Function (Oxford, England)最新文献

{"title":"Pairing ampakine with brief hypoxia evokes phrenic neuroplasticity via a spinal NMDA receptor-mediated mechanism.","authors":"Prajwal P Thakre, Sabhya Rana, Raphael R Perim, Gordon S Mitchell, David D Fuller","doi":"10.1152/function.019.2026","DOIUrl":"10.1152/function.019.2026","url":null,"abstract":"<p><p>Brief hypoxic episodes drive neuroplasticity in animal models and humans. Pretreatment with an allosteric α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (R) modulator (\"ampakine\") enables a single hypoxic exposure to induce sustained increases in phrenic motor activity [\"phrenic motor facilitation\" (pMF)]. Phrenic nerve activity was recorded in anesthetized rats to determine whether the ampakine-hypoxia (A-H) combination is unique in its ability to evoke pMF and to determine its underlying mechanisms. Pairing ampakine CX717 with brief moderate or severe hypercapnia failed to produce pMF. Pairing doxapram, a respiratory stimulant, with hypoxia did not produce pMF. We then sequentially tested the hypotheses that A-H-induced pMF requires spinal serotonin, adenosine, or NMDA receptor activation. Cervical intrathecal delivery of serotonin (methysergide) or adenosine 2 A receptor (MSX-3) antagonists before A-H failed to prevent pMF. In contrast, the NMDA-R blocker MK-801 prevented pMF when administered before but not after A-H. Finally, as a step in the translational pathway, we tested the safety and efficacy of acute A-H exposure in unanesthetized rats with indwelling diaphragm electromyogram (EMG) wires after cervical spinal cord injury (SCI). A-H was well tolerated, and at 3 mo after SCI, increased diaphragm EMG output. We conclude that the mechanism driving sustained increases in phrenic motor output after A-H is independent of spinal adenosine or serotonin receptor activation, but requires spinal NMDA-R activation for the induction, but not maintenance, of A-H pMF. Ampakine pretreatment may be useful to increase the efficacy of hypoxia-based rehabilitation paradigms after SCI, particularly since clinical trials report a substantial number of \"low responders.\"<b>NEW & NOTEWORTHY</b> Rehabilitation paradigms using brief hypoxia exposure can improve recovery after spinal cord injury. A low dose of ampakines, which enhance AMPA neurotransmission, coupled with brief hypoxia (A-H), uniquely evokes respiratory neuroplasticity (\"phrenic motor facilitation\" or pMF) <i>via</i> a mechanism that requires spinal NMDA, but not serotonin or adenosine receptor activation. A-H also increased diaphragm activation in rats with chronic SCI, suggesting that the A-H pairing may be useful in neurorehabilitation.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0192026"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148474642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ampakine-hypoxia pairing reveals a novel NMDA-dependent respiratory neuroplasticity.","authors":"Pauline Michel-Flutot, Kun-Ze Lee, Stéphane Vinit","doi":"10.1152/function.047.2026","DOIUrl":"10.1152/function.047.2026","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0472026"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148474637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type 1 diabetes differentially disrupts right and left ventricular daily rhythms.","authors":"Sharanya S Bettadapura, Samantha J Torres, Marjie P Schmitt, Brandon L Roberts, Danielle R Bruns","doi":"10.1152/function.041.2026","DOIUrl":"10.1152/function.041.2026","url":null,"abstract":"<p><p>Circadian rhythms are endogenous ∼24-h cycles that regulate cardiovascular physiology. Although circadian regulation of the left ventricle (LV) is well established, whether the right ventricle (RV) exhibits intrinsic rhythmicity is not known. Here, we provide the first evidence that the healthy RV exhibits robust rhythms in function and molecular gene expression. Cardiovascular disease is the leading cause of mortality in type 1 diabetes (T1D). T1D disrupts circadian rhythms, yet how T1D alters chamber-specific circadian control remains unclear. We investigated RV and LV function and gene expression across the 24-h light-dark cycle in male streptozotocin-induced T1D and control