{"doi":"10.1113/jp280588","title":"Good things come in small packages…except after spinal injury","abstract":"The saying ‘good things come in small packages’ is the main lesson from the fable ‘The Lion and the Mouse’ by Aesop (620–554, BC). In the fable, a mouse, when caught by a lion, promises to help him later in exchange for his life. The sceptical lion releases him and is later rewarded when, after being caught by hunters, the mouse chews through his bonds and frees him. In his own way, the tiny mouse had greater power than the king of beasts. In this issue of The Journal of Physiology, Rana et al. (2020) investigated the effects of cervical spinal hemisection on glutaminergic excitatory drive to phrenic motoneurons. They show that seven days after spinal hemisection at the C2 level, expression of the glutamate transporters VGLUT-1 and VGLUT-2 that mediate brainstem motor drive to phrenic motoneurons was significantly reduced. In particular, VGLUT expression on smaller motoneurons was more severely affected than that associated with larger motoneurons innervating the diaphragm. These results provide an important mechanistic explanation for the ‘crossed phrenic phenomenon’. This phenomenon describes loss of excitatory motor drive to the ipsilateral hemidiaphragm following cervical spinal hemisection and can be observed in many different mammalian species, even in Mus musculus (Minor et al. 2006) and Felis felis (Deason & Robb, 1911) (although to my knowledge not yet in Felis leo). These authors also go on to show that preserved excitatory glutaminergic drive to larger phrenic motoneurons appears to originate from the contralateral brainstem or from spinal sources. These results elaborate on previous findings by this team extending back to the late 1980s. Sieck and Fourier (1989) showed that motor performance of the diaphragm during airway protective and resuscitative behaviours greatly exceeded that observed with maximal chemical drive. These authors concluded that fast twitch type motor units that are associated with larger phrenic motoneurons were primarily responsible for the greater drive to the diaphragm. These findings led to the concept of a ‘reflex reserve’ (Mantilla et al. 2010) of motor drive within the phrenic motoneuron pool, consisting of larger phrenic motoneurons. This pool of phrenic motoneurons, when activated, mediate very large force increases in the diaphragm that are necessary to execute airway protective behaviours like cough and sneeze or even gastrointestinal protective behaviours like vomiting. This reflex reserve pool of motoneurons is not thought to normally participate in motor activation of the diaphragm during breathing, where slow twitch (type S) motor units predominate. Indeed, Rana et al. (2020) also show that diaphragm electromyograms during augmented breaths (sighs) and during prolonged airway occlusion are relatively unaffected by C2 spinal hemisection compared with eupnoea or large respiratory chemical drive (10% O2 and 5% CO2). Cervical spinal injury results in profound respiratory morbidity due to the loss of respiratory drive to the inspiratory muscles, often requiring long-term ventilatory support and leading to pulmonary infection, which is the main cause of death in this patient group. The results of Rana et al. (2020) support the hypothesis that ventilatory impairment following cervical spinal injury in humans is due to greater impairment of the excitatory drive to smaller phrenic motoneurons than larger ones. This concept begs the translational question ‘how do we activate the reflex reserve pool during breathing to replace lost inspiratory drive from the smaller motoneurons due to spinal injury?’ Certainly, spontaneous recovery in breathing-related inspiratory drive occurs in the weeks and months following cervical spinal injury. However, the functional impact of this recovery in animal models is low (Fuller et al. 2006). Repurposing the reflex reserve motoneuron pool to enhance phrenic motor drive during breathing could represent a viable therapeutic approach to respiratory depression ","journal":"The Journal of Physiology","year":2020,"id":130822,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9581,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":286666,"name":"Donald C. Bolser","orcid":"0000-0002-4577-8954","position":0,"is_corresponding":true}],"reference_count":7,"raw_metadata":null,"created_at":"2026-07-18T23:15:56.698770Z","pmid":"32833267","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}