bluuebunny/crossref_metadata_2025_split huggingface dataset:
The distribution and structural plasticity of excitatory synapses along interneuron dendrites in the adult hippocampus
Authors: Chirillo Michael , Weisberg Seth , Parker Patrick , Bourne Jennifer , Harris Kristen 
Published: May 2024

Hippocampal interneurons form a large, heterogeneous group with differing structural, physiological, and chemical phenotypes. Most CA1 interneuron dendrites, however, lack spines. To investigate structural synaptic plasticity along interneuron dendrites, we generated three-dimensional (3D) reconstructions from serial section electron microscopy (EM) of excitatory synapses along aspiny dendrites in CA1 stratum radiatum of young adult rats under control conditions and at 2 h during LTP induced with theta-burst stimulation. In total, 43 aspiny dendritic segments and their synapses were identified and reconstructed in 3D. Aspiny dendrites were categorized as smooth or varicose based on dendritic volume contours along each segment. We further sub-segmented varicose dendrites varicosities and inter-varicose regions using automated and manual methods. We found synapses and total synaptic input per length were distributed uniformly along smooth dendrites. Synapses along varicose dendrites, however, occurred preferentially at varicosities. While synaptic input per length along varicosities was similar to that along smooth dendrites, both synapse number and total synaptic input per length along inter-varicose regions were lower. Dendritic segments were also analyzed for mitochondria and glycogen content. We found that mitochondria and glycogen were also distributed uniformly along smooth dendrites. In varicose dendrites, however, mitochondrial volume and glycogen granule numbers were highest in varicosities, while inter-varicose regions were comparatively devoid of these resources. The spatial distribution of synapses and dendritic resources in both smooth and varicose dendrites was preserved at 2 h during LTP when compared to control conditions. These findings suggest that synapses occur along interneuron dendrites where dendritic resources are most available. When dendritic resources are distributed uniformly throughout the dendrite, as occurs in smooth dendrites, synapse distribution is also uniform. Varicosities, on the other hand, represent resource-rich sites along varicose dendrites where synaptic clustering occurs. This work was supported by the National Science Foundation (NSF 1707356, NSF 2014862) and the National Institutes of Health (R01 5R01MH09598). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Quantitative EEG Microstates Predict Correct Responses During Visuo-Spatial Working Memory Task
Authors: Nayyar Madhavi , Soni Sunaina , Sharma Ratna , Sood Mamta , Prakash Suriya , Kaur Simran , Tayade Prashant 
Published: May 2024

Hypothesis: EEG microstate maps during pre-response period of Visuo-Spatial Working Memory (VSWM) Task can predict correct or incorrect response in healthy population and patients with schizophrenia. Methods: After taking informed consent, 30 patients diagnosed with schizophrenia (as per DSM-5 criteria) and 30 controls (both age and gender matched) were recruited. Thereafter, 128 channel EEG was recorded during eyes closed and eyes open states as well as during VSWM task performance. The VSWM task entails matching pairs of identical multicolored abstract pictures hidden in arrays of different cognitive loads after an initial encoding. Following the acquisition; EEG pre-processing, down sampling, average referencing, and Independent Component Analysis were done. Epoch of 100 milliseconds just before each response was taken and grouped into either correct or incorrect trials following which they were subjected to microstate analysis. Statistical analysis was done to compare temporal microstate parameters (Global explained variance, mean duration, time coverage, and segment count density) of each microstate map found between correct and incorrect trials. Data and Results: Microstate maps of pre-response state during correct and incorrect trials were compared in patients with schizophrenia and controls taken together as well as separately. Global explained variance of Microstate Map A (RA-LP, Right Anterior- Left Posterior orientation) was found to be significantly more during pre-response period when the responses were correct as compared to incorrect trials. GEV of Map A emerged out to be the key predictor of correct response in all three groups: overall Correct versus incorrect trials (patients and controls taken together), among patients with schizophrenia, and among controls. Conclusions: Global Explained Variance of EEG microstates Map A is a good predictor of correct response in VSWM task. Department of Physiology, All India Institute of Medical Sciences, New Delhi. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Metabolic-Dysfunction Associated Liver Disease Progresses Independent of Weight in a Rodent Model
Authors: Skinner Roy , Alawadi Ayad , Warren Derek , Benedito Vagner , Tou Janet 
Published: May 2024