mice. Echocardiographic assessment of diabetes-induced remodeling at ZT0-4 and ZT12-16 [zeitgeber time (ZT)] revealed time-dependent functional impairment, including reversal of the normal diurnal heart rate pattern. T1D impaired day-night RV and LV systolic function, with loss of day-night difference in LV ejection fraction and impaired active period RV stroke volume. Cosinor analysis of RV and LV gene expression demonstrated preserved 24-h rhythmicity of core clock genes <i>Arntl1</i> and <i>Per2</i> in both ventricles with T1D, whereas the clock output genes <i>Nr1d1</i> and <i>Dbp</i> had dampened amplitude in the RV but amplified expression in the T1D LV. These findings demonstrate that T1D differentially disrupts circadian regulation of the RV and LV, with selective vulnerability of the clock-controlled output genes despite preservation of the core oscillator. Chamber-specific circadian remodeling may contribute to the elevated cardiovascular risk in T1D and has implications for the timing of diagnostic and therapeutic interventions.<b>NEW & NOTEWORTHY</b> This study provides the first evidence that the healthy right ventricle (RV), like the left ventricle (LV), possesses an intrinsic circadian clock with robust 24-h rhythmicity. Using a mouse model of type 1 diabetes, we show that diabetes does not uniformly suppress cardiac clocks but instead differentially rewires RV and LV rhythms, dampening clock-output gene amplitude in the RV while amplifying it in the LV. Together, we reveal chamber-specific circadian vulnerability with implications for diabetic cardiomyopathy and chronotherapy.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0412026"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148690472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ROS Scavenging Mitigates TNFα Induced Endoplasmic Reticulum Stress and Mitochondrial Fragmentation in Human Airway Smooth Muscle.","authors":"Debanjali Dasgupta, Sanjana Mahadev Bhat, Gary C Sieck","doi":"10.1152/function.036.2026","DOIUrl":"https://doi.org/10.1152/function.036.2026","url":null,"abstract":"<p><p>The pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) mediates airway responses to acute inflammation. Previously we demonstrated that, in human airway smooth muscle (hASM) cells, TNFα increases reactive oxygen species (ROS) formation. TNFα also selectively activates the inositol-requiring enzyme 1α (pIRE1α^S724 autophosphorylation) endoplasmic reticulum (ER) stress pathway involving splicing of X-box binding protein 1 (XBP1s) and transcriptionally activates cyclin-dependent kinases 1 and 5 (CDK1 and CDK5), promoting dynamin-related protein 1 (DRP1) phosphorylation at serine 616 (pDRP1^S616) and mitochondrial fragmentation. In the present study, we hypothesized that in hASM, TNFα-induced ROS triggers pIRE1α^S724/XBP1s ER stress pathway. To test this hypothesis, we examined the impact of the ROS scavenger Tempol on TNFα-induced pIRE1α^S724/XBP1s ER stress pathway and downstream signaling mediating mitochondrial fragmentation. Bronchiolar tissue samples were obtained from 6 patients with no history of smoking or chronic pulmonary disease. The smooth muscle layer was dissected, and hASM cells were dissociated and randomly assigned to four treatment groups: 1) Vehicle, 2) Vehicle + TNFα (20 ng/mL, 6 h), 3) Tempol (500 μM) only, and 4) Tempol (500 μM) + TNFα (20 ng/mL, 6 h). ROS formation was determined by confocal imaging using MitoSOX™ Red. Mitochondria were labeled with MitoTracker Red and imaged using confocal microscopy. Using Western blot, we demonstrated that Tempol reduced cellular ROS formation and mitigated the TNFα-induced increase in pIRE1α^S724, XBP1s, CDK1/5, pDRP1^S616 protein levels and reduced mitochondrial fragmentation. These findings support our hypothesis and indicate a role of ROS in mediating TNFα-induced ER stress and mitochondrial fragmentation.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0362026"},"PeriodicalIF":3.