Direct evidence for phosphorus limitation on Amazon forest productivity.

The productivity of rainforests growing on highly weathered tropical soils is expected to be limited by phosphorus availability1. Yet, controlled fertilization experiments have been unable to demonstrate a dominant role for phosphorus in controlling tropical forest net primary productivity. Recent syntheses have demonstrated that responses to nitrogen addition are as large as to phosphorus2, and adaptations to low phosphorus availability appear to enable net primary productivity to be maintained across major soil phosphorus gradients3. Thus, the extent to which phosphorus availability limits tropical forest productivity is highly uncertain. The majority of the Amazonia, however, is characterized by soils that are more depleted in phosphorus than those in which most tropical fertilization experiments have taken place2. Thus, we established a phosphorus, nitrogen and base cation addition experiment in an old growth Amazon rainforest, with a low soil phosphorus content that is representative of approximately 60% of the Amazon basin. Here we show that net primary productivity increased exclusively with phosphorus addition. After 2 years, strong responses were observed in fine root (+29%) and canopy productivity (+19%), but not stem growth. The direct evidence of phosphorus limitation of net primary productivity suggests that phosphorus availability may restrict Amazon forest responses to CO2 fertilization4, with major implications for future carbon sequestration and forest resilience to climate change.

Post-translational modifications on RNA-binding proteins: accelerators, brakes, or passengers in neurodegeneration?

RNA-binding proteins (RBPs) are critical players in RNA expression and metabolism, thus, the proper regulation of this class of proteins is critical for cellular health. Regulation of RBPs often occurs through post-translational modifications (PTMs), which allow the cell to quickly and efficiently respond to cellular and environmental stimuli. PTMs have recently emerged as important regulators of RBPs implicated in neurodegenerative disorders, in particular amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we summarize how disease-associated PTMs influence the biophysical properties, molecular interactions, subcellular localization, and function of ALS/FTD-linked RBPs, such as FUS and TDP-43. We will discuss how PTMs are believed to play pathological, protective, or ambiguous roles in these neurodegenerative disorders.

Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation.

Post-translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA-binding protein TAR DNA-binding protein (TDP-43), is hyperphosphorylated in disease on several C-terminal serine residues, a process generally believed to promote TDP-43 aggregation. Here, we however find that Casein kinase 1δ-mediated TDP-43 hyperphosphorylation or C-terminal phosphomimetic mutations reduce TDP-43 phase separation and aggregation, and instead render TDP-43 condensates more liquid-like and dynamic. Multi-scale molecular dynamics simulations reveal reduced homotypic interactions of TDP-43 low-complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP-43, but suppress accumulation of TDP-43 in membrane-less organelles and promote its solubility in neurons. We speculate that TDP-43 hyperphosphorylation may be a protective cellular response to counteract TDP-43 aggregation.

Neuron populations use variable combinations of short-term feedback mechanisms to stabilize firing rate.

Neurons tightly regulate firing rate and a failure to do so leads to multiple neurological disorders. Therefore, a fundamental question in neuroscience is how neurons produce reliable activity patterns for decades to generate behavior. Neurons have built-in feedback mechanisms that allow them to monitor their output and rapidly stabilize firing rate. Most work emphasizes the role of a dominant feedback system within a neuronal population for the control of moment-to-moment firing. In contrast, we find that respiratory motoneurons use 2 activity-dependent controllers in unique combinations across cells, dynamic activation of an Na+ pump subtype, and rapid potentiation of Kv7 channels. Both systems constrain firing rate by reducing excitability for up to a minute after a burst of action potentials but are recruited by different cellular signals associated with activity, increased intracellular Na+ (the Na+ pump), and membrane depolarization (Kv7 channels). Individual neurons do not simply contain equal amounts of each system. Rather, neurons under strong control of the Na+ pump are weakly regulated by Kv7 enhancement and vice versa along a continuum. Thus, each motoneuron maintains its characteristic firing rate through a unique combination of the Na+ pump and Kv7 channels, which are dynamically regulated by distinct feedback signals. These results reveal a new organizing strategy for stable circuit output involving multiple fast activity sensors scaled inversely across a neuronal population.

Plasticity in the Functional Properties of NMDA Receptors Improves Network Stability during Severe Energy Stress.

