bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of chronic exposure to THIP on brainstem neuronal excitability in a female mouse model of Rett syndrome
Authors: Zhong Weiwei , Johnson Christopher M , Cui Ningren , Xing Hao , Wu Yang , Mo Huanbiao M , Jiang Chun 
Published: November 2023

Rett Syndrome (RTT) is a neurodevelopmental disease with ~ 0.01% morbidity rate in live‐born girls worldwide. Mutations of MECP2 gene encoding methyl CpG binding protein 2 (MeCP2) underlies over 90% of RTT cases clinically. One of the characteristic features of the disease is defective autonomic function, showing breathing instability, gastrointestinal disorders and cardiac arrhythmia. Imbalanced neuron excitation/inhibition ratio may underlie the development of the symptoms. In Mecp2−/Y mice, several groups of brainstem neurons show excessive excitability, which may contribute to the instability of neuronal networks for the autonomic function. One way to control the neuronal hyperexcitability is to enhance the GABAergic inhibition. We have previously reported that THIP (Gaboxadol), an extrasynaptic GABAA receptor agonist, relieved many RTT‐like symptoms in a male mouse model of RTT. However, several questions are still open as to what the THIP effects are at the cellular level, whether increased excitability of brainstem neurons also occurs in female Mecp2+/− mice, how the mosaic expression of MeCP2 affects the neuronal excitability, and how the MeCP2 expression affects neuronal responses to THIP. Thus, we performed studies to address these questions. After symptomatic Mecp2+/− (sMecp2+/−) female mice were identified with a two‐step screening method, the mice were divided into THIP and vehicle groups. Whole‐cell recording was performed in brain slices from the mice with a prior 5‐week exposure to low‐dose THIP or vehicle. Neurons in the locus coeruleus (LC) and the mesencephalic trigeminal nucleus (Me5) showed excessive firing activity in the vehicle‐treated sMecp2+/− mice. When the effect of mosaic expression of MeCP2 on neuronal hyperexcitability was studied in identified LC cells, we found that the level of hyperexcitability was similar in LC neurons with and without MeCP2 expression. THIP pretreatment stabilized the hyperexcitability of both LC and Me5 neurons of sMecp2+/− mice to a level similar to their WT counterparts. The THIP exposure also suppressed the excessive firing activity of MeCP2‐positive and MeCP2‐negative LC neurons, suggesting that the THIP effects appeared to be determined by not only the MeCP2 expression, but also cellular environmental cues. The alleviation of LC neuronal hyperexcitability seems to benefit brainstem autonomic function as THIP also improved breathing abnormalities of these sMecp2+/− mice.Support or Funding InformationThis work was supported by National Institutes of Health [grant number R01‐NS‐073875] and Brain and Behavior fellowship at Georgia State University.
Pseudomonas aeruginosa‐induced pulmonary endothelial amyloid proteins impair long‐term plasticity
Authors: Lin Mike T , Balczon Ron , Morrow K. Adam , Wagener Brant M , Pittet Jean‐Francois , Stevens Troy 
Published: November 2023

We have recently reported that following bacterial infection with Pseudomonas aeruginosa, injury to the pulmonary endothelium induces tau hyperphosphorylation and release as a cytotoxic amyloid protein. Further, cytotoxic amyloid production requires an intact type 3 secretion system (PA103 strain), because a non‐functional type 3 secretion system (e.g. ΔPcrV strain) does not result in the production of cytotoxic amyloid oligomers. Aberrant formation of protein aggregation is a common mechanism linked to several neurodegenerative diseases. Therefore, in this study we tested whether endothelial amyloid protein(s) affect synaptic plasticity. We employed the well‐characterized hippocampal Schaffer Collateral‐CA1 synaptic pathway to study the effect of supernatants from PA103‐, ΔPcrV‐, or non‐treated endothelial cells on long‐term potentiation (LTP) as a cellular model for animal learning. In field recordings, high frequency stimulation induced LTP. In mouse hippocampal slices exposed to supernatants from ΔPcrV‐ or non‐infected endothelial cells, the induced LTP were 192 ± 12% (n = 6) and 180 ± 16% (n = 6), respectively. In comparison, in slices exposed to supernatant from PA103‐infected endothelial cells, the LTP was reduced (128 ± 9.0%, n = 9; P < 0.05, ANOVA). Importantly, LTP suppression seemed to be ameliorated when endothelial amyloid(s) were immunodepleted with a pan antibody that recognizes neural amyloids, A11 (LTP: 176 ± 18%, n = 4). These results suggest that A11 neutralizes PA103‐induced amyloid cytotoxicity. Whole cell patch clamp recordings in CA1 pyramidal neurons further showed that hyperexcitability and changes in presynaptic neurotransmitter release might be attributable to the LTP suppression induced by endothelial amyloid cytotoxicity. Taken together, our results suggest that acute pneumonia may directly or indirectly impair brain cognitive function.Support or Funding InformationSupported by HL66299 and HL60224 (TS) and AHA16POST27250139 (KAM).
Sex and age differences in cardiac autonomic nervous regulation in response to recumbent positions
Authors: Sasaki Konosuke , Bao Sarina , Sato Haruka , Saiki Yoshikatsu , Maruyama Ryoko 
Published: November 2023

