scholarly journals Neural circuit mechanisms of sensorimotor disability in cancer treatment

2021 ◽  
Vol 118 (51) ◽  
pp. e2100428118
Author(s):  
Stephen N. Housley ◽  
Paul Nardelli ◽  
Travis M. Rotterman ◽  
Timothy C. Cope
Keyword(s):  
Cancer Treatment ◽  
Rat Model ◽  
Neural Circuit ◽  
Sensory Information ◽  
Mechanical Responses ◽  
Synaptic Potentials ◽  
Central Elements ◽  
Peripheral Sensory

Cancer survivors rank sensorimotor disability among the most distressing, long-term consequences of chemotherapy. Disorders in gait, balance, and skilled movements are commonly assigned to chemotoxic damage of peripheral sensory neurons without consideration of the deterministic role played by the neural circuits that translate sensory information into movement. This oversight precludes sufficient, mechanistic understanding and contributes to the absence of effective treatment for reversing chemotherapy-induced disability. We rectified this omission through the use of a combination of electrophysiology, behavior, and modeling to study the operation of a spinal sensorimotor circuit in vivo in a rat model of chronic, oxaliplatin (chemotherapy)–induced neuropathy (cOIN). Key sequential events were studied in the encoding of propriosensory information and its circuit translation into the synaptic potentials produced in motoneurons. In cOIN rats, multiple classes of propriosensory neurons expressed defective firing that reduced accurate sensory representation of muscle mechanical responses to stretch. Accuracy degraded further in the translation of propriosensory signals into synaptic potentials as a result of defective mechanisms residing inside the spinal cord. These sequential, peripheral, and central defects compounded to drive the sensorimotor circuit into a functional collapse that was consequential in predicting the significant errors in propriosensory-guided movement behaviors demonstrated here in our rat model and reported for people with cOIN. We conclude that sensorimotor disability induced by cancer treatment emerges from the joint expression of independent defects occurring in both peripheral and central elements of sensorimotor circuits.

scholarly journals Synaptic plasticity in the mesolimbic dopamine system

2003 ◽  
Vol 358 (1432) ◽  
pp. 815-819 ◽  
Author(s):  
Mark J. Thomas ◽  
Robert C. Malenka
Keyword(s):  
Synaptic Plasticity ◽  
Drugs Of Abuse ◽  
Neural Circuit ◽  
Long Term Potentiation ◽  
Brain Regions ◽  
Mesolimbic Dopamine ◽  
Dopamine System ◽  
Mesolimbic Dopamine System

Long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical mechanisms that contribute to the neural circuit modifications that mediate all forms of experience-dependent plasticity. It has, however, been difficult to demonstrate directly that experience causes long-lasting changes in synaptic strength and that these mediate changes in behaviour. To address these potential functional roles of LTP and LTD, we have taken advantage of the powerful in vivo effects of drugs of abuse that exert their behavioural effects in large part by acting in the nucleus accumbens (NAc) and ventral tegmental area (VTA); the two major components of the mesolimbic dopamine system. Our studies suggest that in vivo drugs of abuse such as cocaine cause long-lasting changes at excitatory synapses in the NAc and VTA owing to activation of the mechanisms that underlie LTP and LTD in these structures. Thus, administration of drugs of abuse provides a distinctive model for further investigating the mechanisms and functions of synaptic plasticity in brain regions that play important roles in the control of motivated behaviour, and one with considerable practical implications.

Long-Term Tensile Properties of Tension-Free Vaginal Tape, Suprapubic Arc Sling System and Urethral Sling in an In Vivo Rat Model

2007 ◽  
Vol 177 (3) ◽  
pp. 1195-1198 ◽  
Author(s):  
Kevin C. Zorn ◽  
Philippe E. Spiess ◽  
Gurdip Singh ◽  
Marcelo A. Orvieto ◽  
Bob Moore ◽  
...  
Keyword(s):  
Tensile Properties ◽  
Rat Model ◽  
Tension Free ◽  
Tension Free Vaginal Tape

Novel anti-inflammatory actions of amlodipine in a rat model of arteriosclerosis induced by long-term inhibition of nitric oxide synthesis

2004 ◽  
Vol 286 (2) ◽  
pp. H768-H774 ◽  
Author(s):  
Chu Kataoka ◽  
Kensuke Egashira ◽  
Minako Ishibashi ◽  
Shujiro Inoue ◽  
Weihua Ni ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Rat Model ◽  
Vascular Inflammation ◽  
Monocyte Chemoattractant Protein 1 ◽  
Beneficial Effects ◽  
Pressure Lowering ◽  
Anti Inflammatory ◽  
Synthase Inhibitor