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence that myoglobin PO₂ is a non-invasive measure of <i>in vivo</i> skeletal muscle mitochondrial PO₂ during exercise in humans.","authors":"Ryan M Broxterman, Bradley A Ruple, Peter D Wagner, Russell S Richardson","doi":"10.1152/function.022.2026","DOIUrl":"https://doi.org/10.1152/function.022.2026","url":null,"abstract":"<p><p>Muscle mitochondrial partial pressure of oxygen (P_mitoO₂) is a key determinant of skeletal muscle oxygen consumption (V̇O₂), metabolism, gene regulation, and adaptation in health and disease. Yet P_mitoO₂ remains difficult to measure directly <i>in vivo</i> in humans during exercise. Myoglobin-associated PO₂ (P_MbO₂), measured non-invasively using proton magnetic resonance spectroscopy, may provide a measure of P_mitoO₂ during maximal exercise in humans because Mb is coupled to mitochondrial oxygen availability and P_MbO₂ falls in the low PO₂ range expected for P_mitoO₂ <i>in vivo</i>. However, it remains unknown whether P_MbO₂ during maximal exercise varies systematically with muscle V̇O_2max, as would be expected if P_MbO₂ reflects P_mitoO₂ <i>in vivo.</i> We analyzed data from five initially sedentary males before and after 8 weeks of single-leg knee-extensor exercise (KE) training. During maximal KE under 0.12, 0.21, and 1.00 fractions of inspired oxygen (F_IO₂), we measured P_MbO₂ using myoglobin desaturation measured by proton magnetic resonance spectroscopy and muscle V̇O_2max from leg blood flow and the arterial-femoral venous O₂ content difference. Across F_IO₂ conditions, muscle V̇O_2max varied systematically with P_MbO₂ both before and after training, consistent with O₂-dependent mitochondrial respiration. When interpreted within a canonical hyperbolic framework, the V̇O₂-P_MbO₂ relationship yielded low apparent mitochondrial P₅₀ values that were broadly consistent with values reported for human skeletal muscle isolated mitochondria studied <i>in vitro</i>. A complementary linear P₅₀ analysis that did not assume a hyperbolic relationship supported the same interpretation. Together, these findings provide data-supported, proof-of-concept evidence that P_MbO₂ reflects <i>in vivo</i> P_mitoO₂ during maximal exercise in humans.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0222026"},"PeriodicalIF":3.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alcohol and calorie-dense diets modulate immune phenotype and metabolic health in simian immunodeficiency virus infection.","authors":"Liz Simon, Megan Mire, Patrick M McTernan, Eden M Gallegos, Larry Coleman, Robert W Siggins, Adam C Caro, Carol L Baker, Patricia E Molina","doi":"10.1152/function.033.2026","DOIUrl":"10.1152/function.033.2026","url":null,"abstract":"<p><p>Alcohol misuse and calorie-dense diets, especially those rich in sugar and fat, independently increase comorbidity risk among people with HIV. The objective of this study was to define the combined effects of chronic binge alcohol administration and consumption of a high-fat high-sucrose diet (HFSD) on systemic metabolic, immunologic, and body composition outcomes under controlled conditions in an established nonhuman primate (NHP) model of HIV infection. Male NHPs fed HFSD diet were administered alcohol or vehicle. A subset of animals in the vehicle (VEH) and alcohol groups was infected with simian immunodeficiency virus (SIV) and treated with antiretroviral therapy (ART). ART treatment decreased viral loads, which did not differ between the vehicle- and alcohol-administered NHPs. There was a main effect of alcohol to significantly reduce peripheral CD4⁺ T cell counts and the CD4⁺/CD8⁺ T-cell ratio. Overall body composition was not significantly different between the treatment groups. However, bone mineral density was significantly lower in the alcohol/SIV+ group. Alcohol decreased the acute insulin response to glucose. ART effectively suppressed viral loads in vehicle and alcohol/SIV NHPs. Alcohol produced significant immunological alterations, impaired glucose-insulin dynamics, and decreased bone mineral density. These findings highlight alcohol misuse as a modifiable driver of metabolic and immunologic dysfunction. Our ongoing studies will dissect the tissue-specific effects of alcohol and calorie-dense diets that contribute to the systemic changes.