Background: Metabolic dysfunction associated steatotic liver disease (MASLD) is the most prevalent liver disease worldwide with an estimated 25% of U.S. adults having MASLD. MASLD is typically regarded as a diet driven disease, with the Western diet (high fat, high sugar, low fiber) being a major driver. Recently, evidence suggests MASLD can be present regardless of body weight. There is not good evidence on how prevalent this is, but reports suggest it could be as high as nearly 30% of MASLD patients. As such, there is a critical need to better understand MASLD independent of weight to ensure all individuals with the disease are receiving proper diagnosis and treatment. Methods: Young female rats were fed either a Control (AIN-93G) or Western (45% fat, 34% sugar) diet for 8 weeks. Histology, RT-qPCR, and standard biological assays were performed to analyze differences in hepatic function and fatty acid analysis was used to analyze fatty acid deposition in the liver, adipose tissue, and brain. Results: There were no statistically significant differences in the weights of rats consuming a Control or Western diet. However, consuming a Western diet had increased histological evidence of fat deposition and inflammation compared to Control. Rats consuming a Western diet also displayed increased ( p<0.05) hepatic triglyceride content and relative expression of several key genes involved in lipogenesis and oxidative stress. Fatty acid analysis found Western diet rats to have increased (p<0.05) hepatic monounsaturated fatty acid (MUFA) content, while adipose tissue of those same animals had decreased (p<0.05) MUFAs. Conclusions: The Western diet plays a significant role in the development of MASLD independent of differences in weight. This model may serve to better elucidate mechanisms at play in lean MASLD. We are currently conducting additional experiments on the role of alcohol in this phenomenon. WVU Davis College Dean's Opportunity Fund and the UVM Food Systems Research Center. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Characterisation of a Novel Osmosensitive Pathway from the Supraoptic Nucleus to the Median Preoptic Nucleus
Authors: Nedelkoska Teodora , Burke Peter , Hildreth Cara 
Published: May 2024

The Supraoptic Nucleus (SON) is well regarded for the neuroendocrine release of vasopressin and oxytocin through the posterior pituitary gland. Evidence also exists for extra-pituitary efferent projections of SON neurons, mainly collaterals to the lateral hypothalamus and central amygdala. The objective of this study was to examine the existence of a central SON projection to the median preoptic nucleus (MnPO) of the hypothalamus. Microinjections of the retrograde tracer Cholera Toxin B Subunit (CTb) into the MnPO of male Wistar rats (n = 3) retrogradely labelled SON neurons. Fluorescence immunohistochemistry revealed equal involvement of vasopressin (AVP) and oxytocin (OXT) — producing SON neurons (n = 107 AVP+/CTb+, n = 110 OXT+/ CTb+, n = 417 total CTb+ neurons). This major collateral projection was also examined in an animal model of Polycystic Kidney Disease, the Lewis Polycystic Kidney (LPK) rat (n = 3 animals; n = 104 AVP+/CTb+, n = 41 OXT+/CTb+, n = 372 total CTb+ neurons) and its healthy Lewis control (n = 3 animals; n = 115 AVP+/CTb+, n = 100 OXT+/CTb+, n = 430 total CTb+ neurons). Although the function of this projection is currently unclear, preliminary data in a subset of LPKs shows these SON neurons with MnPO collateral projections are activated by osmotic stressors (e.g., hypertonic saline). In summary, we report a major collateral projection from the SON to MnPO that is activated by osmotic stress. Given the well-known role of the MnPO in drinking behaviour, we suggest this SON-MnPO circuit may be involved in the coordination of fluid regulation and drinking behaviour. This project was funded by Macquarie University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Boldine Promotes Recovery of Function After Motor-Incomplete Spinal Cord Injury in Mice
Authors: Toro Carlos A. , Siddiq Mustafa , Hansen Jens , Zhao Wei , Iyengar Ravi , Cardozo Christopher 
Published: May 2024

