bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age‐related loss of neurotrophic signaling at the diaphragm muscle (871.4)
Authors: Greising Sarah , Ermilov Leonid , Sieck Gary , Mantilla Carlos 
Published: June 2021

The age‐related mechanisms of diaphragm muscle (DIAm) sarcopenia are largely unknown. We hypothesize that sarcopenia may be related to neurotrophic signaling, specifically that of brain derived neurotrophic factor (BDNF) acting through the high‐affinity tropomyosin‐related kinase receptor subtype B (TrkB). In total 47, adult male TrkBF616A mice were examined at 6, 18, and 24 months of age (mo), representing survival rates of 100, 90, and 75%. At each age, ex vivo contractility of the DIAm was assessed to determine maximal force as well DIAm‐phrenic nerve neuromuscular transmission failure under the following preincubation conditions; control (vehicle) solution, BDNF, 1NMPP1 (inhibiting TrkB kinase activity), or co‐treatment of BDNF and 1NMPP1. Specific DIAm maximal twitch and isometric tetanic force, in addition to fatigue index were all negatively impacted at 24 mo (P蠄0.02). A significant interaction between age and neurotrophic treatment was found for DIAm‐phrenic nerve neuromuscular transmission failure (P蠄0.01). Specifically, at 6 and 18 mo BDNF decreased failure, while this was lost at 24 mo. Conversely, TrkB kinase inhibition increased failure at 6 mo, but this relationship was lost at both 18 and 24 mo. Taken together, neurotrophic signaling is key to the physiological function of the DIAm, however there is likely an age‐related loss of BDNF and TrkB signaling that detrimentally affects the DIAm.Grant Funding Source: Supported by R01‐AG044615, T32‐HL105355, and the Mayo Clinic.
The Ca2+‐activated K+ channels play a braking role in locus coeruleus neurons during CO2 exposure (872.1)
Authors: Patrone Luis Gustavo , Bicego Kenia , Putnam Robert , Gargaglioni Luciane 
Published: June 2021

The LC has an important role in central chemoreception and K+ channels have been suggested to be sensitive to changes of pH. Studies have shown that some ion channels present in the cell membrane of LC neurons, among them the Ca2+‐activated K+ channels (KCa), are activated by high levels of CO2. These channels appear to hyperpolarize LC neurons and limit increased firing rate in response to hypercapnic acidosis. We evaluated the participation of KCa in the CO2‐drive to breath in unanesthetized adult rats by bilaterally microinjecting Paxiline (KCa blocker, 100µM or 500µM / 0.1µL) or vehicle (aCSF) intra‐LC. Bilateral KCa blockade in LC neurons did not affect resting ventilation. However, the increase in ventilation produced by hypercapnia (7% CO2) was amplified by 39 and 33% after Paxilline (100µM or 500µM, respectively) injection (1305.2 ± 164.2 mL.kg‐1.min‐1 in vehicle group vs 1822.0 ± 201.7 in Paxilline 100µM group and 1735.3 ± 116.5 in Paxilline 500µM group) due largely to a increase in tidal volume. The results suggest that KCa++ modulate the hypercapnic ventilatory response as braking pathway, but that they are not involved in respiratory control during normocapnia, in the LC of adult rats.Grant Funding Source: FAPESP and CNPq
State‐dependent regulation of breathing by the retrotrapezoid nucleus (872.10)
Authors: Burke Peter , Kanbar Roy , Hodges Walter , Viar Kenneth , Coates Melissa , Stornetta Ruth , Guyenet Patrice 
Published: June 2021