<b>NEW & NOTEWORTHY</b> This study examined the interactions of a calorie-dense diet and alcohol in SIV-infected and SIV-seronegative nonhuman primates on systemic viral loads and immunological and metabolic measures. ART effectively suppressed viral loads, irrespective of alcohol administration. Alcohol produced significant immunological alterations and decreased bone mineral density in SIV infection. Alcohol impaired glucose-insulin dynamics irrespective of SIV infection, highlighting a significant metabolic maladaptation. The results highlight the interaction of diet and alcohol on increasing the risk for comorbidities in HIV.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0332026"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13460388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circadian clock protein Bmal1 regulates respiratory motor plasticity in male rats.","authors":"Aaron A Jones, Alexandria B Marciante, Pierce Berardi, Gordon S Mitchell","doi":"10.1152/function.016.2026","DOIUrl":"10.1152/function.016.2026","url":null,"abstract":"<p><p>Acute intermittent hypoxia (AIH) elicits respiratory motor plasticity in the phrenic, intercostal, and hypoglossal motor pools and has emerged as a promising therapeutic strategy to improve respiratory function in people with neuromuscular disorders that compromise breathing. Although we recently reported that time-of-day regulates moderate ([Formula: see text] ∼40-50 mmHg) AIH-induced respiratory motor plasticity, it is unknown whether diurnal effects on AIH-induced phrenic (pLTF) or ventilatory (vLTF) long-term facilitation are mediated via the endogenous circadian clock versus other factors. Since many biological rhythms are driven by the endogenous clock and clock genes (including the essential clock gene Bmal1) are rhythmically expressed in the phrenic motor system, we hypothesized that the molecular clock within respiratory motor neurons exerts time-of-day effects on pLTF and vLTF in Sprague Dawley rats (3-6 mo old males). Intrapleural injections of small-interfering RNAs (siRNAs) were used to selectively knock down Bmal1 within respiratory motor neurons by ∼30%. AIH consisting of 15, 1-min hypoxic episodes ([Formula: see text] = 0.09) was delivered in the midrest (i.e., light) or midactive (i.e., dark) phases, and pLTF (Δintegrated phrenic burst amplitude) and vLTF (ΔV̇e/V̇co₂) were assessed in rats given siRNAs targeting Bmal1 versus nontargeting controls. In midrest phase, pLTF was reduced, and vLTF was abolished in rats given siBmal1 versus nontargeting siRNA. However, siBmal1 had no significant effect on either pLTF or vLTF in the midactive phase. Thus, the phrenic motor neuron circadian clock regulates AIH-induced respiratory motor plasticity in a time-of-day-dependent manner. It is important to consider circadian biology in future studies of AIH-induced respiratory motor plasticity.<b>NEW & NOTEWORTHY</b> Although diurnal cycle influences respiratory motor plasticity elicited by acute intermittent hypoxia (AIH), it is unknown how endogenous circadian clock mechanisms contribute to time-of-day effects on plasticity. We report that knockdown of the circadian clock protein Bmal1 within respiratory motor neurons attenuates phrenic and ventilatory long-term facilitation in a manner dependent on diurnal phase. Thus, circadian biology is an important consideration for studies of respiratory motor plasticity.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0162026"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13308673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148213461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Constitutive mTORC1 activation in skeletal muscle increases inflammation but is not sufficient to impair glucose tolerance.","authors":"Erik D Marchant, Hanna Kalenta, Sean P Kilroe, Jacquelyn May, Wenjun Z Martini, Korri S Weldon, Zhao Lai, Blake B Rasmussen","doi":"10.1152/function.039.2026","DOIUrl":"10.1152/function.039.2026","url":null,"abstract":"<p><p>Aberrant mechanistic target of rapamycin complex 1 (mTORC1) signaling in skeletal muscle has been implicated in aging and insulin resistance; however, it is not known whether chronic mTORC1 activation directly causes glucose intolerance. We tested the hypothesis that constitutive mTORC1 activation in mouse skeletal muscle impairs glucose homeostasis. Six-month-old female and male mice