M.Chevalier, M.Thoby Brisson et al. in eNeuro

Sigh and Eupnea Rhythmogenesis Involve Distinct Interconnected Subpopulations: A Combined Computational and Experimental Study(1,2,3).
Toporikova N, Chevalier M, Thoby-Brisson M.
eNeuro. 2015 Apr 22;2(2). pii: ENEURO.0074-14.2015. doi: 10.1523/ENEURO

 

Muriel Thoby-Brisson
Institut de Neurosciences Cognitives et Intégratives d’Aquitaine
team leader: Organisation et Adaptabilité des Systèmes Moteurs
CNRS UMR 5287, Université Bordeaux

 

Sighing is healthy, but how does it work?

In mammals, eupneic breathing (generated as small amplitude, high frequency monophasic bursts) is periodically interrupted by spontaneous augmented breaths (so-called sighs, generated as large-amplitude, low frequency biphasic bursts). Respiratory rhythmogenesis arises from oscillatory neuronal assemblages located within the brainstem. One of the respiratory oscillators, the pre-Bötzinger complex network (preBötC), which is essential for normal breathing, comprises neural circuitry thought to control different inspiratory-related activities, including eupnea and sigh production. However, how a single neural network can generate several rhythmic activities at different time scales remains unclear. 

To address this issue we combined computational modeling of the respiratory network and physiological recordings of fictive inspiratory activities on mouse brainstem slices in vitro, and used the model to make predictions that were subsequently tested on the isolated preBötC in brainstem slice preparations. More specifically we intended to test the hypothesis that two distinct but strongly interconnected subpopulations within the respiratory preBötC network are responsible for the generation of sigh and eupnea. We designed a two-compartment computational model for sigh and eupnea subpopulations of neurons with several different parameters reflecting distinct burst generating mechanisms.

The sigh subpopulation generates a low frequency rhythm based on slow intracellular Ca^(2+) oscillations and the eupnea subnetwork generates fast oscillations mainly driven by activation/inactivation of the persistent Na^+ current. We established that only the combination of an inhibitory connection from the eupnea to sigh compartments and a reciprocal excitatory connection correctly reproduced the in vitro experimental recordings.
Furthermore we found that calcium-dependent signaling pathways (including activation of voltage-dependent calcium conductances and intracellular calcium machinery) and the activation of the hyperpolarization-activated current (Ih) play a prominent role for rhythmogenesis into the sigh population.

Finally we established that sigh sub-population is less sensitive to network excitability as it remains rhythmically active in low extracellular concentration of K+, due to particular Ih properties in this population. Altogether our in silico and in vitro results provide evidence supporting the hypothesis that eupnea and sigh rhythmogenesis rely on the interaction between two distinct subpopulations within the respiratory network and thus bring new insights regarding possible mechanisms allowing one network to generate rhythmic activities differing in terms of frequencies of occurrence.
Sigh production is important for effective lung function, since it augments residual volume, increases lung compliance and recruits atelectatic alveoli. Sighs can also be involved in triggering arousal responses, failure of which is suspected to be the cause of premature or unexplained death, such as in cases of Sudden Infant Death Syndrome (SIDS).

In addition sighs might also have clinical relevance for premature babies often suffering from Acute Respiratory Distress Syndrome (ARDS). Therefore a better understanding of the underlying mechanisms for sigh generation might be helpful in a clinical context.

Sigh and eupnea activity patterns in vitro and in silico. (A) Schematic representation of an in vitro transverse brainstem slice preparation isolating the pre-Bötzinger complex respiratory network (preBötC). Raw (upper trace) and integrated (bottom trace) preBötC activity recordings were obtained with an extracellular macro-electrode positioned at the surface of the slice. (B) Diagrams of sigh (left) and eupnea (right) network models connected through an inhibitory synapse (bottom) from eupnea to sigh and an excitatory synapse (top) from sigh to eupnea subpopulations. The difference in symbol thickness represents the difference in synaptic strength. Except parameter values for the Endoplasmic Reticulum capacity (λ), INaP and I_h, the sigh and eupnea models are identical. The trace below shows the average voltage trace of the coupled model that is concomitantly generating sigh and eupnea bursts, as obtained in vitro. Bottom traces for (A) and (B) represent typical average traces for eupneic bursts (left; monophasic, small amplitude) and sigh bursts (right; bi-phasic and large amplitude). Orange stars indicate sigh events. XII: hypoglossal nucleus; io: inferior olive; na: nucleus ambiguus.

Muriel Thoby-Brisson / INCIA / CNRS UMR 5287, Université Bordeaux /muriel.thoby-brisson(at)u-bordeaux.fr
Dernière mise à jour le 12.11.2015