bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cerebrovascular Reactivity in Habitually Exercising Healthy Adults
Authors: Miller Kathleen B. , Harvey Ronée E. , Howery Anna J. , Greisch Mackenzie L. , Carl Alexandra E. , Joyner Michael J. , Barnes Jill N. 
Published: June 2021

Cerebrovascular reactivity to hypercapnia declines with age and low reactivity may be a biomarker of cognitive decline. Central elastic arteries that perfuse the brain stiffen with age, increasing their transmission of pulsatile mechanical forces into the cerebral microvasculature and impairing cerebral microvessel function. Habitual physical activity, however, has been shown to reduce central arterial stiffness and is associated with better cognitive function. Therefore, the purpose of this study was to evaluate cerebrovascular reactivity in young and older healthy adults who habitually exercise. We hypothesized that older adults who habitually exercised would have similar cerebrovascular reactivity when compared with young adults. However, because the underlying mechanisms of cerebral blood flow regulation may differ with age, we also evaluated blood pressure and central hemodynamic measures. We recruited 25 young (YA: age = 27 ± 1 y) and 20 older (OA: age = 59 ± 1 y) habitual exercisers. Middle cerebral artery velocity (MCAv) was recorded using transcranial Doppler ultrasound. In order to assess cerebrovascular reactivity, mean arterial pressure (MAP), end‐tidal carbon dioxide (ETCO2), and MCAv were continuously recorded at rest and during stepwise elevations of inhaled CO2. Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. Reactivity was calculated as the linear relationship between the change in ETCO2 and the change in each variable of interest (MCAv, CVCi and MAP). Central arterial stiffness (carotid‐femoral pulse wave velocity, PWV) and central hemodynamics (augmentation index, AIx) were assessed by applanation tonometry. Older adults had higher MAP (YA: 85 ± 2 mmHg; OA: 90 ± 3 mmHg; p<0.05) and AIx (YA: 0 ± 3 %; OA: 20 ± 2 %; p<0.05) at rest compared with young adults. PWV was not statistically different between groups (YA: 4.9 ± 0.3 cm/s; OA: 5.7 ± 0.5 cm/s; p=0.18). MCAv and CVCi reactivity to hypercapnia were similar between young and older adults (MCAv reactivity, YA: 2.0 ± 0.2 cm/s/mmHg; OA: 2.2 ± 0.1 cm/s/mmHg; p=0.46, CVCi reactivity, YA: 0.018 ± 0.002 cm/s/mmHg2; OA: 0.016 ± 0.001 cm/s/mmHg2; p=0.42); however, older adults demonstrated higher MAP reactivity to hypercapnia (YA: 0.3 ± 0.1 a.u.; OA: 0.8 ± 0.1 a.u.; p<0.05). PWV and AIx were not associated with MCAv, CVCi, or MAP reactivity to hypercapnia (p>0.05). Our results suggest that habitual exercise preserves cerebrovascular reactivity; however, MAP reactivity is augmented with aging allowing older adults to sufficiently increase cerebral blood flow during hypercapnia.Support or Funding InformationSupported by National Institute of Health grant HL118154This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Kinin B1 Receptor Knockdown Prevents DOCA‐Salt Hypertension by Modulating Mitochondrial Oxidative Stress in the Brain
Authors: Sriramula Srinivas 
Published: June 2021

The imbalance between reactive oxygen species (ROS) production and anti‐oxidant capacity in the central nervous system results in oxidative stress and is implicated in the pathogenesis of hypertension. Deoxycorticosterone acetate (DOCA)‐salt hypertension is associated with increased expression of the pro‐inflammatory kinin B1 receptor (B1R) in the brain. We previously reported that DOCA‐salt hypertension is attenuated in global B1R knockout (B1RKO) mice. However, the functional role of B1R in inducing oxidative stress within the brain during neurogenic hypertension has not been fully studied. In this study, we tested the hypothesis that the beneficial effects of B1R knockdown are mediated by reduction in mitochondrial oxidative stress in the