Journal of Physiology-London最新文献

The mechanisms that drive placental dysfunction in pregnancies complicated by hypoxia and fetal growth restriction remain poorly understood. Changes to mitochondrial respiration contribute to cellular dysfunction in conditions of hypoxia and have been implicated in the pathoaetiology of pregnancy complications, such as pre-eclampsia. We used bespoke isobaric hypoxic chambers and a combination of functional, molecular and imaging techniques to study cellular metabolism and mitochondrial dynamics in sheep undergoing hypoxic pregnancy. We show that hypoxic pregnancy in sheep triggers a shift in capacity away from β-oxidation and complex I-mediated respiration, while maintaining total oxidative phosphorylation capacity. There are also complex-specific changes to electron transport chain composition and a switch in mitochondrial dynamics towards fission. Hypoxic placentas show increased activation of the non-canonical mitochondrial unfolded protein response pathway and enhanced insulin like growth factor 2 signalling. Combined, therefore, the data show that the hypoxic placenta undergoes significant metabolic and morphological adaptations to maintain cellular energy balance. Chronic hypoxia during pregnancy in sheep activated placental mitochondrial stress pathways, leading to alterations in mitochondrial respiration, mitochondrial energy metabolism and mitochondrial dynamics, as seen in the placenta of women with pre-eclampsia. KEY POINTS: Hypoxia shifts mitochondrial respiration away from β-oxidation and complex I. Complex-specific changes occur in the electron transport chain composition. Activation of the non-canonical mitochondrial unfolded protein response pathway is heightened in hypoxic placentas. Enhanced insulin like growth factor 2 signalling is observed in hypoxic placentas. Hypoxic placentas undergo significant functional adaptations for energy balance.

Motor neurons (MNs) within the nucleus ambiguus innervate the skeletal muscles of the larynx, pharynx and oesophagus, which are essential for swallow. Disordered swallow (dysphagia) is a serious problem in elderly humans, increasing the risk of aspiration, a key contributor to mortality. Despite this importance, very little is known about the pathophysiology of ageing dysphagia and the relative importance of frank muscle weakness compared to timing/activation abnormalities. In elderly humans and in aged Fisher 344 (F344) rats, a variety of motor pools exhibit weakness and atrophy (sarcopenia), contemporaneous to MN death. Synchronisation of swallow is dependent on the stability of MN dendrites, which integrate neural circuits. Dendritic derangement occurs in many neuromotor degenerative conditions prior to MN death. We hypothesise behavioural weakness and death of nucleus ambiguus MNs will occur by age 24 months in F344 rats and that this will be preceded by swallow-respiration dyscoordination and dendritic arbour degenerations from 18 months compared to controls at 6 months. Using pressure catheters to estimate laryngeal and diaphragm function during naturalistic water bolus applications, we show that swallow number and post-swallow apnoeas are altered from 18 months. Swallow pressure (weakness) and nucleus ambiguus MN numbers (evaluated via stereological assessments of Nissl staining) were reduced at 24 months. Dendritic lengths, surface areas and dendritic spines were reduced in nucleus ambiguus MNs from 18 months (evaluated by confocal imaging of Golgi-Cox impregnated brainstem). These results show that synapse loss occurs prior to MN death and behavioural weakness. Strategies to preserve synapses may be of utility in ameliorating sarcopenia. KEY POINTS: Dysphagia is a major contributor to ageing morbidity and mortality, but the underling pathophysiology is unexplored. Here, in Fischer 344 rats, we use pressure and timing evaluations of swallow-respiration, showing timing impairments occur prior to frank pressure defects. In nucleus ambiguus motor neurons, dendritic defects were apparent with the onset of swallow-respiration dyscoordination, with frank motor neuron loss occurring subsequently to synapse loss. Our results show that synapse loss occurs prior to motor neuron death and behavioural impairments. Strategies to preserve synapses may be of utility in ameliorating sarcopaenia.