Membrane channels such as connexins (Cx) and pannexins (Panx) are permeable to calcium ions and other small molecules such as ATP and glutamate. Release of ATP and glutamate through these channels is a key mechanism driving tissue response to traumas such as spinal cord injury (SCI). Boldine, an alkaloid isolated from the Chilean boldo tree, blocks both Cx hemichannels (HC) and Panx. To test if boldine could improve function after SCI, boldine or vehicle was administered to treat mice with a moderate severity contusion-induced SCI. Boldine led to greater spared white matter and increased locomotor function as determined by the Basso Mouse Scale and horizontal ladder rung walk tests. Boldine treatment reduced immunostaining for markers of activated microglia (Iba1) and astrocytic (GFAP) markers while increasing that for axon growth and neuroplasticity (GAP-43). RT-qPCR studies showed that boldine treatment reduced expression of chemokine Ccl2, cytokine IL-6 and microglial gene CD68, while increasing expression of the neurotransmission genes Snap25 and Grin2b, and Gap-43. Bulk RNA sequencing revealed that boldine modulated a large number of genes involved in neurotransmission in spinal cord tissue just caudal from the lesion epicenter at 14 days after SCI. Numbers of genes regulated by boldine was much lower at 28 days after injury. Furthermore, physical activity through treadmill training together with boldine showed an additive effect in recovery of function after SCI. Overall, our results indicate that boldine treatment ameliorates injury and spares tissue to increase locomotor function. DOD SCIRP SC170315; VA RR&D Service Grant B-2020-C; NIH GM54508 and GM137056. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Deletion of ADAM17 on microglia attenuates salt-sensitive hypertension
Authors: Mohan Uma Priya , Scarborough Amy , Restivo Luke , Xia Huijing , Lazartigues Eric 
Published: May 2024

Previous work from our group identified ADAM17-mediated shedding as a major mechanism responsible for ACE2 shedding, thus impairing ACE2 compensatory activity and contributing to the development of salt sensitive hypertension. While microglia have been shown to contribute to salt sensitive hypertension, the mechanisms responsible are unknown. Accordingly, we hypothesize that ADAM17 promotes microglia priming, sympatho-excitation and neuro-inflammation in salt sensitive hypertension, and thus targeting ADAM17 or its maturation, via iRhom2, provides a multi-pronged strategy to normalize BP. Here, we aimed to evaluate whether deletion of ADAM17 on microglia attenuates hypertension. Uninephrectomized male and female mice (14–16-week-old, n=10/group) with selective deletion of ADAM17 in microglia (Cx3CR1-ADAM17tom) or with global deletion of iRhom2 (iRhom2-KO) and littermate controls (Cx3CR1-Cretom) mice were used to monitor blood pressure (BP telemetry, DSI) at baseline and following the initiation of salt sensitive hypertension (DOCA 1mg/g body weight sc + 1% saline po for 3 weeks). Following the establishment of hypertension (7 days post DOCA implantation) mice were injected with tamoxifen (200 nl ICV) and monitored for 2 more weeks. At the end of the treatment, mice were euthanized, and their brains were collected. Baseline mean arterial pressure (MAP) was not different in Cx3CR1-ADAM17tom, iRhom2-KO compared to controls (102±1, 106±1 and 104±1 mmHg, respectively). Surprisingly, all mice developed hypertension following DOCA implantation, including iRhom2 KO (Cx3CR1-ADAM17tom: 131±1, iRhom2 KO: 131±1, control: 126±1 mmHg, respectively. p<0.05). Interestingly, following tamoxifen injection Cx3CR1-ADAM17tom mice showed a blunted hypertension compared to the control group (MAP: 122±0.2 vs. 146±0.5 mmHg, one way ANOVA, p<0.05) suggesting that ADAM17 in microglia contributes to salt sensitive hypertension. In vitro, human microglia cells (iCell microglia — hIPSC) were shown to express lower ACE2 protein (0.03 ± 0.1 vs. 1.18 ± 0.3, Student’s t test, p<0.05) when exposed to Ang-II (100 ng) with a trend for ADAM17 upregulation (1.5 ± 0.3 vs. 1.1 ± 0.1, p<0.05). Together, our data suggest that overactivity of the renin-angiotensin system is associated with overexpression of ADAM17 in microglia and a simultaneous downregulation of ACE2. In addition, knockdown of ADAM17 specifically on microglia blunted the development of hypertension. We conclude that ADAM17 expression in microglia plays a pivotal role in salt sensitive hypertension. This work was supported in part by a research grant from the National Institutes of Health (HL163588). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Chronic Hypoxia during Gestation Disrupts Spontaneous Ca2+ Oscillations in Middle Cerebral Arterial Myocytes of Fetal Sheep
Authors: Boskind Madison , Nelapudi Nikitha , Romero Monica , Albert-Minckler Eris , Chan Michelle , Zhang Lubo , Blood Arlin 
Published: May 2024