Not much research has been conducted to determine sex and age differences in autonomic nervous activity during different positions, namely the supine, left recumbent, and right recumbent positions. Our aim was to evaluate whether the left and right recumbent positions affect heart rate variability (HRV) differently than the supine position dose in young and old adults of both sexes. Twenty‐nine young male (22.5 ± 0.5 years), 29 young female (23.1 ± 0.7 years), 18 elderly male (76.1 ± 1.1 years), and 27 elderly female (72.6 ± 1.0 years) volunteers participated in this study. After lying in the supine position, the participants maintained each recumbent position in random order for 10 min. We recorded electrocardiographic data throughout this experiment to evaluate HRV. Heart rate during the left recumbent position was the lowest among the three positions regardless of age or sex. No significant differences were observed for low‐frequency (LF) HRV, high‐frequency (HF) HRV, or their ratio (LF/HF) in young adults of both sexes and elderly women when the position was changed from supine to recumbent. However, in elderly men, the LF/HF ratio during the right recumbent position was significantly lower than that during the supine position. While in supine position, elderly men showed high LF/HF ratios when compared to the other groups. These results suggest that the right recumbent position attenuates cardiac sympathetic nerve activity, which is expressed as the LF/HF ratio, in elderly male adults. Therefore, reduction in heart rate during the left recumbent position may not be associated with autonomic nervous activity.Support or Funding InformationThis work was supported in part by a Grant‐in‐Aid for Challenging Exploratory Research from the Japan Society for the Promotion of Science.
Neuromuscular Signaling in Myasthenia Gravis [MG] Patients
Authors: Sainvil Frantz L , Einstein George P , Tulp Orien L 
Published: November 2023

Myasthenia gravis (MG) is one of the most common disorders of neuromuscular signaling, with a prevalence of 13 to 21 per 100,000 in the United States. The symptoms experienced by people with MG include muscle weakness and generalized fatigue. In healthy patients, the presynaptic terminals release acetylcholine (ACH) from the motor nerve terminal in quanta, which then diffuse across the synaptic cleft and connect to receptors on the post synaptic membrane of the muscle, resulting in membrane depolarization and muscle contraction. In MG patients, however, the post synaptic ACH membrane receptors are destroyed or damaged mostly due to immunological or genetic abnormalities. Thymic tumors are also commonly seen in patients with MG. In MG, immune system B‐cells interact with helper T‐cells to produce antibodies to the ACH receptors. The destruction of the thymic tolerance can cause or contribute to an immune attack on the ACH receptors. MG can often be treated with cholinesterase inhibitors such as neostigmine bromide or thymectomy to enhance the diminished hormone‐ligand interaction needed to effect depolarization and muscle contraction. The current study utilized a Meta‐analysis approach for data interpretation in order to compare neuromuscular signaling in MG patients who were treated with cholinesterase inhibitors versus those who were treated surgically. Furthermore, this study intends to show that neuromuscular signaling in MG patients who have had surgical interventions tend to have more favorable outcomes than those treated with cholinesterase inhibitors alone. In our studies we also included noninvasive biophotonic diagnostic and electroceutical neuromuscular stimulation as alternative diagnostic and therapeutic measures with good success.Support or Funding InformationSupported by Institutional resources of USAT College of Medicine and the Einstein Medical Institute
Optogenetic stimulation of PVN‐RVLM neurons increases sympathetic nerve activity in anesthetized rats
Authors: Koba Satoshi , Hanai Eri , Kumada Nao , Kataoka Naoya , Nakamura Kazuhiro , Watanabe Tatsuo 
Published: November 2023