In this study we stimulated the retrotrapezoidal neurons (RTN) by optogenetics in behaving animals to determine ventilatory responses across sleep and wake states. We targeted the rostral RTN region (n=12) with a PRSX8 promoter lentivirus and limited ChannelRhodopsin expression to RTN neurons and noradrenergic A5 neurons. A subset of rats (n=6) also received intraspinal anti‐DBH‐saporin, a catecholaminergic‐specific neurotoxin, to eliminate A5 neurons. We observed no significant differences for the resting or evoked ventilatory behavior after effective lesion. In quiet awake and non‐rapid eye movement (nREM; quiet asleep) states, RTN stimulation increased respiratory frequency and tidal volume, and could entrain respiratory rate between 1.2Hz ‐ 2Hz. We also observed active expiration in the wake state only. The increase in breathing by RTN stimulation was occluded by hypercapnia (6% CO2), but not hypoxia (12% O2). Surprisingly, RTN stimulation in REM (active sleep) failed to increase or pace respiratory rate and only tidal volume was significantly increased. This REM phenomenon draws an intriguing parallel to voluntary breathing (active wake), where homeostatic mechanisms are limited to adjusting the depth of each cortically‐triggered breath.Grant Funding Source: Supported by NIH (HL28785, HL74011)
Antagonism of orexin receptors significantly lowers blood pressure and exaggerated CO2 chemoreflex in spontaneously hypertensive rats (872.2)
Authors: Li Aihua , Hindmarch Charles , Paton Julian , Nattie Eugene 
Published: June 2021

The orexin system is involved in cardiorespiratory function as well as wake‐sleep regulation. We recently showed that in spontaneously hypertensive rats (SHRs): 1) blocking both orexin receptors by oral administration of an antagonist, almorexant (almxt), significantly lowers blood pressure in wakefulness and NREM sleep in both dark and light periods of the diurnal cycle, 2) the anti‐hypertension effect is accompanied by decreased sympathetic vasomotor tone and noradrenaline levels in cerebrospinal fluid and plasma, 3) there is a strong trend towards increased orexin‐A mRNA expression in the rostral ventrolateral medulla, a projection site for orexinergic lateral hypothalamic (LHA) neurons, 4) there is an exaggerated CO2 ventilatory chemoreflex, which can be normalized by blocking orexin receptors with almxt. Antagonism of orexin receptors had no effect on resting blood pressure in normotensive WKY rats. We interpret these results to suggest that an overactive orexin system may play a significant role in the development and maintenance of high blood pressure and enhanced CO2 chemoreflex in SHRs. Modulation of orexin and the hypothesized overactive central chemoreflex could be a potential target in treating hypertension.Grant Funding Source: NIH HL 28066
TASK‐2 channels contribute to pH sensitivity of retrotrapezoid nucleus chemoreceptor neurons (872.4)
Authors: Kumar Natasha , Wang Sheng , Benamer Najate , Zanella Sebastian , Shi Yingtang , Bevengut Michelle , Penton David , Guyenet Patrice , Lesage Florian , Gestreau Christian , Barhanin Jacques , Bayliss Douglas 
Published: June 2021

Phox2b‐expressing neurons of the retrotrapezoid nucleus (RTN) function as central respiratory chemoreceptors; they are directly activated by CO2/H+, via an unidentified pH‐sensitive background K+ channel, to drive breathing. Here, we test the effect of TASK2 (K2P5, an alkaline‐activated background K+ channel) channel deletion on the pH sensitivity of RTN neurons and on CO2 modulation of central respiratory output. For patch clamp recordings in brainstem slices, individual RTN neurons were identified by GFP expression (driven by the Phox2b promoter) or β‐galactosidase (from the gene trap used for TASK2 deletion). Whereas 95% of RTN cells from control mice were pH sensitive, only 56% from TASK2‐/‐ mice were classified as pH sensitive; the remaining cells were pH insensitive (44%). The alkaline‐activated background K+ currents were reduced in amplitude in pH‐sensitive RTN neurons from TASK2‐/‐ mice but were absent from pH‐insensitive cells. TASK2 was strongly expressed in 63% of Phox2b‐expressing RTN neurons (by X‐gal staining), and in 85% (by a more sensitive scPCR approach). Using an in situ working heart‐brainstem preparation, we found diminished inhibition of phrenic burst amplitude by alkalization in TASK2‐/‐ mice, with apneic threshold shifted to higher pH levels. We conclude that TASK2 channels represent a molecular substrate for pH sensing in RTN respiratory chemoreceptor neurons.Grant Funding Source: Supported by: NIH HL074011 and NIH HL108609; and ANR‐RESPITASK and ANR‐11‐LABX‐0015‐01
Coping with acute hypertensive stressors after selective carotid body ablation in conscious spontaneously hypertensive rats (873.10)
Authors: Pijacka Wioletta , McBryde Fiona , Paton Julian 
Published: June 2021

