Ischemic stroke triggers acidosis, glutamate excitotoxicity and oxidative stress, which converge to disturb ionic homeostasis through several cation channels, including acid-sensing ion channel 1a (ASIC1a), N-methyl-D-aspartate receptors (NMDARs) and transient receptor potential melastatin (TRPM) channels. Emerging evidence suggests that ASIC1a functions as a context-dependent integrating node: protons directly gate ASIC1a, glutamate and bilirubin-associated signaling can modulate ASIC1a-dependent injury pathways. ASIC1a directly couples with NMDAR-dependent signaling and indirectly engages TRPM-associated pathways. Here, we discuss the mechanistic basis, therapeutic potential and unresolved questions regarding ASIC1a-associated signaling in ischemic brain injury.
The preBötzinger complex (preBötC) is essential for inspiratory rhythm generation, yet the biological processes that repeatedly establish the excitability state required for neuronal recruitment remain incompletely understood. This unresolved issue is reflected in computational models of respiratory rhythmogenesis, which rely on a phenomenological baseline excitability parameter, g_tonic-e , without a defined biological substrate. Ambient extracellular glutamate signaling is well established in other brain regions, but its relevance to the respiratory network remains largely untested. Here, we evaluate the hypothesis that ambient extracellular glutamate outside synaptic clefts–termed glutamate tone–represents one biologically plausible candidate for a distributed extracellular network-state variable in the preBötC. We define glutamate tone as a continuously maintained but dynamically regulated extracellular glutamate signal arising from the balance of glutamate release, diffusion, transporter-mediated clearance, and astrocyte-dependent metabolism. We critically review evidence that extracellular glutamate handling can influence respiratory network activity, while emphasizing that direct evidence for a compartment-specific, rhythmogenesis-relevant glutamate tone remains lacking. We then evaluate candidate glutamate-sensing mechanisms, including peri-/extrasynaptic NMDA receptors and metabotropic glutamate receptors, and place them within the established framework of recurrent excitation, intrinsic membrane conductances, and inhibitory circuitry. We propose that glutamate tone, if present, would not generate the inspiratory burst directly, but could bias the excitability landscape from which neuronal recruitment and synchronization emerge. Finally, we outline experimental criteria for distinguishing a causal excitability bias from glutamate signals that merely reflect ongoing network activity.
Circadian disruption and vitamin D deficiency (VDD) are increasingly prevalent and independently associated with cardiovascular dysfunction. However, their combined impact on vascular reactivity and receptor signaling remains insufficiently defined. This study investigated the independent and interactive effects of melatonin (MEL) suppression induced by continuous light (CL) or pinealectomy (Px) and VDD on vascular contractility, endothelial function, and MT1/vitamin D receptor (VDR) gene expression in rat thoracic aorta. Isolated aortic rings were subjected to cumulative concentration response curves for phenylephrine (PE) and acetylcholine (ACh). Pharmacodynamic parameters, potency (pD₂), maximal efficacy (Emax), and area under the curve (AUC) were calculated. MEL and calcitriol modulation with receptor antagonism was performed to determine receptor dependence. Relative MT1 and VDR mRNA expression was quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). CL, Px, and VDD significantly enhanced PE-induced maximal contraction, with the combined deficiency groups exhibiting the greatest augmentation of α₁-adrenergic responsiveness. In contrast, ACh-induced relaxation was selectively impaired under dual-deficiency conditions, characterized by reduced Emax without major changes in pD2, indicating compromised endothelial efficacy rather than altered receptor sensitivity. MEL attenuated vasoconstriction and enhanced relaxation in a receptor-dependent manner, whereas calcitriol potentiated contractility through VDR signaling. Notably, combined CL + VDD produced marked upregulation of MT1 ( 10-fold) and VDR ( 108-fold), suggesting compensatory transcriptional remodeling. Circadian disruption and VDD synergistically promote vascular hyperreactivity and endothelial dysfunction. Their convergence amplifies α₁-adrenergic signaling while impairing nitric oxide (NO) mediated relaxation, identifying a mechanistic axis linking modern light exposure and hypovitaminosis D to heightened cardiovascular risk.
Amyotrophic lateral sclerosis (ALS) is typically characterized by progressive degeneration of upper and lower motor neurons. However, the contribution of afferent sensory pathways to spinal motor network disorganization has received little attention. Converging human histological evidence from multiple independent laboratories demonstrates that fusimotor (gamma) motor neuron innervation of muscle spindles degenerates in ALS while sensory endings remain morphologically intact at the end organ, although the afferent neurons and ascending sensory pathways are also affected. This dissociation creates unmodulated proprioceptive input. Spindle-derived sensory signals reach spinal interneuron circuits without fusimotor gain-control adjustment, degrading spindles from forward sensory models encoding predicted kinematic states into crude stretch receptors. We propose that this gain-control failure, compounded by the loss of associated alpha–gamma coactivation and beta skeletofusimotor denervation, constitutes an upstream driver of the spinal inhibitory interneuron circuit dysfunction documented by recent electrophysiological studies in ALS. The resulting early disinhibition, followed by maladaptive excitation, mirrors cortical ALS pathophysiology. However, transgenic mouse ALS models show selective sparing of gamma motor neurons, unlike the human disease, constituting a critical translational limitation. We present a temporal model of human ALS, linking fusimotor denervation to progressive disruption of spinal inhibitory and excitatory circuits.
Skeletal muscle disuse during injury decreases muscle mass and function. Previous studies have determined differential gene expression associated with atrophy, but changes in alternative splicing (AS) in response to unloading is poorly defined. This study aimed to identify global changes in differential alternative splicing (DAS) in skeletal muscle following unloading. Twenty-one healthy males (26.0 ± 5.7 years; 81.2 ± 11.6 kg) underwent 14 days unilateral knee-brace immobilization. Participants underwent strength and muscle mass assessment before and after the immobilization and vastus lateralis muscle biopsies were taken pre-immobilization, and on days 3 and 14. RNA-sequencing was performed, and DAS events were identified using the rMATS package. Leg strength decreased − 21.5 kg (P < 0.0001) while mid-thigh circumference was reduced 2
