Phrenic long-term facilitation following intrapleural CTB-SAP-induced respiratory motor neuron death

Nichols, Nicole L.; Craig, Taylor A.; Tanner, Miles A.

doi:10.1016/j.resp.2017.08.003

Cited by 11 publications

(5 citation statements)

References 35 publications

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“…Thus, another limitation is that although we see many aspects mimicked here, some of the surviving neurons not showing obvious signs may impact the amount of plasticity. However, we find a similar amount of motor neuron death around the same time frame in our CTB-SAP respiratory model, and these rats exhibit enhanced plasticity (Nichols et al, 2015b; 2017). Thus, we believe this will also likely be the case with hypoglossal plasticity in rats intralingually injected with CTB-SAP.…”

Section: Discussionsupporting

confidence: 63%

Hypoglossal Motor Neuron Death Via Intralingual CTB–saporin (CTB–SAP) Injections Mimic Aspects of Amyotrophic Lateral Sclerosis (ALS) Related to Dysphagia

et al. 2018

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Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to degeneration of motor neurons and skeletal muscles, including those required for swallowing. Tongue weakness is one of the earliest signs of bulbar dysfunction in ALS, which is attributed to degeneration of motor neurons in the hypoglossal nucleus in the brainstem, the axons of which directly innervate the tongue. Despite its fundamental importance, dysphagia (difficulty swallowing) and strategies to preserve swallowing function have seldom been studied in ALS models. It is difficult to study dysphagia in ALS models since the amount and rate at which hypoglossal motor neuron death occurs cannot be controlled, and degeneration is not limited to the hypoglossal nucleus. Here, we report a novel experimental model using intralingual injections of cholera toxin B conjugated to saporin (CTB-SAP) to study the impact of only hypoglossal motor neuron death without the many complications that are present in ALS models. Hypoglossal motor neuron survival, swallowing function, and hypoglossal motor output were assessed in Sprague-Dawley rats after intralingual injection of either CTB-SAP (25 g) or unconjugated CTB and SAP (controls) into the genioglossus muscle. CTB-SAP treated rats exhibited significant (p ≤ 0.05) deficits vs. controls in: (1) lick rate (6.0 ± 0.1 vs. 6.6 ± 0.1 Hz; (2) hypoglossal motor output (0.3 ± 0.05 vs. 0.6 ± 0.10 mV); and (3) hypoglossal motor neuron survival (398 ± 34 vs. 1018 ± 41 neurons). Thus, this novel, inducible model of hypoglossal motor neuron death mimics the dysphagia phenotype that is observed in ALS rodent models, and will allow us to study strategies to preserve swallowing function.

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Section: Discussionsupporting

confidence: 63%

Hypoglossal Motor Neuron Death Via Intralingual CTB–saporin (CTB–SAP) Injections Mimic Aspects of Amyotrophic Lateral Sclerosis (ALS) Related to Dysphagia

et al. 2018

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“…In close similarity to our model, other authors have proposed rodent models, where defined, small subpopulations of MNs have been removed by using CTB-Sap injection to mimic different aspects of ALS pathogenesis separately from each other. For instance, intrapleural injection can be used to mimic respiratory dysfunctions [60,61,62], and also to study respiratory plasticity after motoneuron depletion, without the concurrent participation of other confounding factors that are present in ALS models and patients [62]. Similarly, injecting CTB-Sap in the tongue muscles represents a simple model of dysphagia, which is another typical symptom of bulbar ALS [61].…”

Section: Discussionmentioning

confidence: 99%

Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss

Gulino

Vicario

Giunta

et al. 2019

IJMS

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Despite the relevant research efforts, the causes of amyotrophic lateral sclerosis (ALS) are still unknown and no effective cure is available. Many authors suggest that ALS is a multi-system disease caused by a network failure instead of a cell-autonomous pathology restricted to motoneurons. Although motoneuronal loss is the critical hallmark of ALS given their specific vulnerability, other cell populations, including muscle and glial cells, are involved in disease onset and progression, but unraveling their specific role and crosstalk requires further investigation. In particular, little is known about the plastic changes of the degenerating motor system. These spontaneous compensatory processes are unable to halt the disease progression, but their elucidation and possible use as a therapeutic target represents an important aim of ALS research. Genetic animal models of disease represent useful tools to validate proven hypotheses or to test potential therapies, and the conception of novel hypotheses about ALS causes or the study of pathogenic mechanisms may be advantaged by the use of relatively simple in vivo models recapitulating specific aspects of the disease, thus avoiding the inclusion of too many confounding factors in an experimental setting. Here, we used a neurotoxic model of spinal motoneuron depletion induced by injection of cholera toxin-B saporin in the gastrocnemius muscle to investigate the possible occurrence of compensatory changes in both the muscle and spinal cord. The results showed that, following the lesion, the skeletal muscle became atrophic and displayed electromyographic activity similar to that observed in ALS patients. Moreover, the changes in muscle fiber morphology were different from that observed in ALS models, thus suggesting that some muscular effects of disease may be primary effects instead of being simply caused by denervation. Notably, we found plastic changes in the surviving motoneurons that can produce a functional restoration probably similar to the compensatory changes occurring in disease. These changes could be at least partially driven by glutamatergic signaling, and astrocytes contacting the surviving motoneurons may support this process.

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“…We also assessed a toxin-based model of motoneuronal depletion established using CTB-Sap [ 14 , 26 , 27 ], which selectively targets axon terminals and kills motoneurons by retrograde suicide transport [ 28 , 29 ], thus inducing both muscular denervation and behavioural impairment of motor performance. Our reductionist in vivo model of motoneuronal disorders showed functional deficits and electromyographic signs typical of both transgenic ALS mouse model and human ALS patients [ 30 – 32 ].…”

Section: Discussionmentioning

confidence: 99%

Increased expression of connexin 43 in a mouse model of spinal motoneuronal loss

Spitale

Vicario

Rosa

et al. 2020

Aging

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Amyotrophic lateral sclerosis (ALS) is one of the most common motoneuronal disease, characterized by motoneuronal loss and progressive paralysis. Despite research efforts, ALS remains a fatal disease, with a survival of 2-5 years after disease onset. Numerous gene mutations have been correlated with both sporadic (sALS) and familiar forms of the disease, but the pathophysiological mechanisms of ALS onset and progression are still largely uncertain. However, a common profile is emerging in ALS pathological features, including misfolded protein accumulation and a cross-talk between neuroinflammatory and degenerative processes. In particular, astrocytes and microglial cells have been proposed as detrimental influencers of perineuronal microenvironment, and this role may be exerted via gap junctions (GJs)- and hemichannels (HCs)-mediated communications. Herein we investigated the role of the main astroglial GJs-forming connexin, Cx43, in human ALS and the effects of focal spinal cord motoneuronal depletion onto the resident glial cells and Cx43 levels. Our data support the hypothesis that motoneuronal depletion may affect glial activity, which in turn results in reactive Cx43 expression, further promoting neuronal suffering and degeneration.

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Phrenic long-term facilitation following intrapleural CTB-SAP-induced respiratory motor neuron death

Cited by 11 publications

References 35 publications

Hypoglossal Motor Neuron Death Via Intralingual CTB–saporin (CTB–SAP) Injections Mimic Aspects of Amyotrophic Lateral Sclerosis (ALS) Related to Dysphagia

Hypoglossal Motor Neuron Death Via Intralingual CTB–saporin (CTB–SAP) Injections Mimic Aspects of Amyotrophic Lateral Sclerosis (ALS) Related to Dysphagia

Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss

Increased expression of connexin 43 in a mouse model of spinal motoneuronal loss

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