Understanding the Rhythm of Breathing: So Near, Yet So Far

Abstract

Understanding the mechanisms leading from DNA to molecules to neurons to networks to behavior is a major goal for neuroscience, but largely out of reach for many fundamental and interesting behaviors. The neural control of breathing may be a rare exception, presenting a unique opportunity to understand how the nervous system functions normally, how it balances inherent robustness with a highly regulated lability, how it adapts to rapidly and slowly changing conditions, and how particular dysfunctions result in disease. Why can we assert this? First and foremost, the functions of breathing are clearly definable, starting with its regulatory job of maintaining blood (and brain) O2, CO2 and pH; failure is not an option. Breathing is also an essential component of many vocal and emotive behaviors including, e.g., crying, laughing, singing, and sniffing, and must be coordinated with such vital behaviors as suckling and swallowing, even at birth. Second, the regulated variables, O2, CO2 and pH (and temperature in non-primate mammals), are continuous and are readily and precisely quantifiable, as is ventilation itself along with the underlying rhythmic motor activity, i.e., respiratory muscle EMGs. Third, we breathe all the time, except for short breaks as during breath-holding (which can be especially long in diving or hibernating mammals) or sleep apnea. Mammals (including humans) breathe in all behavioral states, e.g., sleep-wake, rest, exercise, panic, or fear, during anesthesia and even following decerebration. Moreover, essential aspects of the neural mechanisms driving breathing, including rhythmicity, are present at levels of reduction down to a medullary slice. Fourth, the relevant circuits exhibit a remarkable combination of extraordinary reliability, starting ex utero with the first air breath – intermittent breathing movements actually start in utero during the third trimester – and continuing for as many as ~109 breaths, as well as considerable lability, responding rapidly (in less than one second) and with considerable precision, over an order of magnitude in metabolic demand for O2 (~0.25 to ~5 liters of O2/min). Breathing does indeed persist! Finally, breathing is genetically determined to work at birth, with a well-defined developmental program underlying a neuroanatomical organization with apparent segregation of function, i.e., rhythmogenesis is separate from motor pattern (burst shape and coordination) generation. Importantly, single human gene mutations can affect breathing, and several neurodegenerative disorders compromise breathing by direct effects on brainstem respiratory circuits (See below).

Neural mechanisms underlying respiratory rhythm generation in the lamprey

“…These findings are consistent, at least to some extent, with recent results in adult mammals (e.g. Bongianni et al, 2010;Feldman et al, 2013;Janczewski et al, 2013;Kam et al, 2013 also for further Refs. ).…”

“…We believe that the pTRG has a crucial role in respiratory rhythm generation similar to that attributed to the preBötC in mammals (Feldman and Del Negro, 2006;Smith et al, 1991). Like the pTRG, the preBötC contains predominantly glutamatergic neurons that express NK1 receptors and are specifically sensitive to opioids and SP (Gray et al, 1999(Gray et al, , 2001Guyenet et al, 2002;Feldman and Del Negro, 2006;Feldman et al, 2013). A possible difference is that the lamprey pTRG is located in the rostral rhombencephalon/isthmic region corresponding to the rostral pons, while the preBötC is located in the medulla.…”

“…As to the inhibitory control of respiration, the respiratory rhythmogenesis persists after a blockade of synaptic inhibition, not only in neonatal rodent preparations (reviewed in Feldman et al, 2013), but also in the adult lamprey (Rovainen, 1983;Bongianni et al, 2006;Cinelli et al, 2014) and in the adult turtle (Johnson et al, 2002(Johnson et al, , 2007. In addition, a blockade of synaptic inhibition in the pre-metamorphic tadpole abolishes fictive gill ventilation, but not lung ventilation (Galante et al, 1996;Broch et al, 2002).…”

“…the hypothesized rostral expiratory oscillator of mammals (see e.g. Onimaru et al, 2009;Thoby-Brisson et al, 2009;Guyenet and Mulkey, 2010;Feldman et al, 2013;Smith et al, 2013). This oscillator may display burst activity involving endogenous I NaP -dependent properties, as it occurs in the preBötC ThobyBrisson et al, 2009;Molkov et al, 2010).…”

Mecanismos purinérgicos no bulbo ventrolateral rostral modulam respostas cardiovasculares e respiratórias promovidas pela ativação dos quimiorreceptores centrais e periféricos.

“…O Grupamento Respiratório Ventrolateral rostral (GRVr), localizado ao nível da área postrema, apresenta neurônios pré-motores inspiratórios que projetam para neurônios motores que dão origem ao nervo frênico e inervam o principal músculo respiratório, o diafragma (STORNETTA; SEVIGNY; GUYENET, 2003). Imediatamente adjacente ao GRVr está localizado o grupamento pré-Bötzinger (pré-BötC), onde evidências experimentais apontam para atividade marcapasso destes neurônios e, desta forma, seriam responsáveis por gerar o ritmo inspiratório (FELDMAN; DEL NEGRO; GRAY, 2012;DEL NEGRO, 2006;SMITH et al, 1991). O grupamento denominado de complexo Bötzinger (BötC), localizado imediatamente rostral ao pré-BötC, contém interneurônios inibitórios, envolvidos no processo expiratório (SCHREIHOFER; .…”