brain. DOCA‐salt treatment (1mg/g body wt. DOCA, 1% saline in drinking water for 3 weeks) resulted in significantly lower blood pressure (BP; telemetry) level in B1RKO mice (121 ±2 mmHg, n=12) compared to wild‐type controls (WT) (138 ±3 mmHg, n=12). DOCA‐salt treatment resulted in decreased catalase (79.1 ±5.6 vs. 150.3 ±10.4 mmol/min/ml, p<0.01), total superoxide dismutase (SOD, 4.19 ±0.3 vs. 5.97 ±0.3 U/ml, p<0.01), and the mitochondrial antioxidant manganese SOD (0.67 ±0.09 vs. 1.58 ±0.05 U/ml, p<0.01) activities in hypothalamic homogenates of WT mice, which were prevented in B1RKO mice (134.8 ±4.6 mmol/min/ml, 5.89 ±0.1 U/ml, and 1.68 ±0.22 U/ml, respectively, p<0.01). WT mice treated with DOCA‐salt showed increased oxidative stress as indicated by increased total ROS levels in the hypothalamus as measured using electron paramagnetic resonance spectrometer. This increase in ROS production was not observed in B1RKO mice treated with DOCA‐salt. Furthermore, DOCA‐salt hypertension resulted in decreased phosphorylation of eNOS‐ser1177 in the PVN (35 ±5 % decrease, n=9, p<0.05 vs WT), which was prevented in B1RKO mice. In addition, the gene expression of PPAR Gamma coactivator (PGC) 1‐Alpha and Uncoupling protein‐2 (UCP‐2), two important genes involved in mitochondrial function, were decreased in the PVN of DOCA‐salt treated WT mice but not in B1RKO mice. Together, these data provide evidence that kinin B1R knockdown reduces mitochondrial oxidative stress, improves antioxidant and nitric oxide signaling, and there by attenuates the development of DOCA‐salt hypertension.Support or Funding InformationThe American Heart Association (15SDG25720021)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
CVS role of TRPV: from single channels to HRV assessment with Artificial Intelligence.
Authors: O'Brien Fiona , Williams Bryan M , Pratt Harry M. , Barrett‐Jolley Richard 
Published: June 2021

The paraventricular nucleus (PVN) of the hypothalamus is an important autonomic control centre in the brain with roles in stress, metabolism, cardiovascular function and homeostasis. Identified PVN neurones project directly to the spinal cord and can modulate cardiovascular function via sympathetic control, however, the underlying mechanisms are not fully understood. Work from our group has highlighted roles for TRPV4 in osmosensing and thermoregulation in the PVN. To investigate whether TRPV4 channels may play a role in modulating cardiovascular function, we have used a combination of in vivo, in vitro and in silico techniques.Heart rate, blood pressure (BP) and tail blood volume were recorded from CD1 mice using noninvasive tail plethysmography at varying cage temperatures. To record cardiovascular parameters and internal body temperature in unrestrained animals, we employed radio‐telemetry in Wistar rats. To analyse ECG signals, we began by comparing an artificially intelligent (AI) 1D Convolutional Neural Network beat detection model (in Python‐Keras) with traditional peak detection methods. We used heart rate variability analyses (HRVA) to investigate autonomic nervous system influences with and without a TRPV4 agonist. To characterise TRPV4 channel gating, we used patch‐clamp electrophysiology on PVN neurones from mouse hypothalamic brain slices. Results are given as mean ± SEM; significances were assessed by one‐way ANOVA or Student's t‐tests where appropriate.Intraperitoneal administration of the selective TRPV4 antagonist GSK 2193874 (300 μg/kg) resulted in an increased temperature evoked vasodilation, which was not observed in controls (n=3, 5 p<0.01). In radio telemetry experiments, the blind AI detected beat frequency significantly correlated (Rho 0.88, p<0.001, n=10) to the human supervised peak detection methods in the physiological range (<800bpm, >400bpm) and was therefore used for the remaining analysis. Intraperitoneal administration of the the TRPV4 agonist GSK 1016790A (50 