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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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Isoproterenol increases the burst frequency of INap pacemaker neurons. (A) Recording of an inspiratory pacemaker neuron that bursts during fictive sigh activity. (B) This neuron continues to burst in synaptic blockade (cocktail). (C) Application of isoproterenol 20 μM increases the burst frequency of INap pacemaker neuron. (D) Application of riluzole 20 μM abolishes the bursting properties of this neuron, but the neuron continues to generate action potentials. Histograms summarize the effects of isoproterenol on burst duration (E), burst area (F), burst amplitude (G), and burst frequency (H). Note only burst frequency was significantly affected (ns: not significant, *p < 0.05, n = 6).
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Figure 7: Isoproterenol increases the burst frequency of INap pacemaker neurons. (A) Recording of an inspiratory pacemaker neuron that bursts during fictive sigh activity. (B) This neuron continues to burst in synaptic blockade (cocktail). (C) Application of isoproterenol 20 μM increases the burst frequency of INap pacemaker neuron. (D) Application of riluzole 20 μM abolishes the bursting properties of this neuron, but the neuron continues to generate action potentials. Histograms summarize the effects of isoproterenol on burst duration (E), burst area (F), burst amplitude (G), and burst frequency (H). Note only burst frequency was significantly affected (ns: not significant, *p < 0.05, n = 6).

Mentions: We next explored the modulatory effect on neurons that possess pacemaker bursting properties (Ramirez et al., 2011; Carroll and Ramirez, 2013). In the preBötC region, two types of inspiratory bursting pacemaker mechanisms can be discriminated based on their responses to the general calcium channel blocker cadmium, (ICAN or Cadmium-sensitive, and INap or Cadmium-insensitive pacemakers, Thoby-Brisson and Ramirez, 2001; Peña et al., 2004; Viemari et al., 2011). All ICAN and INap pacemaker neurons (n = 10) burst during both fictive eupneic and fictive sigh activity in vitro when embedded in the inspiratory network (Lieske et al., 2000, Figures 6A, 7A). Isoproterenol had no significant effects on the membrane potential of ICAN pacemaker neurons (P = 0.25). Moreover, in all examined, synaptically isolated, ICAN pacemaker neurons bursting was unaffected by isoproterenol (20 μM, n = 4, Figure 6). No effect was observed on burst amplitude (34.6 ± 2.7 vs. 33.2 ± 3.2 mV, Figure 6E), burst frequency (0.33 ± 0.1 vs. 0.36 ± 0.1 Hz, Figure 6F), burst duration (0.98 ± 0.2 vs. 1.02 ± 0.3 s, Figure 6G) and burst area (29.35 ± 1.56 vs. 27.15 ± 1.5, Figure 6H), suggesting that ICAN pacemaker neurons are unlikely involved in the modulation or the generation of the fictive sigh activity in vitro.


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)

Isoproterenol increases the burst frequency of INap pacemaker neurons. (A) Recording of an inspiratory pacemaker neuron that bursts during fictive sigh activity. (B) This neuron continues to burst in synaptic blockade (cocktail). (C) Application of isoproterenol 20 μM increases the burst frequency of INap pacemaker neuron. (D) Application of riluzole 20 μM abolishes the bursting properties of this neuron, but the neuron continues to generate action potentials. Histograms summarize the effects of isoproterenol on burst duration (E), burst area (F), burst amplitude (G), and burst frequency (H). Note only burst frequency was significantly affected (ns: not significant, *p < 0.05, n = 6).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Isoproterenol increases the burst frequency of INap pacemaker neurons. (A) Recording of an inspiratory pacemaker neuron that bursts during fictive sigh activity. (B) This neuron continues to burst in synaptic blockade (cocktail). (C) Application of isoproterenol 20 μM increases the burst frequency of INap pacemaker neuron. (D) Application of riluzole 20 μM abolishes the bursting properties of this neuron, but the neuron continues to generate action potentials. Histograms summarize the effects of isoproterenol on burst duration (E), burst area (F), burst amplitude (G), and burst frequency (H). Note only burst frequency was significantly affected (ns: not significant, *p < 0.05, n = 6).
Mentions: We next explored the modulatory effect on neurons that possess pacemaker bursting properties (Ramirez et al., 2011; Carroll and Ramirez, 2013). In the preBötC region, two types of inspiratory bursting pacemaker mechanisms can be discriminated based on their responses to the general calcium channel blocker cadmium, (ICAN or Cadmium-sensitive, and INap or Cadmium-insensitive pacemakers, Thoby-Brisson and Ramirez, 2001; Peña et al., 2004; Viemari et al., 2011). All ICAN and INap pacemaker neurons (n = 10) burst during both fictive eupneic and fictive sigh activity in vitro when embedded in the inspiratory network (Lieske et al., 2000, Figures 6A, 7A). Isoproterenol had no significant effects on the membrane potential of ICAN pacemaker neurons (P = 0.25). Moreover, in all examined, synaptically isolated, ICAN pacemaker neurons bursting was unaffected by isoproterenol (20 μM, n = 4, Figure 6). No effect was observed on burst amplitude (34.6 ± 2.7 vs. 33.2 ± 3.2 mV, Figure 6E), burst frequency (0.33 ± 0.1 vs. 0.36 ± 0.1 Hz, Figure 6F), burst duration (0.98 ± 0.2 vs. 1.02 ± 0.3 s, Figure 6G) and burst area (29.35 ± 1.56 vs. 27.15 ± 1.5, Figure 6H), suggesting that ICAN pacemaker neurons are unlikely involved in the modulation or the generation of the fictive sigh activity in vitro.

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