Brain energy stress leads to neuronal hyperexcitability followed by a rapid loss of function and cell death. In contrast, the frog brainstem switches into a state of extreme metabolic resilience that allows them to maintain motor function during hypoxia as they emerge from hibernation. NMDA receptors (NMDARs) are Ca2+-permeable glutamate receptors that contribute to the loss of homeostasis during hypoxia. Therefore, we hypothesized that hibernation leads to plasticity that reduces the role of NMDARs within neural networks to improve function during hypoxia. To test this, we assessed a circuit with a large involvement of NMDAR synapses, the brainstem respiratory network of female bullfrogs, Lithobates catesbeianus Contrary to our expectations, hibernation did not alter the role of NMDARs in generating network output, nor did it affect the amplitude, kinetics, and hypoxia sensitivity of NMDAR currents. Instead, hibernation strongly reduced NMDAR Ca2+ permeability and enhanced desensitization during repetitive stimulation. Under severe hypoxia, the normal NMDAR profile caused network hyperexcitability within minutes, which was mitigated by blocking NMDARs. After hibernation, the modified complement of NMDARs protected against hyperexcitability, as disordered output did not occur for at least one hour in hypoxia. These findings uncover state-dependence in the plasticity of NMDARs, whereby multiple changes to receptor function improve neural performance during metabolic stress without interfering with their normal role during healthy conditions.

Neural processing without O2 and glucose delivery: from the pond to the clinic.

Neuronal activity requires a large amount of ATP, leading to a rapid collapse of brain function when aerobic respiration fails. Here, we summarize how rhythmic motor circuits in the brainstem of adult frogs, which normally have high metabolic demands, transform to produce proper output during severe hypoxia associated with emergence from hibernation. We suggest that general principles underlying plasticity in brain bioenergetics may be uncovered by studying non-mammalian models that face extreme environments, yielding new insights to combat neurological disorders involving dysfunctional energy metabolism.

The new missense G376V-TDP-43 variant induces late-onset distal myopathy but not amyotrophic lateral sclerosis.

TDP-43-positive inclusions in neurons are a hallmark of several neurodegenerative diseases including familial amyotrophic lateral sclerosis (fALS) caused by pathogenic TARDBP variants as well as more common non-Mendelian sporadic ALS (sALS). Here we report a G376V-TDP-43 missense variant in the C-terminal prion-like domain of the protein in two French families affected by an autosomal dominant myopathy but not fulfilling diagnostic criteria for ALS. Patients from both families presented with progressive weakness and atrophy of distal muscles, starting in their 5th-7th decade. Muscle biopsies revealed a degenerative myopathy characterized by accumulation of rimmed (autophagic) vacuoles, disruption of sarcomere integrity and severe myofibrillar disorganization. The G376 V variant altered a highly conserved amino acid residue and was absent in databases on human genome variation. Variant pathogenicity was supported by in silico analyses and functional studies. The G376 V mutant increased the formation of cytoplasmic TDP-43 condensates in cell culture models, promoted assembly into high molecular weight oligomers and aggregates in vitro, and altered morphology of TDP-43 condensates arising from phase separation. Moreover, the variant led to the formation of cytoplasmic TDP-43 condensates in patient-derived myoblasts and induced abnormal mRNA splicing in patient muscle tissue. The identification of individuals with TDP-43-related myopathy but not ALS implies that TARDBP missense variants may have more pleiotropic effects than previously anticipated and support a primary role for TDP-43 in skeletal muscle pathophysiology. We propose to include TARDBP screening in the genetic work-up of patients with late-onset distal myopathy. Further research is warranted to examine the precise pathogenic mechanisms of TARDBP variants causing either a neurodegenerative or myopathic phenotype.

Evaluation of Sexual Function of Transgender Individuals.

