Role of the locus coeruleus catecholaminergic neurons in the chemosensory control of breathing in a Parkinson's disease model

Oliveira, Luíz M.; Tuppy, Marina; Moreira, Thiago S.; Takakura, Ana C.

doi:10.1016/j.expneurol.2017.04.006

Cited by 49 publications

(57 citation statements)

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“…We confirm data from the literature that a significant loss of neuronal profiles in brainstem regions involved in breathing control dramatically affect breathing output (Feldman & Ellenberger 1988;Feldman, Del Negro, & Gray, 2013;Guyenet & Bayliss, 2015;Oliveira et al, 2017;Richter, 1982;Richter, 2001;Smith, Abdala, Koizumi, Rybak, & Paton, 2007;Tuppy et al, 2015).…”

Section: Breathing Control In Parkinson's Diseasesupporting

confidence: 87%

Correlation between neuroanatomical and functional respiratory changes observed in an experimental model of Parkinson's disease

Fernandes‐Junior

Carvalho

Moreira

et al. 2018

Experimental Physiology

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We showed previously that 60 days after the induction of Parkinson's disease (PD) in a rat model, there are decreases in baseline breathing and in the number of phox2b-expressing neurons of the retrotrapezoid nucleus (RTN) and nucleus of the solitary tract (NTS), as well as a reduction in the density of the neurokinin-1 receptor (NK1r) in the pre-Bötzinger complex (preBötC) and rostral ventrolateral respiratory group (rVRG). Here, our aim was to evaluate the correlation between neuroanatomical and functional respiratory changes in an experimental model of PD. Male Wistar rats with bilateral injections of 6-hydroxydopamine (6-OHDA, 24 μg μl ) or vehicle into the striatum had respiratory parameters assessed by whole-body plethysmography 1 day before and 30, 40 or 60 days after the ablation. From the 30th day after the ablation, we observed a reduction in the number of phox2b neurons in the RTN and NTS and a reduction in the density of astrocytes in the rVRG. At 40 days after the ablation, we observed decreases in the density of NK1r in the preBötC and rVRG and of astrocytes in the RTN region. At 60 days, we observed a reduction in the density of astrocytes in the NTS and preBötC regions. The functional data showed changes in the resting and hypercapnia-induced respiratory rates and tidal volume from days 40-60 after injury. Our data suggest that the neuroanatomical changes impair respiratory activity and are presumably a major cause of the respiratory problems observed in PD.

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Section: Breathing Control In Parkinson's Diseasesupporting

confidence: 87%

Correlation between neuroanatomical and functional respiratory changes observed in an experimental model of Parkinson's disease

Fernandes‐Junior

Carvalho

Moreira

et al. 2018

Experimental Physiology

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“…Previous findings also demonstrated in a rat model of PD that central chemoreception is initially reduced, but then recovers during the course of PD (Oliveira et al., ). One explanation for that recovery is the fact that the LC is intact and responsible for the activation of breathing during hypercapnia (Oliveira et al., ).…”

Section: Discussionmentioning

confidence: 70%

“…Then, the neurotoxin is retrogradely transported and selectively kills dopaminergic neurons of the substantia nigra pars compacta (SNpc) by inhibition of mitochondrial complexes I and IV and formation of reactive oxygen species (Glinka, Tipton, & Youdim, 1996;Hernandes et al, 2013). The dose of 6-OHDA used in the present study was selected based on previous reports (Blandini, Armentero, & Martignoni, 2008;Fulceri et al, 2006;Lima, Oliveira, Botelho, Moreira, & Takakura, 2018;Oliveira et al, 2017;Schwarting & Huston, 1996). The 6-OHDA injections were performed bilaterally in the striatum to induce a retrograde neuronal nigrostriatal injury (Blum et al, 2001).…”

Section: • What Is the Main Finding And Its Importance?mentioning

confidence: 99%

“…Several pieces of evidence suggest a massive degeneration in areas of the brainstem that are involved in control of breathing, mainly the preBötC and the RTN (Benarroch et al, 2003;Tuppy et al, 2015). Furthermore, it was recently proposed that neuronal loss could be linked to breathing abnormalities, such as bradypnoea at rest and impaired response to central chemoreflex activation (Oliveira, Tuppy, Moreira, & Takakura, 2017;Tuppy et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Respiratory disturbances in a mouse model of Parkinson's disease