μg/kg) caused no change in mean HR, but a significant increase in Low Frequency (LF) power, consistent with an effect on the autonomic system. In brain slice experiments on PVN neurones, ion channels that fit the TRPV4 ‘gating profile, for example the slope conductance (58±9 pS), reversal potential (‐8±3 mV), sensitivity to 4αDD and gating kinetics were sensitive to temperature changes (n=4‐6, p<0.05).Our electrophysiology results illustrate that temperature changes lead to activation of TRPV4‐ like channels on PVN neurones. We show that inhibition of TRPV4 channels has profound effects on thermosensing responses such as vasodilation, further iimplicating its role in thermoregulation and modulation of autonomic outflow from the PVN.Support or Funding InformationThis work was funded by the BBSRC.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Second hand smoke exposure depresses neuronal excitability and enhances 4‐AP sensitive channel function of cardiac vagal neurons in the nucleus ambiguus
Authors: Sun Jun‐Qing , Pan Shi‐Yue , Karey Emma , Chen Chao‐Yin 
Published: June 2021

BACKGROUNDSecond hand smoke (SHS) is a significant risk factor for cardiac dysfunction including arrhythmias and sudden cardiac death. Previously we showed that environmentally relevant concentrations of SHS reduce heart rate variability (HRV), an index of autonomic function. We also showed that SHS exposure significantly reduces cardiac vagal neuronal excitability in the nucleus ambiguus (NA), the final vagal cardiac output regulating HRV. We further showed that SHS‐induced attenuation of SK channel activity that may serve as a partial compensatory mechanism to the reduction in overall neuronal excitability. Here, we sought to test the hypothesis that SHS exposure, at an environmentally relevant concentration that reduces HRV, depresses neuronal excitability of cardiac vagal neurons in the NA by enhancing 4‐AP sensitive potassium channel function.METHODSAdult male C57BL6/J mice underwent open chest surgeries to retrograde label cardiac vagal neurons by applying a fluorescent dye (DiI) to the sinoatrial node. After two weeks of recovery from surgery, mice were randomly assigned to either filtered air (FA) or SHS (3 mg/m3, 6 hr/d, 5 d/wk) for 4‐, 8‐ or 12‐weeks. Whole‐cell current clamp recordings in brainstem slices were performed on anatomically identified cardiac vagal neurons in the NA with fluorescent labeling.RESULTSSHS exposure significantly (p < 0.05) reduced spiking response to depolarizing current injections after 4‐ and 12‐weeks – but not 8‐weeks – of exposure. Perfusion with 1 mM of 4‐AP, a voltage‐activated potassium channel blocker, similarly increased spiking response by 5–10 spikes/s across all time points. The 4‐AP induced changes in spiking responses were not different between SHS and FA (p > 0.05). SHS exposure also significantly (p < 0.05) increased voltage and current threshold for action potential generation for all time points tested (4‐, 8‐, and 12‐weeks). 4‐AP significantly lowered the voltage threshold; these effects were significantly (p < 0.05) bigger in the SHS group (−1.2 ± 0.5 mV vs. −3.7 ± 0.4 mV, FA vs. SHS respectively). In contrast, 4‐AP similarly lowered current threshold for action potential generation in both FA and SHS groups (−80 ± 13 pA vs. −103 ± 12 pA, FA vs. SHS, respectively).CONCLUSIONSWe conclude that environmentally relevant SHS exposure induces time‐dependent changes in neuronal excitability of cardiac vagal neurons. Some of these changes may be the result of increased voltage‐activated potassium channel function.Support or Funding InformationR01 ES025229; T32 HL086350This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Stress Dampening and Anxiolytic Effects of Overexpressing Angiotensin Converting Enzyme 2 in Female Mice
Authors: Cahill Karlena M. , Alleyne Amy R. , Smeltzer Michael D. , Raizada Mohan K. , de Kloet Annette D. , Krause Eric G. 