with tamoxifen-inducible, muscle-specific knockout of the DEP domain containing 5, GATOR1 subcomplex subunit gene (<i>Depdc5</i>), a key component of the GAP activity toward rag 1 (GATOR1) complex and negative regulator of mTORC1, were fed normal chow or Western diet (WD; 45% fat, 17% sucrose) for 12 wk. <i>Depdc5</i> knockout (KO) increased mTORC1 signaling and altered autophagy markers. WD increased body and fat mass and impaired glucose tolerance independent of genotype. KO had minimal effects on fasting glucose, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), glycosylated hemoglobin (HbA1c), or oral glucose tolerance, although female KO mice showed a modest increase in WD-induced weight gain and fasting glucose. Mitochondrial respiration and content were unchanged by KO or WD. KO increased mitochondrial H₂O₂ production capacity but did not drive clear signs of oxidative stress. Transcriptomic analysis revealed robust KO-driven upregulation of genes related to cell division and immune pathways. Consistent with this, KO increased TNF-α and IL-6 protein expression and shifted macrophage polarization toward an M2-like phenotype without altering total macrophage content. Collectively, these findings indicate that chronic activation of mTORC1 in skeletal muscle promotes inflammatory remodeling but is insufficient to impair systemic glucose homeostasis, even under dietary stress.<b>NEW & NOTEWORTHY</b> Chronic skeletal muscle mTORC1 hyperactivation is widely assumed to drive insulin resistance and metabolic decline, yet direct causal evidence remains limited. Using adult-onset <i>Depdc5</i> deletion to constitutively activate mTORC1 via GATOR1 disruption, we show that this is insufficient to impair glucose homeostasis even under a Western diet challenge. Strikingly, glucose tolerance and mitochondrial respiration remained preserved despite inflammation and immune transcriptional reprogramming-challenging the prevailing model of mTORC1-driven metabolic dysfunction in muscle.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0392026"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148474673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Layer-specific choroidal vascular adaptation to high-altitude hypoxia revealed by functional OCT at 3,800 m.","authors":"Mohammad Amin Safarzadeh, Jacquie R Baker, Satish R Raj, Usman Alim, Trevor A Day, Nicholas G Jendzjowsky, Richard J A Wilson","doi":"10.1152/function.002.2026","DOIUrl":"10.1152/function.002.2026","url":null,"abstract":"<p><p>Ascent to high-altitude induces systemic and ocular changes that alter vision. The functional responses of the choroidal vasculature at different depths to hypoxia remain incompletely understood. In this study, we used functional optical coherence tomography (f-OCT) to quantify changes in choroidal vascular perfusion density (VPD) across superficial, deep, and total choroidal layers in 16 healthy participants. Imaging was performed at baseline (1,100 m) and during acute (<i>day 2</i>) and prolonged exposure (<i>day 9</i>) to high altitude (3,800 m). Our depth-resolved analysis showed a modest but statistically significant decline in superficial choroidal VPD from baseline to <i>day 2</i> (<i>P</i> = 0.031; Cohen's <i>d</i> = -0.73). In contrast, both deep and total choroidal VPD increased significantly from baseline to <i>day 2</i> (<i>P</i> = 0.002 and <i>P</i> = 0.003, respectively; Cohen's <i>d</i> > 0.9). Changes in superficial, deep, and total choroidal VPD persisted from <i>day 2</i> through <i>day 9</i> at 3,800 m. [Formula: see text] showed a strong negative correlation with deep choroidal (<i>r</i> = -0.655; <i>P</i> = 0.0003) and total choroid VPD (<i>r</i> = -0.566; <i>P</i> = 0.0014), but no significant correlation was observed with the VPD of the superficial layer (<i>r</i> = 0.018; <i>P</i> = 0.93). The strong correlation between VPD and the stimulus index ([Formula: see text]/[Formula: see text]) in the total choroid suggests that hypoxia-induced vasodilation outweighs hypocapnic vasoconstriction, leading to increased perfusion (<i>r</i> = 0.629; <i>P</i> = 0.0003). These findings suggest that deep choroidal hyperperfusion on ascent to high altitude helps sustain outer retinal oxygenation. Depth-resolved choroid imaging may offer new insights into ocular resilience to environmental challenges and provide a valuable tool to monitor spaceflight-related ocular changes associated with neuro-ocular syndrome.