Amlodipine (a new class of calcium channel antagonist) has been shown to limit the progression of arteriosclerosis and decrease the incidence of cardiovascular events. The mechanisms underlying the beneficial effects of amlodipine, however, remain unclear. Therefore, we hypothesized that amlodipine attenuates the development of arteriosclerosis through the inhibition of inflammation in vivo. Long-term inhibition of nitric oxide (NO) by administration of a NO synthase inhibitor, Nω-nitro-l-arginine methyl ester (l-NAME), to rats induces coronary vascular inflammation [monocyte infiltration, monocyte chemoattractant protein-1 (MCP-1) expression, increased activity of angiotensin-converting enzyme (ACE)], and arteriosclerosis. Here, we used the rat model to investigate the anti-inflammatory effects of amlodipine in vivo. Treatment with amlodipine markedly inhibited the l-NAME-induced increase in vascular inflammation, oxidative stress, and local ACE and Rho activity and prevented arteriosclerosis. Interestingly, amlodipine prevented the l-NAME-induced increase in MCP-1 receptor CCR2 expression in circulating monocytes. Amlodipine markedly attenuated the high mortality rate at 8 wk of treatment. These data suggest that amlodipine attenuated arteriosclerosis through inhibiting inflammatory disorders in the rat model of long-term inhibition of NO synthesis. The anti-inflammatory effects of amlodipine seem to be mediated not only by the inhibition of local factors such as MCP-1 but also by the decrease in CCR2 in circulating monocytes. Inhibition of the MCP-1 to CCR2 pathway may represent novel anti-inflammatory actions of amlodipine beyond blood pressure lowering.

scholarly journals Optimization of Degradation Profile for New Scaffold in Cartilage Repair

Cartilage ◽  
2017 ◽  
Vol 9 (4) ◽  
pp. 438-449 ◽  
Author(s):  
Sarav S. Shah ◽  
Haixiang Liang ◽  
Sandeep Pandit ◽  
Zalak Parikh ◽  
John A. Schwartz ◽  
...  
Keyword(s):  
Cartilage Repair ◽  
Subchondral Bone ◽  
Rat Model ◽  
Articular Chondrocytes ◽  
Short Term ◽  
Morphological Studies ◽  
Biomaterial Scaffold

Objective To establish whether a novel biomaterial scaffold with tunable degradation profile will aid in cartilage repair of chondral defects versus microfracture alone in vitro and in a rat model in vivo. Design In vitro—Short- and long-term degradation scaffolds were seeded with culture expanded articular chondrocytes or bone marrow mesenchymal stem cells. Cell growth and differentiation were evaluated with cell morphological studies and gene expression studies. In vivo—A microfracture rat model was used in this study to evaluate the repair of cartilage and subchondral bone with the contralateral knee serving as the empty control. The treatment groups include (1) empty osteochondral defect, (2) polycaprolactone copolymer–based polyester polyurethane–urea (PSPU-U) caffold short-term degradative profile, and (3) PSPU-U scaffold long-term degradative profile. After placement of the scaffold, the rats were then allowed unrestricted activity as tolerated, and histological analyses were performed at 4, 8, and 16 weeks. The cartilage defect was measured and compared with the contralateral control side. Results In vitro—Long-term scaffolds showed statistically significant higher levels of aggrecan and type II collagen expression compared with short-term scaffolds. In vivo—Within 16 weeks postimplantation, there was new subchondral bone formation in both scaffolds. Short-term scaffolds had a statistically significant increase in defect filling and better qualitative histologic fill compared to control. Conclusions The PSPU short-term degradation scaffold may aid in cartilage repair by ultimately incorporating the scaffold into the microfracture procedure.

scholarly journals Long-term precision editing of neural circuits using engineered gap junction hemichannels

2021 ◽  
Author(s):  
Elizabeth Ransey ◽  
Kirill Chesnov ◽  
Elias Wisdom ◽  
Ryan Bowman ◽  
Tatiana Rodriguez ◽  
...  
Keyword(s):  
Neural Circuit ◽  
White Perch ◽  
Cell Types ◽  
Brain Cell ◽  
Vitro Assay ◽  
Multiple Species ◽  
Connexin Hemichannel

The coordination of activity between brain cells is a key determinant of neural circuit function; nevertheless, approaches that selectively regulate communication between two distinct cellular components of a circuit, while leaving the activity of the presynaptic brain cell undisturbed remain sparce. To address this gap, we developed a novel class of electrical synapses by selectively engineering two connexin proteins found in Morone americana (white perch fish): connexin34.7 (Cx34.7) and connexin35 (Cx35). By iteratively exploiting protein mutagenesis, a novel in vitro assay of connexin docking, and computational modeling of connexin hemichannel interactions, we uncovered the pattern of structural motifs that broadly determine connexin hemichannel docking. We then utilized this knowledge to design Cx34.7 and Cx35 hemichannels that dock with each other, but not with themselves nor other major connexins expressed in the human central nervous system. We validated these hemichannels in vivo, demonstrating that they facilitate communication between two neurons in Caenorhabditis elegans and recode a learned behavioral preference. This system can be applied to edit circuits composed by pairs of genetically defined brain cell types across multiple species. Thus, we establish a potentially translational approach, Long-term integration of Circuits using connexins (LinCx), for context-precise circuit-editing with unprecedented spatiotemporal specificity.