We have previously shown that bilateral carotid sinus denervation in SHR reduces arterial pressure (AP). This technique, however, also removes carotid sinus baroreceptors. We hypothesized that the fall in basal AP with selective bilateral CBA would not impair the normal cardiovascular responses to hypoxia, exercise and restraint stress. SHR were implanted with telemetry devices to record AP, and responses to hypoxia (10% O2), exercise (10m/min) and restraint stress were tested. The chemoreflex was tested with i.v. sodium cyanide (120μg.kg‐1); this response was abolished after CBA (n=4) but preserved in Shams (n=3). Basal systolic AP fell significantly after 14 days in CBA (‐18.2±2mmHg) compare to Sham (2.5±0.6mmHg), (P<0.05). SHR with CBA showed a depressor effect to 10% oxygen (‐15.3±7mmHg) whereas a pressor response was seen in Sham (15.9±6mmHg; P<0.029); heart and respiratory rates were not different. The change in AP was similar between groups during both exercise (CBA 12±7 vs. Sham 23±8mmHg, respectively; NS) and restraint stress (CBA 28±8 vs. Sham 17±9mmHg; NS). We conclude that chronic CBA prevents the pressor response to hypoxia but does not affect cardiovascular adjustment to exercise and restraint stress.Grant Funding Source: Supported by the British Heart Foundation and Cibiem
Peripheral chemoreceptor contribution to ventilatory control during steady‐state exercise (873.2)
Authors: Peinado Ana , Johnson Blair , Taylor Jennifer , Joyner Michael 
Published: June 2021

We tested the hypothesis that the carotid body chemoreceptors (CB) contribute to ventilatory control during steady‐state exercise. Six men completed two randomized bouts of cycling exercise at 65% VO2max for up to 2 hours during an IV infusion of dopamine (D; 2 µg/kg/min) to acutely inactivate the CB, or a saline infusion (S). Expired gases were analyzed at baseline, resting‐infusion, and during exercise (25%, 50%, 75% and 100% of total exercise time). A hypoxic ventilatory response (HVR) test was performed after exercise during the infusion condition. Subjects were classified as responders (RS; n=3) if their HVR was lower during D vs. S (1.03 ± 0.6 vs. 2.14 ± 0.4 L/min/%SaO2). In RS, partial pressure of end‐tidal CO2 had a greater delta from baseline at 75% (2.9 ± 2.1 vs. 1.1 ± 1.9 mmHg) and 100% (0.9 ± 3.4 vs. ‐0.3 ±3.3 mmHg) during D than S, and the increase in oxygen uptake at 100% was greater during D vs. S (34.7 ± 2.6 vs. 33.0 ± 2.6 mL/min/kg). In RS, there were no differences in the changes from baseline for ventilation (VE), VE/VCO2, respiratory rate, tidal volume, and respiratory exchange ratio between conditions. In the non‐responders group, there were no differences between D and S in any variables. When the data was pooled, HVR accounted for 37% of the variance in VE at 100%. Despite evidence that CB chemosensitivity was blunted, the CB appear to play a minor role in controlling ventilation during steady state exercise.Grant Funding Source: NIH R01DK090541
Electrophysiological properties of RVLM pre‐sympathetic neurons modulated by the respiratory network in rats (875.11)
Authors: Moraes Davi , da Silva Melina , Bonagamba Leni , Mecawi André , Zoccal Daniel , Antunes‐Rodrigues José , Varanda Wamberto , Machado Benedito 
Published: June 2021