<b>NEW & NOTEWORTHY</b> This study reveals that the human choroid mounts a depth-specific vascular response to high-altitude hypoxia. Rather than showing uniform vasodilation, superficial choroidal perfusion decreases, whereas deep choroidal perfusion increases and remains elevated after prolonged altitude exposure. The strong relationship between deep choroidal perfusion and arterial blood gases suggests that hypoxia-driven vasodilation outweighs hypocapnic vasoconstriction. These data highlight functional OCT as a powerful tool for measuring how physiological stress reshapes ocular vascular function and suggest that combining high-altitude exposure with depth-resolved functional OCT may provide a useful terrestrial model for vascular changes relevant to spaceflight-associated neuro-ocular syndrome.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0022026"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13290071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148151979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synchronization of the 12-h circatidal rhythm maintains the kidney through repeated cycles of warm reperfusion in the hibernating ground squirrel.","authors":"Austin E Gillen, David J Orlicky, Rui Fu, Swati Jain, Alkesh Jani, Sandra L Martin","doi":"10.1152/function.015.2026","DOIUrl":"10.1152/function.015.2026","url":null,"abstract":"<p><p>The hibernating 13-lined ground squirrel kidney is a unique natural model of resistance to damage caused by cold storage and warm reperfusion. Over months, the kidney is exposed to cycles between multiday periods of torpor with low perfusion at ice-cold temperature and rapid warm reperfusion during arousals. Serum creatinine accumulates during torpor but normalizes during arousal, and animals emerge each spring with functioning kidneys. After confirming a lack of kidney histopathology in sections from 11 animals that had completed 11-22 torpor-arousal cycles, we collected RNA sequencing (RNA-Seq) data from 32 ground squirrel kidneys representing 6 key transitional time points based on seasonal and torpor-arousal cycle physiology. Hibernation state-specific gene expression changes were identified after removing three informative outliers. Both seasonal and torpor-arousal cycle-specific gene expression changes were found. These differentially expressed genes illuminated molecular mechanisms that mitigate damage while supporting full recovery during each ∼12 h rewarming. As with the response to renal ischemia-reperfusion injury in other species, the arousing hibernator induced immediate early genes during warm reperfusion. But, in the hibernator, this response did not precipitate the gene expression program of maladaptive repair that is characterized by cell death, immune system activation, and fibrosis. Rather, it appears that induction of immediate early genes activated a universal 12-h, \"circatidal\" rhythm. The efficient unfolding of this rhythm across each arousal from torpor was facilitated by the seasonally changed background primed for rapid cell division and minimal energy consumption. Adaptive repair was achieved, with proteostasis and cell type-specific function restored, assuring that minor damage did not accumulate.<b>NEW & NOTEWORTHY</b> The hibernator kidney exhibits no damage after 10-22 cycles between prolonged cold exposure and rapid warm reperfusion occurring over several months. As found with kidney damage in other species, each rewarming activates an immediate early gene response. Unique to the hibernator, adaptive repair is completed within 12 h, facilitated by rapid activation of the universal \"circatidal\" rhythm unfolding on a seasonally primed background that assures minimal cell death, rapid cell division, and repair.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0152026"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13387086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148341440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}