Long Term Hypoxic (LTH) stress is associated with an elevated risk of intracranial hemorrhage and stroke in newborns. Existing evidence illustrates that fetal sheep subjected to LTH conditions exhibit compromised cerebrovascular reactivity and arterial development, leading to perturbations in cerebral blood flow. Given the critical role of whole-cell Ca2+ waveforms in the contraction of middle cerebral arterial (MCA) myocytes and the regulation of cerebral blood flow, a comprehensive understanding of Ca2+ signaling patterns can provide insight into hypoxia-related cerebrovascular disease in neonates. This study was designed to test the hypothesis that intrauterine LTH disrupts whole-cell Ca2+ oscillations in fetal MCA myocytes. The hypothesis was addressed using MCAs isolated from term fetal sheep (approximately 140 days of gestation) delivered by cesarean section. These fetuses were carried by ewes residing at low-altitude (700 m) or high-altitude conditions (3801 m) for over 100 days of gestation. Ca2+ oscillatory activity was recorded using confocal fluorescence imaging techniques in an en face myocyte preparation. Spontaneous Ca2+ oscillations were evaluated in the presence and absence of 30 mM K+ to depolarize the myocytes, with or without 10 μM ryanodine, which blocks ryanodine receptor mediated Ca2+ release. The results of the study reveal that LTH decreases oscillatory activity and restricts the augmentation of activity following membrane depolarization. Furthermore, LTH induces dysregulation in spatial and temporal Ca2+ signals, manifesting as reduced event amplitude, shortened event duration, and decreased area under the curve (AUC). These findings highlight the impact of gestational hypoxia on multiple aspects of Ca2+ signaling in fetal lamb MCA, which may contribute to cerebrovascular dysfunction in the newborn. R01HL155295, R01HL149608, Advanced Imaging and Microscopy Core Loma Linda University School of Medicine. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Inhibiting renal Traf2 and NCK interacting kinase (TNIK) decreases NKKC2 phosphorylation and blunts salt-sensitive hypertension
Authors: Granados Jessica , Caceres Paulo , Ortiz Pablo 
Published: May 2024