The respiratory pattern generator modulates the sympathetic outflow which strength is enhanced by hypoxia. This coupling is due to the respiratory‐modulated pre‐sympathetic neurons in the RVLM, but the underlining electrophysiological mechanisms remain unclear. For a better understanding of the central generation of respiratory‐sympathetic coupling, we combined immunofluorescence, single cell qRT‐PCR and whole cell patch clamp recordings of the pre‐sympathetic neurons in in situ preparations from normal and rats submitted to chronic intermittent hypoxia (CIH). Our results show that the spinally projected C1‐ and non‐C1 respiratory‐modulated pre‐sympathetic neurons (inspiratory‐modulated: 22; post‐I‐modulated: 23; inspiratory‐inhibited: 11; non‐modulated: 20) present distinct electrophysiological properties, synaptic inputs and expression of ionic currents, albeit all neurons presented iNaP‐dependent intrinsic pacemaker after synaptic blockade. Only the non‐C1 post‐I‐modulated neurons presented enhanced excitatory synaptic inputs from the respiratory network after CIH (n=14), which may contribute to the increased sympathetic activity observed in CIH rats. We conclude that the different respiratory‐modulated pre‐sympathetic neurons contribute to the central generation of respiratory‐sympathetic coupling and in response to the challenges produced by CIH may contribute to respiratory‐related increase in the sympathetic activity and hypertension observed in this experimental model.Grant Funding Source: Supported by CAPES and FAPESP
Cardiovascular responses to disinhibition of rostral ventrolateral medulla (RVLM) following unilateral RVLM blockade in sedentary or physically active, sinoaortic denervated rats (875.13)
Authors: Dombrowski Maryetta , Azar Toni , Mueller Patrick 
Published: June 2021

The RVLM is a bilateral region in the brainstem important for sympathetic control of arterial pressure (AP). Although tonically active, both RVLMs receive strong γ‐amino‐butyric acid (GABA)‐mediated inhibition, due in part to tonic arterial baroreceptor input. Previous studies report that unilateral inhibition of the RVLM in sinoaortic denervated (SAD) rabbits leads to dramatic decreases in AP and sympathetic nerve activity (SNA), demonstrating the importance of the baroreflex to resting AP. Following SAD, a strong GABAergic input to RVLM persists and likely suppresses the activity of the RVLM in the absence of baroreceptor input. However, whether this inhibition is altered in sedentary (SED) and active conditions is unknown. The current study was aimed at testing the hypothesis that inhibition of one RVLM in SAD rats would result in enhanced non‐barosensitive GABAergic input in the remaining intact RVLM, and this input would be greater in the SEDs compared to the active rats (i.e., 12 weeks of chronic wheel running on average =WR ). In Inactin‐anesthetized SEDs (n=4) and WRs (n=4), AP and splanchnic SNA were recorded following surgical SAD. Following inhibition of one RVLM (muscimol 2mM, 90nl), bicuculline (5mM, 90nl) was microinjected into the contralateral RVLM. Preliminary data indicate that changes in mean AP appeared to be higher in the SEDs (∆60±12mmHg) compared to the WRs (∆44±15mmHg). Due to small sample size, however, we were unable to support our finding statistically. Splanchnic SNA responses between SEDs (∆52%±16) and WRs (∆49%±23) did not appear to differ. These preliminary data suggest that in the absence of baroreceptor input, MAP and SNA are significantly reduced due to strong non‐barosensitive GABAergic input to the intact RVLM. However, non‐barosensitive GABAergic input may be altered in response to sedentary and active conditions.Grant Funding Source: Supported by R01‐HL096787; R01‐ HL096787‐S1
The relationship between muscle sympathetic nerve activity and hemodynamics in women taking oral contraceptive pills (875.2)
Authors: Harvey Ronee , Hart Emma , Charkoudian Nisha , Curry Timothy , Carter Jason , Fu Qi , Minson Christopher , Joyner Michael , Barnes Jill 
Published: June 2021