Fañanas cells (FCs) are cerebellar glia of unknown function. First described more than a century ago, they have been almost absent from the scientific literature ever since. Here, we combined whole-cell, patch clamp recordings, near-UV laser photolysis, dye-loading and confocal imaging for a first characterization of FCs in terms of their morphology, electrophysiology and glutamate-evoked currents. We identified FCs of the molecular layer in cerebellar slices by their stubby process and small cell bodies. Despite their more compact shape compared to Bergmann glia (BGs), FCs showed similar membrane resistances and basal currents, suggesting that these passive currents are partly a result of electrical coupling between neighbouring glia. Dye filling and pharmacological experiments confirmed both homo- and heterotypic gap-junction coupling among FCs and BGs. Parallel-fibre stimulation evoked TTX-sensitive slow inward currents in FCs that were partially blocked by NBQX but not APV. Occasionally, we observed superimposed fast (milliseconds) current transients. Near-UV flash photolysis of MNI-caged glutamate revealed rapid desensitization of these AMPA-receptor mediated currents, which fully recovered only for stimulation intervals >500 ms. We mapped the highest current densities in proximal processes. We conclude that FCs respond with fast AMPA currents to local glutamate release and they integrate ambient glutamate rises to a slow inward current. Interestingly, we found FCs to prevail throughout adulthood at stable but different densities among cerebellar lobules, with the highest cell densities in lobules I-II and X. Our results strongly suggest that FCs are not just displaced BGs, and that they may have lobule-specific functions - both locally and at the circuit level, yet to be uncovered. KEY POINTS: Using whole-cell recordings and near-UV laser photolyisis of caged glutamate, we provide a first characterization of cells of Fañanas (FCs) in mouse cerebellar slices. FCs are present from postnatal day 5 onward throughout adulthood and have a lobule- dependent density. Parallel-fibre stimulation generates biphasic, predominantly AMPA-mediated currents in FCs. Currents induced in FCs by parallel fibre stimulation are not NMDA receptor-dependent and are enhanced upon glutamate-transporter block with TBOA. Local near-UV glutamate uncaging indicates that FCs can detect fast glutamatergic inputs on the millisecond-time scale. FCs functionally integrate into the glial syncytium.

Cognitive and physical stress have significant effects on brain health, particularly through their influence on the central executive network (CEN). The CEN, which includes regions such as the dorsolateral prefrontal cortex, anterior cingulate cortex and inferior parietal lobe, is central to managing the demands of cognitively challenging motor tasks. Acute stress can temporarily reduce connectivity within the CEN, leading to impaired cognitive function and emotional states. However a rebound in these states often follows, driven by motivational signals through the mesocortical and mesolimbic pathways, which help sustain inhibitory control and task execution. Chronic exposure to physical and cognitive challenges leads to long-term improvements in CEN functionality. These changes are supported by neurochemical, structural and systemic adaptations, including mechanisms of tissue crosstalk. Myokines, adipokines, anti-inflammatory cytokines and gut-derived metabolites contribute to a biochemical environment that enhances neuroplasticity, reduces neuroinflammation and supports neurotransmitters such as serotonin and dopamine. These processes strengthen CEN connectivity, improve self-regulation and enable individuals to adopt and sustain health-optimizing behaviours. Long-term physical activity not only enhances inhibitory control but also reduces the risk of age-related cognitive decline and neurodegenerative diseases. This review highlights the role of progressive physical stress through exercise as a practical approach to strengthening the CEN and promoting brain health, offering a strategy to improve cognitive resilience and emotional well-being across the lifespan.

The complex microbial community residing in the human gut has long been understood to regulate gastrointestinal physiology and to participate in digestive diseases, but its extraintestinal actions and influences are increasingly recognized. This article discusses bidirectional interactions between the gut microbiome and athletic performance, metabolism, longevity and the ability of the gut-brain axis to influence cognitive function and mental health.