PURPOSE: The current study sought to evaluate the sexual function of transgender men and women and to identify associated factors. METHODS: Trans individuals who were outpatients at our gender incongruence (GI) center for follow-up of gender-affirming hormone therapy with age ranging 27 to 50 years were invited to participate in this cross-sectional study. Clinical data were collected from the medical records. Two scales, the Female Sexual Function Index (FSFI) and the Male Sexual Function Index (MSFI), were administered to all females (n = 50) and all males (n = 58). Each participant also responded to a semi-structured questionnaire that assessed feelings regarding being transgender and satisfaction with sexual life. RESULTS: Relative to trans women, trans men had a higher total FSFI score, and higher scores in the FSFI domains of arousal, lubrication, orgasm, and satisfaction (all p < 0.01), and in the total MSFI score, and higher scores in the MFSI domains of arousal, erection, orgasm, and satisfaction (all p < 0.01). A separate semi-structured evaluation indicated that more than half of the trans men and almost half of the trans women were satisfied or very satisfied with their sexual life. CONCLUSIONS: The total scores from the FSFI and MSFI indicated a high risk of sexual dysfunction in trans men and especially, in trans women. However, the semi-structured evaluation showed that more than half of the trans men and almost half of the trans women were satisfied with their sexual life.

"What really matters to the patients?": assessing the impact of wound healing on the quality of life in patients undergoing incisional hernia repair.

PURPOSE: We aim to evaluate the impact of surgical wound complications in the first 30 postoperative days after incisional hernia repair on the long-term quality of life of patients. In addition, the impact of the surgical technique and preoperative comorbidities on the quality of life of patients will also be evaluated. METHOD: Prospective cohort study, which evaluates 115 patients who underwent incisional hernioplasty between 2019 and 2020, using the onlay and retromuscular techniques. These patients were initially assessed with regard to surgical wound outcomes in the first 30 postoperative days (surgical site infection (SSI) or surgical site occurrence (SSO)), and then, assessed after three years, through a specific quality of life questionnaire, the Hernia Related Quality of Life Survey (HerQLes). RESULTS: After some patients were lost to follow-up during the study period, due to death, difficulty in contact, refusal to respond to the questionnaire, eighty patients were evaluated. Of these, 11 patients (13.8%) had SSI in the first 30 postoperative days and 37 (46.3%) had some type of SSO. The impact of both SSI and SSO on quality of life indices was not identified. When analyzing others variables, we observed that the Body Mass Index (BMI) had a significant impact on the patients' quality of life. Likewise, hernia size and mesh size were identified as variables related to a worse quality of life outcome. No difference was observed regarding the surgical techniques used. CONCLUSION: In the present study, no relationship was identified between surgical wound outcomes (SSO and SSI) and worse quality of life results using the HerQLes score. We observed that both BMI and the size of meshes and hernias showed an inversely proportional relationship with quality of life indices. However, more studies evaluating preoperative quality of life indices and comparing them with postoperative indices should be carried out to evaluate these correlations.

Synaptic modifications transform neural networks to function without oxygen.

BACKGROUND: Neural circuit function is highly sensitive to energetic limitations. Much like mammals, brain activity in American bullfrogs quickly fails in hypoxia. However, after emergence from overwintering, circuits transform to function for approximately 30-fold longer without oxygen using only anaerobic glycolysis for fuel, a unique trait among vertebrates considering the high cost of network activity. Here, we assessed neuronal functions that normally limit network output and identified components that undergo energetic plasticity to increase robustness in hypoxia. RESULTS: In control animals, oxygen deprivation depressed excitatory synaptic drive within native circuits, which decreased postsynaptic firing to cause network failure within minutes. Assessments of evoked and spontaneous synaptic transmission showed that hypoxia impairs synaptic communication at pre- and postsynaptic loci. However, control neurons maintained membrane potentials and a capacity for firing during hypoxia, indicating that those processes do not limit network activity. After overwintering, synaptic transmission persisted in hypoxia to sustain motor function for at least 2 h. CONCLUSIONS: Alterations that allow anaerobic metabolism to fuel synapses are critical for transforming a circuit to function without oxygen. Data from many vertebrate species indicate that anaerobic glycolysis cannot fuel active synapses due to the low ATP yield of this pathway. Thus, our results point to a unique strategy whereby synapses switch from oxidative to exclusively anaerobic glycolytic metabolism to preserve circuit function during prolonged energy limitations.

Maternal pre-pregnancy body mass index, gestational weight gain and child weight during the first 2 years of life in an Amazonian birth cohort.