The relationship between mean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), and total peripheral resistance (TPR) is altered in young women versus men and postmenopausal women due to endogenous sex hormone differences. Exogenous sex hormones in the form of oral contraceptive pills (OCPs) may further affect this relationship. We performed a retrospective review of 136 premenopausal women in whom MSNA and arterial pressure were measured, including 78 women with natural menstrual cycles in the early follicular phase (26±1 yr) and 58 women in the placebo phase of OCPs (24±1 yr). TPR and cardiac output (CO) were measured in a subset of women in whom continuous intra‐arterial blood pressure was recorded. Compared to those with natural menstrual cycles, women on OCPs had greater MAP (89±1 vs. 84±1 mmHg, p<0.01) and tended to have lower MSNA (15±1 vs. 18±1 bursts/100 heart beats, p=0.06). MAP and MSNA were positively correlated (r=0.22, p<0.05), TPR and MSNA were positively associated (r=0.41, p<0.05) and CO and MSNA (r=‐0.44, p<0.05) were inversely associated in naturally cycling women (n=26) but not in women on OCPs (r=0.15, r=0.11, r=‐0.01, respectively; p>0.05; n=38). In contrast to naturally cycling women, there appears to be no relationship between MSNA and hemodynamics in women on OCPs, suggesting that these women may regulate their blood pressure differently than women.Grant Funding Source: Supported by NIH
Chronic neuroinflammation and cognitive impairment following transient global cerebral ischemia: role of fractalkine/CX3CR1 signaling (877.1)
Authors: Briones Tess , Woods Julie , Wadowska Magdalena 
Published: June 2021

Neuroinflammation has been studied extensively in cerebral ischemia. A major participant in neuroinflammation is microglia its activation is usually regulated by the chemokine fractalkine (CX3CL1) and its receptor, CX3CR1. Here, we examined the involvement of CX3CR1 on ischemia‐induced chronic neuroinflammation and cognitive function using small interfering RNA (siRNA). Forty adult male Wistar rats were included in the study and received either ischemia or sham surgery then randomized to receive either CX3CR1 siRNA or scrambled RNA as control starting at 7 days after reperfusion. Behavioral testing commenced 28 days after and all rats were euthanized after behavioral testing. Our data showed that: (i) transient global cerebral ischemia significantly decreased fractalkine/CX3CR1 signaling in the hippocampus; (ii) inhibition of CX3CR1 function exacerbated the ischemia‐induced chronic increased in microglial activation and pro‐inflammatory cytokine levels; (iii) inhibition of CX3CR1 function worsened ischemia‐induced chronic cognitive impairment; (iv) inhibition of CX3CR1 function in sham rats resulted in increase IL‐1β expression and impaired behavioral performance. No significant effect of CX3CR1 on ischemia‐induced neurodegeneration was seen. This study provides important insight to understanding the role of CX3CR1 in chronic neuroinflammation and cognitive impairment.Grant Funding Source: Supported in part by the National Institutes of Health, NINR grant # RO1 NR005260 and the Wayne Stat
Delayed neuronal death in swine following cardiac arrest and resuscitation (877.12)
Authors: Nguyen Anh , Cherry Brandon , Ryou Myoung‐Gwi , Williams Arthur , Hollrah Roger , Baker Charla , Choudhury Gourav , Olivencia‐Yurvati Albert , Mallet Robert 
Published: June 2021