Oliveira

Moriya

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?Clinical reports have described and suggested central and peripheral respiratory abnormalities in Parkinson's disease (PD) patients; however, these reports have never addressed the occurrence of these abnormalities in an animal model. What is the main finding and its importance?A mouse model of PD has reduced neurokinin‐1 receptor immunoreactivity in the pre‐Bӧtzinger complex and Phox2b‐expressing neurons in the retrotrapezoid nucleus. The PD mouse has impairments of respiratory frequency and the hypercapnic ventilatory response. Lung collagen deposition and ribcage stiffness appear in PD mice. Abstract Parkinson's disease (PD) is a neurodegenerative motor disorder characterized by dopaminergic deficits in the brain. Parkinson's disease patients may experience shortness of breath, dyspnoea, breathing difficulties and pneumonia, which can be linked as a cause of morbidity and mortality of those patients. The aim of the present study was to clarify whether a mouse model of PD could develop central brainstem and lung respiratory abnormalities. Adult male C57BL/6 mice received bilateral injections of 6‐hydroxydopamine (10 μg μl−1; 0.5 μl) or vehicle into the striatum. Ventilatory parameters were assessed in the 40 days after induction of PD, by whole‐body plethysmography. In addition, measurements of respiratory input impedance (closed and opened thorax) were performed. 6‐Hydroxydopamine reduced the number of tyrosine hydroxylase neurons in the substantia nigra pars compacta, the density of neurokinin‐1 receptor immunoreactivity in the pre‐Bӧtzinger complex and the number of Phox2b neurons in the retrotrapezoid nucleus. Physiological experiments revealed a reduction in resting respiratory frequency in PD animals, owing to an increase in expiratory time and a blunted hypercapnic ventilatory response. Measurements of respiratory input impedance showed that only PD animals with the thorax preserved had increased viscance, indicating that the ribcage could be stiff in this animal model of PD. Consistent with stiffened ribcage mechanics, abnormal collagen deposits in alveolar septa and airways were observed in PD animals. Our data showed that our mouse model of PD presented with neurodegeneration in respiratory brainstem centres and disruption of lung mechanical properties, suggesting that both central and peripheral deficiencies contribute to PD‐related respiratory pathologies.

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“…Additional pathophysiologies such as obstructive sleep apnea, ARDS and COPD present with respiratory instability while engaging the hypoxic reflex circuitry to maintain vital functions. A series of studies on Parkinson's disease using 6-hydroxydopamine (6-OHDA) in the striatum showed a loss of CA dopamine neurons and retrotrapezoid nucleus (RTN) neurons resulting in chemosensory dysfunction that was mitigated by potential compensation by the locus coeruleus (Tuppy et al, 2015; Oliveira et al, 2017). Given that this model only shows respiratory instability under hypoxic challenges, the B6.FVB(Cg)-Tg(Th-Cre)FI172Gsat driver defines new populations that either as a whole or separately may play a role in the circuitry that is developmentally perturbed in these pathophysiologies, or engaged when responding to hypoxic stress from obstruction, compromised pulmonary function or neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Tg(Th-Cre)FI172Gsat (Th-Cre)defines neurons that are required for full hypercapnic and hypoxic reflexes

Sun

Ray

2017

Biology Open

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The catecholaminergic (CA) system has been implicated in many facets of breathing control and offers an important target to better comprehend the underlying etiologies of both developmental and adult respiratory pathophysiologies. Here, we used a noninvasive DREADD-based pharmacogenetic approach to acutely perturb Tg(Th-Cre)FI172Gsat (Th-Cre)-defined neurons in awake and unrestrained mice in an attempt to characterize CA function in breathing. We report that clozapine-N-oxide (CNO)-DREADD-mediated inhibition of Th-Cre-defined neurons results in blunted ventilatory responses under respiratory challenge. Under a hypercapnic challenge (5% CO2/21% O2/74% N2), perturbation of Th-Cre neurons results in reduced fR, and . Under a hypoxic challenge (10% O2/90% N2), we saw reduced fR, and , in addition to instability in both interbreath interval and tidal volume, resulting in a Cheyne-Stokes-like respiratory pattern. These findings demonstrate the necessity of Th-Cre-defined neurons for the hypercapnic and hypoxic ventilatory responses and breathing stability during hypoxia. However, given the expanded non-CA expression domains of the Tg(Th-Cre)FI172Gsat mouse line found in the brainstem, full phenotypic effect cannot be assigned solely to CA neurons. Nonetheless, this work identifies a key respiratory population that may lead to further insights into the circuitry that maintains respiratory stability in the face of homeostatic challenges.

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Role of the locus coeruleus catecholaminergic neurons in the chemosensory control of breathing in a Parkinson's disease model

Cited by 49 publications

References 57 publications

Correlation between neuroanatomical and functional respiratory changes observed in an experimental model of Parkinson's disease

Correlation between neuroanatomical and functional respiratory changes observed in an experimental model of Parkinson's disease

Respiratory disturbances in a mouse model of Parkinson's disease

Tg(Th-Cre)FI172Gsat (Th-Cre)defines neurons that are required for full hypercapnic and hypoxic reflexes

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