BACKGROUND: In socially vulnerable populations, evidence is needed regarding the role of maternal nutritional status on child weight during the first 2 years of life. OBJECTIVES: We aimed to assess the association of pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with offspring BMI-for-age z-scores (BAZs) during the first 2 years of life. METHODS: A population-based birth cohort study was conducted with 900 mother-child pairs. Pre-pregnancy weight and weight at delivery were collected from medical records, and anthropometric data were measured at birth and at 6-month, 1-year and 2-year follow-up visits. Linear regression and linear mixed-effect models assessed associations with pre-pregnancy BMI, GWG and BAZ during the first 2 years of life. RESULTS: Pre-pregnancy overweight and obesity and excessive GWG were positively associated with BAZ at birth and at 1- and 2-year follow-up visits. There were no significant additional BAZ changes per year based on the exposures up to age 2 years. CONCLUSIONS: Elevated maternal pre-pregnancy BMI and GWG were associated with a child's higher BAZ at birth, and these differences remained constant throughout the first 2 years of life in Amazonian children. These findings highlight the importance of promoting adequate maternal weight before pregnancy and during prenatal care also in socially vulnerable populations.

Molecular profiling of CO2/pH-sensitive neurons in the locus coeruleus of bullfrogs reveals overlapping noradrenergic and glutamatergic cell identity.

Locus coeruleus (LC) neurons regulate breathing by sensing CO2/pH. Neurons within the vertebrate LC are the main source of norepinephrine within the brain. However, they also use glutamate and GABA for fast neurotransmission. Although the amphibian LC is recognized as a site involved in central chemoreception for the control of breathing, the neurotransmitter phenotype of these neurons is unknown. To address this question, we combined electrophysiology and single-cell quantitative PCR to detect mRNA transcripts that define norepinephrinergic, glutamatergic, and GABAergic phenotypes in LC neurons activated by hypercapnic acidosis (HA) in American bullfrogs. Most LC neurons activated by HA had overlapping expression of noradrenergic and glutamatergic markers but did not show strong support for GABAergic transmission. Genes that encode the pH-sensitive K+ channel, TASK2, and acid-sensing cation channel, ASIC2, were most abundant, while Kir5.1 was present in 1/3 of LC neurons. The abundance of transcripts related to norepinephrine biosynthesis linearly correlated with those involved in pH sensing. These results suggest that noradrenergic neurons in the amphibian LC also use glutamate as a neurotransmitter and that CO2/pH sensitivity may be linkedto the noradrenergic cell identity.

A brainstem preparation allowing simultaneous access to respiratory motor output and cellular properties of motoneurons in American bullfrogs.

Breathing is generated by a complex neural circuit, and the ability to monitor the activity of multiple network components simultaneously is required to uncover the cellular basis of breathing. In neonatal rodents, a single brainstem slice can be obtained to record respiratory-related motor nerve discharge along with individual rhythm-generating cells or motoneurons because of the close proximity of these neurons in the brainstem. However, most ex vivo preparations in other vertebrates can only capture respiratory motor outflow or electrophysiological properties of putative respiratory neurons in slices without relevant synaptic inputs. Here, we detail a method to horizontally slice away the dorsal portion of the brainstem to expose fluorescently labeled motoneurons for patch-clamp recordings in American bullfrogs. This 'semi-intact' preparation allows tandem recordings of motor output and single motoneurons during respiratory-related synaptic inputs. The rhythmic motor patterns are comparable to those from intact preparations and operate at physiological temperature and [K+]. Thus, this preparation provides the ability to record network and cellular outputs simultaneously and may lead to new mechanistic insights into breathing control across vertebrates.

Metabolic trade-offs favor regulated hypothermia and inhibit fever in immune-challenged chicks.