Cardiac arrest, a leading cause of death in the U.S., kills >90% of its victims, and survivors often are disabled by permanent brain injury inflicted by ischemia‐reperfusion. Purkinje cells of the cerebellum and CA1 neurons of the hippocampus are especially vulnerable to post‐ischemic neuronal death. We tested the hypothesis that cardiac arrest in a swine model caused delayed neuronal death. Yorkshire swine (25‐35 kg) were subjected to cardiac arrest‐resuscitation (n = 9) or non‐arrest sham (n = 5) protocols. Ventricular fibrillation was induced by electrical pacing. Precordial compressions (100/min) were given at 6‐10 min arrest, and then sinus rhythm was restored with transthoracic countershocks. NaCl was infused iv at 0.1 mmol/kg/min during CPR and the first 60 min after return of spontaneous circulation (ROSC). At 7 d ROSC, brain regions were fixed in 4% paraformaldehyde and H&amp;E stained. More than 70% of the Purkinje cells were shrunken, lacked dendrites and displayed condensed cytoplasm at 7 d ROSC; in contrast, in shams the majority of Purkinje cells retained the characteristic thick dendrites and well‐defined nuclei. Thus, cardiac arrest‐resuscitation produced marked changes in cerebellar neurons evident 7d after acute insult.Grant Funding Source: NINDS 076975
The effects of melatonin and therapeutic exercise on brain to spinal cord network organization after ischemic brain injury in rats (877.15)
Authors: Lee Seunghoon , Won Jinyoung , Hong Yonggeun 
Published: June 2021

The corticospinal tract (CST), long axons of the cortical pyramidal neurons extending to the spinal cord, connecting with the spinal motor neurons directly or indirectly, is the primary transmission tract from the sensorimotor cortex and, thus, forms the neuroanatomical basis for brain‐controlled voluntary movements of the peripheral muscles, In the view point of this research, we investigated whether CST altered, and affected following melatonin and/or therapeutic exercise intervention from acute to recovery phase after focal cerebral ischemia by MCAo surgery. Following the MCAo, the 8‐week‐old Sprague‐Dawley (SD) rats were treated twice daily with MT (10 mg/kg) at 7:00 and 19:00 hr and control group animals were treated with physiological saline (Veh) instead of MT. Also, the rats were trained twice daily with Ex (20 m/min) at 17:00 and 22:00 hr. Melatonin and/or therapeutic exercise not only showed the increment of neuronal cell in penumbra and contralateral region (p<.01), but also the overexpression of Dcx and NG2‐positive cells (p<.01). Moreover, dually applications of melatonin with therapeutic exercise have a prophylactic effect on neural cell death through Golgi‐cox staining as well as promote to neurite outgrwoth. Moreover, MCAo+MT and MCAo+MT+Ex groups revealed a strengthening of projection fiber from cerebral cortex to spinal motor neuron on both corticospinal and rubrospinal tracts. Finally, melatonin and/or therapeutic exercise might induce the blockage of muscle atrophy through MuRF1/MAFbx signaling pathway as well as the activation of hypertrophy signal pathway. In conclusion, melatonin and therapeutic exercise contributed to faster motor recovery and led to reduced stroke‐induced muscle atrophy. Especially, combined therapy has the most efficiency for both neural network and functional recovery.Kew words: Focal cerebral ischemia, Melatonin, Therapeutic exercise, Brain‐spinal cord network.
Inhibition of DAPK‐1 induces neuronal cell rescue which is linked to ER stress in stroke animal model (877.16)
Authors: Won Jinyoung , Lee Seunghoon , Hong Yonggeun 
Published: June 2021

Background: Death associated protein kinase (DAPK) was identified as key player of multiple cell death. DAPK‐1 related apoptosis is the prototypic member of DAPK family that is activated by signaling pathway such as endoplasmic reticulum (ER) stress. Activation of ER stress response has been found to be associated with neurodegenerative disease. ER stress by the unfolded protein response interfere ER homeostasis and promotes neuronal cell death.Purpose: Here, we are going to determine that cerebral ischemia induces ER stress by reperfusion brain injury following middle cerebral artery occlusion (MCAo) in rats. Additionally, we tried to identify that DAPK‐1 is an essential component in the programmed cell death pathway.Results: Focal cerebral ischemic rats by MCAo are exhibited ER stress response and neuronal cell death. However, brain injury volume was reduced in MCAo rats treated with DAPK inhibitor compared to MCAo vehicles suggesting inhibition of DAPK has not only protective effect on neuronal cells death but also resistant to cerebral ischemic injury.Suggestion: Accordingly, DAPK linked to ER stress may regulate the neuronal cell death. Furthermore, down regulation of DAPK represents a potential therapeutic target for transient focal ischemia and neurodegenerative diseases.