The Na/K/2Cl cotransporter NKCC2 mediates the NaCl reabsorption in the thick ascending limb (TAL). Phosphorylation at Thr-96,101 and traffcking to the surface are increased in the Dahl salt-sensitive (DSS) rat together with SPAK phosphorylation, an upstream kinase for Thr-96,101 in NKCC2. We previously found that deletion of SPAK in the DSS, lowers NKCC2 phosphorylation and blunts salt-sensitive hypertension, but doesn’t completely abolish NKCC2 phosphorylation. Therefore, other kinases may be involved in NKCC2 phosphorylation. We recently found the Traf2 and NCK interacting kinase (TNIK) phosphorylates NKCC2 and is overexpressed in the TALs of DSS rats. We hypothesized that TNIK contributes to salt-sensitive hypertension by increasing NKCC2 hyperphosphorylation in DSS rats. We approached TNIK inhibition in two ways, using a pharmacological inhibitor and its genomic deletion with CRISPR/Cas9. First, we studied the small molecule TNIK inhibitor NCB-0846, and whether it could decrease baseline NKCC2 phosphorylation in TALs from DSS rats. Treating TALs from DSS with NCB-0846 (0.1 μM) for 25 min decreased NKCC2 Thr-96,101 phosphorylation by 21 ± 2% compared to the vehicle group (p<0.001, n=3). To study in vivo effcacy of NCB-0846, we directly infused NCB (or vehicle) into the left kidney via implanted renal medullary catheters connected to minipumps in DSS rats fed 4% NaCl diet. We found that NCB-0846 decreased SBP by 30 mmHg within four days compared to the vehicle-infused group, and BP remained lower for 7 days (n=5, p<0.03 vs control). To decrease TNIK gene expression we used Cas9 mediated gene editing. For this, we designed gRNA sequences targeting TNIK and tested their effcacy in C6 cells. One of the gRNAs designed decreased TNIK expression by 48 ± 22% compared to control (p=0.101, n=3). To decrease TNIK in TALs in vivo, we injected the renal medulla of the left kidney with AAV-gRNA-TNIK together with AAV-NKCC2 promoter-Cas9. After 2 weeks, we isolated medullary TALs and measured TNIK expression and NKCC2 phosphorylation. TNIK expression was decreased by 50 ± 5.5% (n=4, p<0.0001), and pThr-96,101-NKCC2 was decreased by 38.1 ± 10.6% in transduced TALs compared to kidneys transduced with AV-control (n=4, p<0.05). The expression of related kinases SPAK and OSR1 was not modified (SPAK 79.2 ± 18.3%, OSR1 81.3 ± 13.3%, n=4, ns). We conclude that NKCC2 phosphorylation in the DSS rat is in part caused by TNIK and that this new kinase could be a target for salt sensitive hypertension. Future experiments will test the effect of gene editing TNIK in salt sensitive hypertension. 23POST1019882 AHA15GRNT25710369. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Role of L-PGDS in Light Alcohol Consumption-Induced Cerebral Angiogenesis in Male Mice
Authors: Sun Hong , Li Jiyu , Li Chun , Subedi Pushpa , Subedi Utsab 
Published: May 2024

Ischemic stroke is one of the leading causes of death and permanent disability. Promoting cerebral angiogenesis before or after ischemic stroke reduces ischemic brain damage and improves functional recovery. Alcohol is one of the most commonly consumed chemical substances. Light alcohol consumption (LAC) reduces the incidence and improves the prognosis of ischemic stroke. Recently, we found that LAC promotes cerebral angiogenesis under basal conditions and following ischemic stroke. In addition, LAC upregulates lipocalin-type prostaglandin D2 synthase (L-PGDS), the principal PGH2 isomerase mainly expressed in the central nervous and cardiovascular systems. Therefore, we determined the role of L-PGDS in LAC-induced cerebral angiogenesis. In in vitro studies, low-concentration ethanol significantly upregulated L-PGDS and increased angiogenic capability (tube formation, migration, and proliferation) in cultured C57BL/6J mouse brain microvascular endothelial cells (MBMVECs). AT-56, a selective L-PGDS inhibitor, abolished the increased angiogenic capability. In in vivo studies, 8-week gavage feeding with low-dose ethanol significantly upregulated L-PGDS and increased vessel density and vessel branches in the cerebral cortex and subcortical area under physiological conditions and following ischemic stroke in C57BL/6J male mice. AT-56 and endothelial cell-specific L-PGDS conditional knockout did not affect vessel density and vessel branches of the cerebral cortex and subcortical area in water-fed control mice but alleviated the proangiogenic effect in low-dose ethanol-fed mice under basal conditions and following ischemic stroke. Therefore, our findings suggest that L-PGDS may be crucial in LAC-induced cerebral angiogenesis. NIH 2R01AA023610. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.