The febrile response to resist a pathogen is energetically expensive, while regulated hypothermia seems to preserve energy for vital functions. We hypothesized here that immune-challenged birds facing metabolic trade-offs (reduced energy supply/increased energy demand) favor a regulated hypothermic response at the expense of fever. To test this hypothesis, we compared 5 day old broiler chicks exposed to fasting, cold (25°C), and fasting combined with cold with a control group fed under thermoneutral conditions (30°C). The chicks were injected with saline or with a high dose of endotoxin known to induce a biphasic thermal response composed of a drop in body temperature (Tb) followed by fever. Then Tb, oxygen consumption (metabolic rate), peripheral vasomotion (cutaneous heat exchange), breathing frequency (respiratory heat exchange) and huddling behavior (heat conservation indicator) were analyzed. Irrespective of metabolic trade-offs, chicks presented a transient regulated hypothermia in the first hour, which relied on a suppressed metabolic rate for all groups, increased breathing frequency for chicks fed/fasted at 30°C, and peripheral vasodilation in chicks fed/fasted at 25°C. Fever was observed only in chicks kept at thermoneutrality and was supported by peripheral vasoconstriction and huddling behavior. Fed and fasted chicks at 25°C completely eliminated fever despite the ability to increase metabolic rate for thermogenesis in the phase correspondent to fever when it was pharmacologically induced by 2,4-dinitrophenol. Our data suggest that increased competing demands affect chicks' response to an immune challenge, favoring regulated hypothermia to preserve energy while the high costs of fever to resist a pathogen are avoided.

Isoforms of MUC16 activate oncogenic signaling through EGF receptors to enhance the progression of pancreatic cancer.

Aberrant expression of CA125/MUC16 is associated with pancreatic ductal adenocarcinoma (PDAC) progression and metastasis. However, knowledge of the contribution of MUC16 to pancreatic tumorigenesis is limited. Here, we show that MUC16 expression is associated with disease progression, basal-like and squamous tumor subtypes, increased tumor metastasis, and short-term survival of PDAC patients. MUC16 enhanced tumor malignancy through the activation of AKT and GSK3ß oncogenic signaling pathways. Activation of these oncogenic signaling pathways resulted in part from increased interactions between MUC16 and epidermal growth factor (EGF)-type receptors, which were enhanced for aberrant glycoforms of MUC16. Treatment of PDAC cells with monoclonal antibody (mAb) AR9.6 significantly reduced MUC16-induced oncogenic signaling. mAb AR9.6 binds to a unique conformational epitope on MUC16, which is influenced by O-glycosylation. Additionally, treatment of PDAC tumor-bearing mice with either mAb AR9.6 alone or in combination with gemcitabine significantly reduced tumor growth and metastasis. We conclude that the aberrant expression of MUC16 enhances PDAC progression to an aggressive phenotype by modulating oncogenic signaling through ErbB receptors. Anti-MUC16 mAb AR9.6 blocks oncogenic activities and tumor growth and could be a novel immunotherapeutic agent against MUC16-mediated PDAC tumor malignancy.

Use of photodynamic therapy and photobiomodulation as alternatives for microbial control on clinical and subclinical mastitis in sheep.

Evaluate the effects of antimicrobial photodynamic therapy (aPDT) and photobiomodulation (PBM) as alternatives in the treatment of mastitis in sheep. A total of 100 sheep were evaluated, and four teats with clinical mastitis and 16 teats with subclinical mastitis were selected. Milk was collected for isolation and identification of microorganisms. They were grown on TSA, EMB, and MacConkey agar for 24 h, and the microorganisms were identified by Gram stain and biochemical tests. The ceilings were subdivided into four groups: G1, treatment with photosensitizer; G2, treatment with PBM (diode laser λ = 660 nm); G3, aPDT with methylene blue, and G4, control group. Milk samples were collected before, 24 and 48 h after treatments. Cases of subclinical mastitis presented coagulase-negative Staphylococcus and Streptococcus spp, and clinical mastitis had Escherichia coli grow from the samples. The treatments decrease the total bacterial count of negative coagulase Staphylococcus, Streptococcus spp, and Escherichia coli. Comparing the treatments, aPDT stood out, as it was able to photoinactivate all bacteria. Treatment with methylene blue photosensitizer, PBM, and aPDT induced the initial microbial reduction, but aPDT was more effective 48 h after treatment.

Sexual function of transgender women after gender affirming surgery: A mini review.