The hypothalamic paraventricular nucleus (PVN) sends direct projections to the rostral ventrolateral medulla (RVLM). The present study was conducted to examine the effect of optogenetic stimulation of PVN‐RVLM neurons on sympathetic nerve activity in anesthetized rats. Male rats anesthetized with pentobarbital received unilateral microinjection into the PVN with an adeno‐associated virus (AAV) vector that encodes the reporter protein palGFP (control rats, N=4) or the channel rhodopsin variant, ChIEF‐tdTomato (ChIEF rats, N=8). Two‐to‐five weeks later, in the rats anesthetized with a mixture of urethane and α‐chloralose, photostimulation (473 nm wavelength, 8–10 mW) was provided to the RVLM ipsilateral to the PVN into which AAV had been injected. In ChIEF rats, photostimulation of the RVLM at 40 Hz (5‐ms pulse duration) for 2 min significantly (P < 0.05) evoked renal sympathoexcitatory (+126 ± 20% from baseline, means ± SE) and pressor (+13 ± 1 mmHg) responses while this stimulation had no effect in control rats. Moreover, immunofluorescence staining revealed abundant distribution of PVN‐derived, tdTomato‐labeled axons in the ipsilateral RVLM as compared with that in the contralateral RVLM. Confocal imaging further showed close association of tdTomato‐labeled axons with tyrosine hydroxylase‐positive neurons in the RVLM. These observations suggest that excitation of the PVN‐RVLM monosynaptic pathway elicits sympathoexcitation via, at least in part, stimulation of RVLM catecholaminergic neurons, potentially playing a role in sympathetic adjustments to stress such as exercise.Support or Funding InformationJSPS KAKENHI 15H05367 & 16K15190 (SK); 16H05128 & 15H05932 (KN).
Spinal Cord Stimulation Reduces Ventricular Arrhythmogenicity During Ischemia
Authors: Dale Erica A , Howard‐Quijano Kimberly , Takamiya Tatsuo , Kubo Yukiko , Kipke Jasmine P , Mahajan Aman 
Published: November 2023

IntroductionSudden cardiac death is a leading cause of mortality in the United States and is often caused by ventricular tachyarrhythmias (VT) and/or ventricular fibrillation (VF; Mozaffarian et al., 2015). Myocardial ischemia triggers imbalances in sympathetic and parasympathetic balance and leads to the pathophysiology of cardiac arrhythmias. Spinal cord stimulation (SCS) is a useful modality for selective spinal neuromodulation of ventricular excitability (Wang et al., 2015), however the mechanisms remain poorly understood. Cardiac stressors elicit distinct neural signatures within the dorsal horn (DH; the spinal relay for cardiac afferents) and the intermediolateral (IML) nucleus of the thoracic spinal cord (the primary nexus point for modulation of sympathetic efferent outflow). We hypothesize that SCS decreases ventricular excitability during acute ischemia via modulation of afferent neural signaling and attenuation of sympathetic efferent output.MethodsAnesthetized Yorkshire pigs were randomized as follows: 1) epidural SCS via 4 pole lead for 30 min (n=10) or 2) Sham (n=10) before 5 min of myocardial ischemia via ligation of the left anterior descending (LAD) coronary artery. A 56‐lead heart sock was placed for electrophysiological recordings of: activation recovery intervals (ARI), activation time (AT), repolarization time (RT), and dispersion of repolarization (DOR).ResultsSCS reduced myocardial sympathoexcitation after 5 min of LAD ligation since: a) ARI reduction was attenuated (Sham: −79.9 ± 7.1ms vs. SCS: −58.5 ± 7.1; p=0.035); b) RT reduction was attenuated (Sham: −75.5 ± 6.9ms vs. SCS: −49.3 ± 6.9ms; p=0.008); c) there was a greater increase in AT (Sham: 4.2 ± 0.5ms vs. SCS: 6.7 ± 0.5ms; p=0.001) and; d) the increase in DOR was reduced (Sham: 2197.3 ± 262ms2 vs. SCS: 1307.2 ± 262ms2; p=0.006). In addition, there were fewer non‐sustained VTs (1/1 vs. 24/3) and PVCs (6(0–17) vs. 19(0–105); p<0.001) during ischemia and reperfusion.ConclusionThese results suggest SCS attenuates myocardial sympathoexcitation during acute ischemia by neuromodulation within the spinal cord itself. As evidenced by reduction in measures of myocardial excitation and fewer VTs and PVCs, SCS functionally reduces ventricular arrhythmogenicity. Preliminary results from extracellular recording in the thoracic DH and IML indicate that the spinal cord is capable of complex processing of primary afferent inputs. Further experiments are warranted to elucidate the precise mechanisms of SCS neuromodulation in order to develop novel therapeutics for the patient population.Support or Funding InformationNHLBI‐NIH (R01) HL084261 (AM), FAER and SCA‐IARS Starter Grant (KH‐Q).
Effects of L‐arginine Supplementation on the Tissue Production of Nitric Oxide and Cardiovascular Modulation by the Paraventricular Nucleus of Hypothalamus
Authors: de Ataides Raquel Hiviny , Ferreira Nathalia Zerbinatti , Lucchetti Bruno Fernando Cruz , Pinge‐Filho Phileno , Martins‐Pinge Marli Cardoso 
Published: November 2023