Published: June 2021

Accumulating evidence has revealed intricate roles for a number of components of the renin‐angiotensin system (RAS) in the progression or alleviation of stress‐related disorders. Along these lines, the ‘pro‐stress' actions of Angiotensin‐II are largely thought to be mediated by the angiotensin type‐1 receptor (AT1R). On the other hand, a counter regulatory limb of the RAS that depends on the conversion of Angiotensin‐II to Angiotensin‐(1‐7) by angiotensin‐converting enzyme 2 (ACE2) has been postulated to exert stress‐dampening actions. We have previously found that stimulating this enzyme has potent anxiolytic and hypothalamic‐pituitary‐adrenal (HPA) axis dampening effects in male mice; however, the impact of stimulating this counter regulatory limb on stress‐related responses in females is yet to be explored. That being said, females are often considered to be more susceptible to stress‐related mood disorders, making it essential that novel therapeutic options for females are also uncovered. Therefore, in this set of studies, we tested the hypothesis that ACE2 has anxiolytic and endocrine stress‐dampening effects in female mice. We used the Cre/Lox system to generate female mice that ubiquitously overexpress ACE2. Female ACE2 knock‐in (ACEKI) mice and their wild‐type littermate controls were tested in the elevated‐plus maze (EPM) and open field maze (OFM) to evaluate the impact of the genetic manipulation on anxiety‐like behavior. Mice were then subjected to an acute 30 min restraint stress challenge and blood samples were collected for the evaluation of HPA axis reactivity. As expected, overexpression of ACE2 leads to elevated ACE2 expression and activity in all tissues examined (i.e., hypothalamus, pituitary, blood, and brain). In regards to anxiety‐like behavior, a statistically significant increase (p < 0.05) in time spent in the open arms was observed in the ACE2KI mice relative to controls, demonstrating an anxiolytic effect of ACE2 overexpression. Total distance traveled in the EPM and OFM were not different between the groups, indicating that the locomotor activity of the female mice is unchanged by ACE2 overexpression. Finally, ACE2KI female mice also exhibited significantly reduced HPA axis activity relative to their wild‐type littermate counterparts (p < 0.05). Collectively, the results indicate that augmenting ACE2 activity reduces stress reactivity and anxiety‐like behavior in female mice.Support or Funding InformationNIH:HL125805 and AHA GRNT33660969 (AdK), NIH: HL122494 (EGK), NIH HL033610 and HL102033 (MKR).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Thrombin action on NST astrocytes disrupts glycemic and respiratory control
Authors: Hermann Gerlinda E. , Rogers Richard C. 
Published: June 2021

Burns and severe trauma can produce a post‐injury “metabolic self‐destruction” characterized by catabolic metabolism and hyperglycemia. The severity of the hyperglycemia is highly correlated with post‐trauma morbidity and mortality. No mechanism has been posited to connect severe trauma with a loss of autonomic control over metabolism. However, traumatic injury causes other failures of autonomic function; one of those, gastric stasis and ulceration (“Cushing's Ulcer”) has recently been connected with the generation of thrombin. As a protease, thrombin (produced as a consequence of tissue injury) acts on G‐protein‐coupled protease‐activated receptors (PAR). Our previous work established that PAR1 receptors located on astrocytes in the autonomically critical nucleus of the solitary tract (NST) are responsible for modulating gastric control circuit neurons. The NST is at the center of a homeostatic control nexus that receives vast quantities of visceral afferent data from cranial nerve afferents including the vagus. This region of the hindbrain is also outside the “blood‐brain barrier” and is accessible to large molecules from the circulation. The NST uses this neural and chemical information to regulate gastrointestinal, metabolic, cardiorespiratory, endocrine, and behavioral functions. Astrocytes in the hindbrain have been also been implicated as important detectors of low glucose or glucose utilization and when activated, these astrocytes trigger CRR. There may be a convergence between the effects of thrombin to derange hindbrain gastrointestinal control and the hindbrain circuitry that initiates counter‐regulatory responses (CRR) to increase glycemia in reaction to critical hypoglycemia. We tested the hypothesis that administration of thrombin to the floor of the fourth ventricle (4V) or directly into the NST could trigger increases in glycemia through the mediation of astrocytes. Pre‐exposure of the 4V to fluorocitrate (FC; a selective blocker of astrocyte metabotropic signaling) was