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β-Noradrenergic receptor activation specifically modulates the generation of sighs in vivo and in vitro.

Viemari JC, Garcia AJ, Doi A, Elsen G, Ramirez JM - Front Neural Circuits (2013)

Bottom Line: By contrast, all parameters of bursting pacemakers that rely on the non-specific cation current (I(CAN)) remained unaffected.Moreover, riluzole, which blocks bursting in I(Nap) pacemakers abolished sighs altogether, while flufenamic acid (FFA) which blocks the I(CAN) current did not alter the sigh-increasing effect caused by β-NR.Our results suggest that the selective β-NR action of sighs may result from the modulation of I(Nap) pacemaker activity and that disturbances in noradrenergic system may contribute to abnormal arousal response.

View Article: PubMed Central - PubMed

Affiliation: Team P3M, Institut de Neurosciences de la Timone, UMR 7289, CNRS, Aix Marseille Univesité , Marseille, France.

ABSTRACT
The pre-Bötzinger complex (preBötC), an area that is critical for generating breathing (eupnea), gasps and sighs is continuously modulated by catecholamines. These amines and the generation of sighs have also been implicated in the regulation of arousal. Here we studied the catecholaminergic modulation of sighs not only in anesthetized freely breathing mice (in vivo), but also in medullary slice preparations that contain the preBötC and that generate fictive eupneic and sigh rhythms in vitro. We demonstrate that activating β-noradrenergic receptors (β-NR) specifically increases the frequency of sighs, while eupnea remains unaffected both in vitro and in vivo. β-NR activation specifically increased the frequency of intrinsically bursting pacemaker neurons that rely on persistent sodium current (I(Nap)). By contrast, all parameters of bursting pacemakers that rely on the non-specific cation current (I(CAN)) remained unaffected. Moreover, riluzole, which blocks bursting in I(Nap) pacemakers abolished sighs altogether, while flufenamic acid (FFA) which blocks the I(CAN) current did not alter the sigh-increasing effect caused by β-NR. Our results suggest that the selective β-NR action of sighs may result from the modulation of I(Nap) pacemaker activity and that disturbances in noradrenergic system may contribute to abnormal arousal response. The β-NR action on the preBötC may be an important mechanism in modulating behaviors that are specifically associated with sighs, such as the regulation of the early events leading to the arousal response.

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Sighs are spontaneously generated in freely breathing mouse preparation. (A1) Intercostal EMG activity recording in an anesthetized freely breathing mouse. Sigh is generally triggered and preceded by an inspiratory burst of fictive eupneic activity. Histograms summarize the differences between spontaneous sighs and fictive respiratory activity, in amplitude (A2), frequency (A3), and duration (A4). (*p < 0.05, n = 8). (B) Trace of integrated intercostal EMG activity (∫EMG) during control and after injection of isoproterenol into the preBötC (30 μM). (C–E) Histograms show the effects of isoproterenol on sigh frequency (C) duration (D) and on eupnea frequency (E) (ns: not significant, *p < 0.05, n = 4–8).
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Figure 1: Sighs are spontaneously generated in freely breathing mouse preparation. (A1) Intercostal EMG activity recording in an anesthetized freely breathing mouse. Sigh is generally triggered and preceded by an inspiratory burst of fictive eupneic activity. Histograms summarize the differences between spontaneous sighs and fictive respiratory activity, in amplitude (A2), frequency (A3), and duration (A4). (*p < 0.05, n = 8). (B) Trace of integrated intercostal EMG activity (∫EMG) during control and after injection of isoproterenol into the preBötC (30 μM). (C–E) Histograms show the effects of isoproterenol on sigh frequency (C) duration (D) and on eupnea frequency (E) (ns: not significant, *p < 0.05, n = 4–8).

Mentions: In the transverse slice preparation population activity recordings were obtained with suction electrodes positioned on the surface of the slice in the area including the preBötC. The slice preparation is placed rostral side up and encompasses network components rostral to the preBötC that appear to be critical for generating the sigh rhythm in very thin slices (Ruangkittisakul et al., 2008). The signals were amplified 2000 times, filtered (low pass 1.5 KHz, high pass 250 Hz), rectified and integrated using an electronic filter (time constant of 30–50 ms). Integrated population activity from the ventral respiratory group (VRG) was always in phase with integrated inspiratory activity of the hypoglossal motor nucleus (Telgkamp and Ramirez, 1999). Therefore, it was used as a marker for inspiratory population activity (Figure 1A). All recordings were stored on a personal computer using AxoTape (Version 2.0, Axon Instruments, Union City, CA) and analyzed offline using customized analysis software written with IGOR Pro (Wavemetrics, Lake Oswego, OR). Bursts were automatically detected by the IGOR program as described extensively in our previous study (Tryba et al., 2003; Viemari and Ramirez, 2006).