L‐Arginine is the substrate for nitric oxide (NO) synthesis and in the paraventricular nucleus of the hypothalamus (PVN) NO plays an important role in cardiovascular function. The objective of this study was to evaluate the effects of L‐arginine supplementation on cardiovascular responses by PVN and NO production. Wistar rats were used (220–250g) randomly divided into two groups: control (C) or L‐arginine (LA). The supplementation with L‐arginine was conducted in the LA group (62.5 mg/mL/rat/day), by oral gavage, and Group C received water (1 mL) for 4 weeks, 5times/week. Then the animals underwent to guide cannulas implantation to the PVN and artery and femoral vein catheterization. The baseline parameters of mean arterial pressure (MAP) and heart rate (HR) were recorded 24 hours after catheterization and held bilateral administration of 0.9% saline or an nNOS inhibitor (n‐Propyl‐L‐Arginine, 4nmol/100NL) in the PVN. We collected heart, kidneys, thoracic aorta, and punchs of the PVN for nitrite dosages by Cadmium‐Griess method. Spectral analysis was performed by the software Cardio Series (version 2.4). The supplementation with L‐arginine caused resting bradycardia (C: 359 ± 6 vs. LA: 335 ± 6 b/min) without change in MAP, as well as greater pressor response (ΔPAM: C: 17 ± 2 vs. LA: 26 ± 3 mmHg) and tachycardia (ΔFC: C: 86 ± 6 vs. LA: 129 ± 13 b/min) to n‐propyl in the PVN. At baseline the spectral analysis of rats of LA group showed: lower sympathetic modulation for systolic blood pressure (LF: C: 4.6 ± 0.6 vs. LA: 2.1 ± 0.4 mmHg2) smaller variance in pulse interval (C: 42.4 ± 3.2 vs. LA: 24.6 ± 5.1 ms2), lower sympathovagal index (LF/HF: C: 0.8 ± 0.1 vs. LA: 0.3 ± 12:07) and increase of spontaneous baroreflex gain: (Gain full baroreflex: C: 1.3 ± 0.1 vs. LA: 2.2 ± 0.2 ms/mm Hg; Gain Up: C: 1.4 ± 0.1 vs. LA: 2.5 ± 0.3 ms/mm Hg; Gain Down: C: 1.2 ± 0.1 vs. LA: 1.8 ± 0.2 ms/mmHg). In addition, LA animals showed higher concentrations of nitrite in the PVN (C: 3.3 ± 0.7 vs. LA: 5.5 ± 0.7 uM/mg/PVN), kidneys (C: 7 ± 1 vs. LA: 18 ± 3 uM) and thoracic aorta (C: 4 ± 0.6; LA: 12 ± 3 .mu.M). Therefore, supplementation with L‐arginine modified the baseline autonomic control, increase in nitregirc tonus by NO in the PVN via nNOS, and an increase in NO bioavailability, leading to similar effects obtain after exercise training.Support or Funding InformationCNPq (fellowship program)
Postnatal Developmental Changes of Orexin in Spontaneously Hypertensive Rats
Authors: Dunn Savannah , Moushey Alexander , Dong Ruhong , Li Aihua 
Published: November 2023

