developed a novel Pavlovian-like conditioning task to teach mice to voluntarily hold their breath for
the equivalent of humans pausing their breathing for ~45 seconds. Briefly, training involves pairing a neutral odor
(e.g., lemon) with an ammonia puff that reflexively pauses breathing. After several days, mice hold their breath
in response to lemon alone. This robust task, coupled with the advanced murine genetic and viral tools to study
the nervous system, offers a powerful platform to perform a detailed dissection of the neural circuits that are
used for learning and stopping breathing. The focus of this proposal is to determine how the volitional breath
hold is executed (Aim 1) and how the mouse learns to do so (Aim 2). Aim 1 will use a combination of in vivo
multi-electrode electrophysiological recordings and optogenetic manipulations to determine whether the learned
breath-hold is achieved by silencing the breathing pacemaker or by inhibiting downstream premotor or motor
pathways. Aim 2 will firmly establish the primary sensory signal that is used to learn volitional breath-holding,
examining the roles of lung, chemosensory, olfactory, and trigeminal sensory inputs engaged in this task. The
insights gained from this research will not only elucidate how the brain overrides automatic control of breathing
but will also establish a foundation for understanding how other rhythmic, innate actions, such as vocalization,
chewing, and swallowing, become volitionally commanded. Furthermore, this work paves the way to study
whether other learned breathing patterns, such as slow, calming breaths, can be taught and utilized to alleviate
conditions like anxiety and panic disorders. By advancing our understanding of volitional control over breathing,
this research holds the potential to inform behavioral and therapeutic strategies for individuals struggling with
disorders of breathing, emotion regulation,
Istituzione: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
PI: Ilayda Alkislar
Progetto: 1F31HL182436-01
Settori: National Heart Lung and Blood Institute
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