A transgender person has a gender identity opposite to the sex assigned at birth. Transgender individuals may have altered sexual function (SF) due to psychosocial factors related to body image distortion, shame, and dissatisfaction with genital appearance, and these conditions can increase the risk of sexual dysfunction. This study aimed to characterize the SF of trans-women after gender affirming surgery (GAS). We reviewed the Pubmed database for studies published between January 2008 and December 2021. 17 studies were included, four were cross-sectional studies, one prospective study, four prospective cohort studies, five retrospective studies. The instruments used to evaluate the SF were female sexual function index, semistructured questionnaires, patients' opinion, Sexual Desire Inventory, Maudsley Marital Questionnaire-S, WHOQOL-100. The results of our review indicate there is weak evidence that GAS improves the SF of trans-women. We thus recommend that future studies use questionnaires that are validated for the assessment of the SF of trans-women to better determine the impact of genital surgery in this population.

Do men and women have different musculoskeletal symptoms at the same musculoskeletal discomfort level?

Owing to biological and social factors, illness-related musculoskeletal symptoms tend to vary between men and women. However, in the past, conceptualised discomfort metrics were applied uniformly to both genders. This study aimed to develop a scale to measure musculoskeletal discomfort that compares the symptoms between men and women. The scale aimed to determine the gender-based response patterns related to symptoms. A total of 707 men and 1302 women reported their symptoms on a body map. Factor analysis and item response theory were used to differentiate the identified symptoms in the construction of a musculoskeletal discomfort scale. Differences in work exposure appeared to explain the symptom patterns between men and women. The scale had eight levels, and it was found that at the same level of discomfort, men and women reported symptoms in different body regions.Practitioner summary: On this discomfort scale, the response patterns of men and women were categorised into eight levels. Symptoms differed by gender at the same musculoskeletal discomfort level. This is in contrast to previous studies in which scales were devised without considering differences between the genders.Abbreviations: WMSDs: work-related musculoskeletal disorders; BMI: body mass index; FA: factor analysis; IRT: item response theory; KMO: Kaiser-Meyer-Olkin; BST: Bartlett's test of sphericity; F: factor loading; h2: communality; α: Cronbach's alpha; ωt: McDonald's omega; ai: parameters of discrimination of the items; bik: parameters of difficulty of response categories; θj: latent trait; RMSEA: root mean square error of approximation; CFI: comparative fit index; TLI: Tucker-Lewis index; odu: musculoskeletal discomfort units; RA: rarely; OF: often; AL: always.

Lactate ions induce synaptic plasticity to enhance output from the central respiratory network.

Lactate ion sensing has emerged as a process that regulates ventilation during metabolic challenges. Most work has focused on peripheral sensing of lactate for the control of breathing. However, lactate also rises in the central nervous system (CNS) during disturbances to blood gas homeostasis and exercise. Using an amphibian model, we recently showed that lactate ions, independently of pH and pyruvate metabolism, act directly in the brainstem to increase respiratory-related motor outflow. This response had a long washout time and corresponded with potentiated excitatory synaptic strength of respiratory motoneurons. Thus, we tested the hypothesis that lactate ions enhance respiratory output using cellular mechanisms associated with long-term synaptic plasticity within motoneurons. In this study, we confirm that 2 mM sodium lactate, but not sodium pyruvate, increases respiratory motor output in brainstem-spinal cord preparations, persisting for 2 h upon the removal of lactate. Lactate also led to prolonged increases in the amplitude of AMPA-glutamate receptor (AMPAR) currents in individual motoneurons from brainstem slices. Both motor facilitation and AMPAR potentiation by lactate required classic effectors of synaptic plasticity, L-type Ca2+ channels and NMDA receptors, as part of the transduction process but did not correspond with increased expression of immediate-early genes often associated with activity-dependent neuronal plasticity. Altogether these results show that lactate ions enhance respiratory motor output by inducing conserved mechanisms of synaptic plasticity and suggest a new mechanism that may contribute to coupling ventilation to metabolic demands in vertebrates. KEY POINTS: Lactate ions, independently of pH and metabolism, induce long-term increases in respiratory-related motor outflow in American bullfrogs. Lactate triggers a persistent increase in strength of AMPA-glutamatergic synapses onto respiratory motor neurons. Long-term plasticity of motor output and synaptic strength by lactate involves L-type Ca2+ channels and NMDA-receptors as part of the transduction process. Enhanced AMPA receptor function in response to lactate in the intact network is causal for motor plasticity. In sum, well-conserved synaptic plasticity mechanisms couple the brainstem lactate ion concentration to respiratory motor drive in vertebrates.