Orexins are involved in the regulation of cardiorespiratory functions and neurogenic hypertension. Using spontaneously hypertensive rats (SHRs), we have reported that 1) SHRs have more orexin neurons in the hypothalamus at young (postnatal days (P) 30–58) and adult ages than age‐matched, normotensive Wistar‐Kyoto (WKY) rats, 2) blocking orexin receptors (OXRs) with a dual OXR antagonist, almorexant, can normalize high blood pressure (BP) in young SHRs and significantly lower high BP in adult SHRs, and 3) hypercapnia (stress) activates more orexin neurons in the hypothalamus of SHRs than in normotensive WKY rats.Our study objective is to establish a developmental pattern of the orexinergic system in SHRs and WKYs and to better understand the role of the orexin system in hypertension. Specifically, we aim to define at which postnatal age the total number of orexin neurons starts to diverge between SHRs and normotensive rats, and to determine whether the increased number of orexin neurons in SHRs is due to an increase in the number of newly proliferated orexin neurons in the hypothalamus postnatally.To evaluate the total number and dispersion of orexin neurons in SHRs and WKY rats at P7–P25, we used immunohistochemical (IHC) staining of orexin A peptide. To evaluate new postnatal proliferation of orexin neurons, bromodeoxyuridine (BrdU) was injected (50 mg kg−1, i.p.) in SHR and WKY pups for 5 consecutive days beginning at P5, P10, P15, or P25. Up to 7 days after the final injection, brains were harvested and the hypothalamus isolated. To assess the proliferation and maturity of orexinergic neurons in the hypothalamus, orexin positive neurons were double labelled with antibodies for BrdU, which incorporates as a thymidine into the genome of dividing cells and their progeny, doublecortin (DCX), which labels the cytoplasm of immature neurons (< 2 weeks old), or neuronal nuclear antigen (NeuN), which labels the nucleus of mature neurons (> 2 weeks old).Our early results show that 1) SHRs have significantly more orexin A‐immunoreactive (ir) neurons in the hypothalamus than age‐matched WKYs at P10–20, but not at P7, 2) SHRs have more BrdU/orexin‐ir neurons in the hypothalamus at P7–11 than at P25–29, and 3) SHRs have more DCX/orexin‐ir neurons in the hypothalamus at P14–20 than at P35 and later. Our data suggest that the divergence in number of orexin neurons between SHRs and normotensive rats can be seen as early as P10 and that this difference may be mediated by increased postnatal proliferation in the orexin system. This early divergence may imply a causal or upstream role in the development of neurogenic hypertension. These studies are essential in the determination of the mechanistic development of hypertension and thereby treatment of the origin of disease in the future.Support or Funding InformationNIH HL28066
Ventilation Inhibits Sympathetic Neural Recruitment During Severe Chemoreflex Stress
Authors: Badrov Mark B , Barak Otto F , Mijacika Tanja , Drvis Ivan , Dujic Zeljko , Shoemaker J Kevin 
Published: November 2023

The current study investigated the effects of ventilation on sympathetic neural recruitment during severe chemoreflex stress. We measured, in six trained breath‐hold divers (one female; 35±11 yrs, 181±11 cm, 74±13 kg), muscle sympathetic nerve activity (MSNA; microneurography), heart rate (HR; electrocardiogram), blood pressure (BP; Finometer), and arterial hemoglobin saturation (HbSat; pulse oximetry) at baseline (2 mins) and during alternating periods (30 s) of functional residual capacity (FRC) apnea and asphyxic rebreathing, a protocol designed to elicit severe chemoreflex activation in the absence and presence of ventilation, respectively. Subjects were instructed to stop when they achieved ~85% of their self‐perceived ‘maximal’ tolerance for the protocol. The final FRC apnea and rebreathe periods were used for analysis. Sympathetic action potential (AP) discharge patterns were studied using a novel AP detection and analysis technique. This technique quantifies not only the number and morphology of APs within the integrated burst at rest, but also the emergence of latent (and larger) APs as stress develops. Compared to baseline, HbSat decreased to similar levels during FRC apnea and rebreathe (80±3 and 78±11%, respectively; P>0.05). Compared to baseline (18±7 bursts/min), MSNA burst frequency increased during FRC apnea (Δ35±6 bursts/min; P<0.01), but not rebreathe (Δ1±4 bursts/min; P>0.05), whereas burst amplitude (54±12 AU) increased during both FRC apnea (Δ82±30 AU) and rebreathe (Δ26±16 AU; both P<0.05), although the increase was greater during FRC apnea (P<0.01). Compared to baseline (9±3 APs/burst), the mean AP content per integrated burst increased during both FRC apnea (Δ20±6 APs/burst) and rebreathe (Δ7±5 APs/burst; both P<0.01). Similarly, the number of active AP clusters per integrated burst (5±1 clusters/burst) increased during both FRC apnea (Δ4±1 clusters/burst) and rebreathe (Δ2±1 clusters/burst; both P<0.01). However, in both cases, the magnitude of increase was greater during FRC apnea (both P<0.01). Finally, when APs were binned according to peak‐to‐peak amplitude (i.e., into clusters), the number of total AP clusters detected (12±2 total clusters) increased during FRC apnea (Δ6±1 total clusters; P<0.01), but not rebreathe (Δ0±1 total clusters; P>0.05). As such, ventilation restrains sympathetic neural recruitment during severe chemoreflex stimulation. While the increased within‐burst firing frequency of previously active, lower‐threshold sympathetic axons appears preserved, but diminished, in the presence of ventilation (i.e., rebreathe), the recruitment of previously silent, higher‐threshold sub‐populations of larger‐sized sympathetic axons appears specific to apnea, and inhibited by ventilation.Support or Funding InformationSupported by Natural Sciences and Engineering Research Council of Canada.