β-Noradrenergic receptor activation specifically modulates the generation of sighs in vivo and in vitro.

Viemari JC, Garcia AJ, Doi A, Elsen G, Ramirez JM - Front Neural Circuits (2013)

Sighs are spontaneously generated in freely breathing mouse preparation. (A1) Intercostal EMG activity recording in an anesthetized freely breathing mouse. Sigh is generally triggered and preceded by an inspiratory burst of fictive eupneic activity. Histograms summarize the differences between spontaneous sighs and fictive respiratory activity, in amplitude (A2), frequency (A3), and duration (A4). (*p < 0.05, n = 8). (B) Trace of integrated intercostal EMG activity (∫EMG) during control and after injection of isoproterenol into the preBötC (30 μM). (C–E) Histograms show the effects of isoproterenol on sigh frequency (C) duration (D) and on eupnea frequency (E) (ns: not significant, *p < 0.05, n = 4–8).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824105&req=5

Figure 1: Sighs are spontaneously generated in freely breathing mouse preparation. (A1) Intercostal EMG activity recording in an anesthetized freely breathing mouse. Sigh is generally triggered and preceded by an inspiratory burst of fictive eupneic activity. Histograms summarize the differences between spontaneous sighs and fictive respiratory activity, in amplitude (A2), frequency (A3), and duration (A4). (*p < 0.05, n = 8). (B) Trace of integrated intercostal EMG activity (∫EMG) during control and after injection of isoproterenol into the preBötC (30 μM). (C–E) Histograms show the effects of isoproterenol on sigh frequency (C) duration (D) and on eupnea frequency (E) (ns: not significant, *p < 0.05, n = 4–8).
Mentions: In the transverse slice preparation population activity recordings were obtained with suction electrodes positioned on the surface of the slice in the area including the preBötC. The slice preparation is placed rostral side up and encompasses network components rostral to the preBötC that appear to be critical for generating the sigh rhythm in very thin slices (Ruangkittisakul et al., 2008). The signals were amplified 2000 times, filtered (low pass 1.5 KHz, high pass 250 Hz), rectified and integrated using an electronic filter (time constant of 30–50 ms). Integrated population activity from the ventral respiratory group (VRG) was always in phase with integrated inspiratory activity of the hypoglossal motor nucleus (Telgkamp and Ramirez, 1999). Therefore, it was used as a marker for inspiratory population activity (Figure 1A). All recordings were stored on a personal computer using AxoTape (Version 2.0, Axon Instruments, Union City, CA) and analyzed offline using customized analysis software written with IGOR Pro (Wavemetrics, Lake Oswego, OR). Bursts were automatically detected by the IGOR program as described extensively in our previous study (Tryba et al., 2003; Viemari and Ramirez, 2006).

Bottom Line: By contrast, all parameters of bursting pacemakers that rely on the non-specific cation current (I(CAN)) remained unaffected.Moreover, riluzole, which blocks bursting in I(Nap) pacemakers abolished sighs altogether, while flufenamic acid (FFA) which blocks the I(CAN) current did not alter the sigh-increasing effect caused by β-NR.Our results suggest that the selective β-NR action of sighs may result from the modulation of I(Nap) pacemaker activity and that disturbances in noradrenergic system may contribute to abnormal arousal response.

View Article: PubMed Central - PubMed

Affiliation: Team P3M, Institut de Neurosciences de la Timone, UMR 7289, CNRS, Aix Marseille Univesité , Marseille, France.

ABSTRACT
The pre-Bötzinger complex (preBötC), an area that is critical for generating breathing (eupnea), gasps and sighs is continuously modulated by catecholamines. These amines and the generation of sighs have also been implicated in the regulation of arousal. Here we studied the catecholaminergic modulation of sighs not only in anesthetized freely breathing mice (in vivo), but also in medullary slice preparations that contain the preBötC and that generate fictive eupneic and sigh rhythms in vitro. We demonstrate that activating β-noradrenergic receptors (β-NR) specifically increases the frequency of sighs, while eupnea remains unaffected both in vitro and in vivo. β-NR activation specifically increased the frequency of intrinsically bursting pacemaker neurons that rely on persistent sodium current (I(Nap)). By contrast, all parameters of bursting pacemakers that rely on the non-specific cation current (I(CAN)) remained unaffected. Moreover, riluzole, which blocks bursting in I(Nap) pacemakers abolished sighs altogether, while flufenamic acid (FFA) which blocks the I(CAN) current did not alter the sigh-increasing effect caused by β-NR. Our results suggest that the selective β-NR action of sighs may result from the modulation of I(Nap) pacemaker activity and that disturbances in noradrenergic system may contribute to abnormal arousal response. The β-NR action on the preBötC may be an important mechanism in modulating behaviors that are specifically associated with sighs, such as the regulation of the early events leading to the arousal response.

Show MeSH
Related in: MedlinePlus