Abstract P770: An Mri-Based Method for Assessing the Extent and Location of Bleeding in a Rat Model of Subarachnoid Hemorrhage

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Mitchell Butler ◽  
Joseph R Geraghty ◽  
Deepshika Sudhakar ◽  
Tyler Lung ◽  
Fernando Testai ◽  
...  
Keyword(s):  
Spatial Distribution ◽  
Subarachnoid Hemorrhage ◽  
Rat Model ◽  
Alternative Methods ◽  
Slice Thickness ◽  
Brain Extraction ◽  
Spin Echo Sequence ◽  
Long Term Studies

Objective: Studies in subarachnoid hemorrhage (SAH) animal models are limited to early timepoints, after which the brain is extracted to confirm hemorrhage. For long-term studies, blood is resorbed by the time of euthanasia and thus alternative methods of confirming SAH are necessary. Here, we used in vivo MRI to determine the presence, extent, and location of blood in the endovascular perforation rat model of SAH. Methods: Animals were divided into two groups - SAH and sham controls (no perforation). Rats were imaged at 24 hours in a 9.4T MRI scanner. T2-weighted imaging (T2WI) was used to quantify and localize the volume and extension of blood. T2WI was performed with a fast spin echo sequence with TR/TE = 5000/60 ms, FOV = 40x40 mm 2 , 0.75 mm slice thickness, and no interslice gap. SAH was identified as hypointense signal at the skull base, a normally hyperintense region due to cerebrospinal fluid in the basal cisterns. Regions of interest were identified and segmented manually. Pixels were converted to areas, and the total hypointense volume (V hypo ) was computed by summing all areas. V hypo was normalized to total brain volume (TBV) for each animal. Ability to detect blood via MRI was compared to the gold standard of direct visualization of blood after brain extraction using receiver operating characteristic (ROC) curves. The location of blood was plotted along a standardized antero-posterior axis. 3D reconstructions were developed in 3D Slicer to visualize the spatial distribution of hemorrhage. Results: V hypo values were 1.6±1.4 mm 3 sham (n = 8) and 7.5±3.9 mm 3 for SAH (n = 10) [p=0.0003]. This difference persisted when V hypo was normalized to TBV (p=0.0005). There was no difference in the TBV between groups (p=0.1493). V hypo distinguished between SAH and sham animals (p=0.001, area under curve = 0.963). A cutoff of V hypo = 4.63 mm 3 corresponded to 100% specificity and 80% sensitivity for confirming SAH. The spatial distribution of bleeding varied along the antero-posterior axis within the subarachnoid space. Conclusions: We developed an in vivo MRI method for the quantification of SAH blood volume and location in rats. This will be used for future long-term studies to confirm and grade severity of SAH.

Light-dark dependence of electrocardiographic changes during asphyxia and reoxygenation in a rat model

Open Medicine ◽  
2010 ◽  
Vol 5 (5) ◽  
pp. 611-619
Author(s):  
Ivana Bačová ◽  
Pavol Švorc ◽  
Martin Kundrík ◽  
Benjamin Fulton
Keyword(s):  
Rat Model ◽  
Qt Interval ◽  
Pulmonary Ventilation ◽  
Time Intervals ◽  
Surgical Interventions ◽  
Qt Intervals ◽  
Female Wistar Rats ◽  
Electrocardiographic Changes

AbstractThe aim of this study was to evaluate the effect of ventilation on electrocardiographic time intervals as a function of the light-dark (LD) cycle in an in vivo rat model. RR, PQ, QT and QTc intervals were measured in female Wistar rats anaesthetized with both ketamine and xylazine (100 mg/15 mg/kg, i.m., open chest experiments) after adaptation to the LD cycle (12:12h) for 4 weeks. Electrocardiograms (ECG) were recorded before surgical interventions; after tracheotomy, and thoracotomy, and 5 minutes of stabilization with artificial ventilation; 30, 60, 90 and 120 seconds after the onset of apnoea; and after 5, 10, 15, and 20 minutes of artificial reoxygenation. Time intervals in intact animals showed significant LD differences, except in the QT interval. The initial significant (p<0,001) LD differences in PQ interval and loss of dependence on LD cycle in the QT interval were preserved during short-term apnoea-induced asphyxia (30–60 sec) In contrast, long-term asphyxia (90–120 sec) eliminated LD dependence in the PQ interval, but significant LD differences were shown in the QT interval. Apnoea completely abolished LD differences in the RR interval. Reoxygenation restored the PQ and QT intervals to the pre-asphyxic LD differences, but with the RR intervals, the LD differences were eliminated. We have concluded that myocardial vulnerability is dependent on the LD cycle and on changes of pulmonary ventilation.

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