used to evaluate astrocyte involvement in thrombin‐triggered changes in glycemia. Our results suggest that thrombin acts within the NST to increase glycemia through an astrocyte dependent mechanism. Blockade of purinergic, but not glutamatergic, gliotransmission pathways interrupted the effect of thrombin to increase glycemia. Our studies also revealed that thrombin, acting in the NST, produces a rapid, dramatic and potentially lethal suppression of respiratory rhythm that was also a function of purinergic gliotransmission. These results suggest that the critical connection between traumatic injury and a general collapse of autonomic regulation involves thrombin action on astrocytes.Support or Funding InformationNIH NIDDK 108765, NIH NINDS 96113This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evaluation of the cognitive functions of rat pulps and mothers exposed to environmental enrichment, exercise training or social isolation before and during pregnancy
Authors: Okudan Nilsel , Belviranli Muaz 
Published: June 2021

The aim of this study was to examine effects of social isolation, enriched environment and exercise on learning in rats. The study included 36 female Wistar rats. The rats were randomly divided into four different groups; control (n = 6), exercise (n = 10), social isolation (n = 10) and the enriched environment groups (n = 10). The social isolation group and the enriched environment group were housed under their specific conditions and the exercise group and the control group were housed in standard conditions during 6 weeks. The rats in the exercise group swam for 60 min per day, 5 days a week for 6 weeks. After 6 weeks, the rats were evaluated in the Morris water maze. At the end of 6 weeks, brain and blood samples were taken from the rats under anesthesia and the hippocampus tissue was dissected. It was frozen rapidly with liquid nitrogen and stored until use at −80 ° C for biochemical analysis. BDNF and NGF levels were measured in these samples. In conlusion, while enriched environment was a positive effect on spatial learning, social isolation was a negative effect on spatial learning and increase thigmotactic behaviors. According to the analysis results NGF and BDNF levels in the hippocampus and plasma did not change with environmental conditions and exercise. Time of exposure to social isolation, procedures of the enriched environment, time of exposure to the environment, type and duration of exercise and gender may affect the results.Support or Funding InformationThis work was supported by the Selcuk University Scientific Research and Project Coordinatorship (project number: 14401089).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Neuroprotective signaling mechanisms of telomerase in neuronal cells against oxidative stress
Authors: Park Sookyoung , Hong Yonggeun 
Published: June 2021

Canonically, telomerase was viewed as an enzyme with only one action: maintenance and extension of telomeres to prevent cellular senescence/aging. Novel roles for telomerase, particularly its catalytic subunit telomerase reverse transcriptase (TERT), in normal brain function and protection of CNS cells have recently emerged. However, little is known about whether telomerase also exerts neuroprotective effects in neuronal cells against oxidative stress and how its activity may be modulated by known neuroprotective agents such as estrogen (17β‐estradiol, E2). Human origin SH‐SY5Y neuroblastoma cells were differentiated into cholinergic phenotype by 10 μM retinoic acid over 6 days following, then E2 and hydrogen peroxide were treated respectively. E2 treatment reduced apoptotic changes including Bax:Bcl‐2 ratio and apoptosis‐related proteases caspase‐3, as well as neuronal cell death induced by oxidative stress. In addition, E2 treatment enhanced TERT expression and activity in neuronal cells. To characterize changes in NF‐κB and I‐κB expression/translocation, their protein levels were compared in cytosolic/nuclear fractions. The change in NF‐κB:I‐κB ratio was shown in neuronal cells following oxidative stress, then E2 attenuated NF‐κB transcriptional activity in neuronal cells. To determine whether TERT is required for the neuroprotective effects of estrogen in neuronal cells against oxidative stress, hTERT siRNA was employed. Specific knockdown of hTERT in E2‐treated cells showed significant apoptotic changes following oxidative stress, indicating cytoprotective effects of estrogen was lost in cells treated with hTERT knockdown. Taken together, these findings suggest that TERT is an essential mediator of estrogen neuroprotection.Support or Funding InformationNRF‐2014R1A1A3051724 to S.P., NRF‐2017R1A2A2A01067169 to Y.H., KGM4611714 to Y.H., Korea.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.