Authors acknowledge this study was supported by grants from the American Heart Association, American Epilepsy Society, and SUNY Upstate Department of Pharmacology.

<ol>
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The authors have nothing to disclose.

This experimental setup facilitates detailed simultaneous video-EEG-ECG-oximetry-capnography recordings and analyses in rabbits, particularly in models of cardiac and/or neuronal diseases. The results of this article show that this method is capable of detecting seizures and arrhythmias and differentiating them from electrographic artifacts. Expected results were obtained when giving rabbits a proconvulsant, which induced seizures. The data obtained from the video-EEG recordings were able to be further analyzed to differentiate voluntary movements vs. increasing severity of motor seizures and electroencephalographic abnormalities, including photic driving response, encephalopathy and epileptiform discharges. Various types of epileptiform discharges were further characterized and correlated with motor activity. Analysis of the ECG demonstrated a method that produced a high signal-to-noise ratio and allowed for identification and quantification of each electrical correlate of the cardiac cycle. This method was also able to detect the presence of cardiac abnormalities, including premature ventricular complexes, bradycardia, heart block, tachycardia, tachy-arrhythmias and asystole. The development of a robust method to further investigate neuro-cardiac interactions of multi-system diseases provides an important technological advance that is necessary in order to better understand these diseases. In addition, monitoring of respiratory function over time facilitates a better understanding of respiratory failure after seizures and its contribution to sudden death.
This set-up also provides a robust system for drug studies, such as cardiac safety testing. Research projects that employ these techniques are able to investigate the interaction between the neuronal,&#160;cardiac, and respiratory manifestations in real-time. Although many studies have been conducted on rodent hearts, results in the rabbit heart are better for translational studies, as the ion channel expression, action potential properties, and ECG measures are similar to humans. As this is a clinically used video-EEG-ECG set-up, in the future the same design can be applied to large mammals, such as pigs, dogs or sheep. Additionally, this recording setup can be used for intracranial EEG monitoring in the freely moving rabbit, which enables more extensive recordings at various physiological states, surrounding spontaneous neuro-cardiac events, and preceding sudden death. These methods will be invaluable for elucidating the mechanism of SUDEP and for finding novel therapies directed at treating diseases of the brain and heart.
The protocol presented in this article has many critical steps that must be followed to produce data with a high signal to noise ratio. Importantly before the experiment begins, the rabbit must be secured in the restrainer to limit large body movements that could result in spinal injury. All electrodes are checked for signal quality. If all electrodes are noisy, then the reference electrode can be replaced to improve the signal. If single electrodes are noisy, then that one electrode should be pushed deeper into the skin or removed and re-implanted. During the experiment, movement of the rabbits may cause electrodes to be displaced. As soon as possible, try to replace the electrodes without obstructing the view of the camera so that data can still be gathered from the experiment.&#160;
An advantage of the methodology outlined in this study is it facilitates the investigator to screen a large number of animals, and is cost effective. There are limitations of this protocol. Although, few studies have been performed to specifically investigate the physiologic impact of restraint on rabbits, we found that rabbits tolerated restraint extremely well. Many studies of the auditory system have been performed on awake rabbits in light restraints. Under these conditions, rabbits sit quietly for hours without any signs of stress or discomfort39. After being placed in the restrainer, rabbits rarely try to escape the restrainer. They exhibit a heart rate that is near baseline and often fall asleep, as noted by the presence of sleep spindles on the EEG. Rabbits do not exhibit visual, heart rate, or any other manifestations to suggest they are stressed.
A future direction is to develop a system for telemetric EEG and ECG recording. This would allow for more detailed analysis during various physiological states, the detection of spontaneous seizures, and the cascade of neuro-cardiac changes preceding sudden unexpected death in epilepsy (SUDEP.) Due to technological constraints and a relative lack of literature on EEG in rabbits, the method presented was developed first. In order to adapt this method to freely moving rabbits, it would require continuous video monitoring, intra-cranial EEG implants, and subcutaneous ECG electrodes.&#160;Yet, chronic respiratory capnography would not be feasible. Due to institutional regulations (IACUC), the methodology is for &#8804;5-hours recordings in the restrainer. In rodents, it is common to assess the threshold, dynamics, and types of seizures using provocative measures, such as febrile, auditory, maximal electro-shock,&#160;hyperventilation, sleep deprivation, and drug induced seizures16,40,41,42,43. This protocol would allow for testing of any of the previously mentioned provocative measures.

Electrocardiography (ECG) is routinely used in the clinical setting to assess the dynamics of cardiac electrical conduction and the electrical activation-recovery process. ECG is important for detecting, localizing, and assessing the risk of arrhythmias, ischemia, and infarctions. Typically, electrodes are affixed to the patient&#39;s chest, arms, and legs in order to provide a three-dimensional view of the heart. A positive deflection is produced when the direction of myocardial depolarization is toward the electrode and a negative deflection is produced when the direction of myocardial depolarization is away from the electrode. Electrographic components of the cardiac cycle include atrial depolarization (P wave), atrial-ventricular conduction (P-R interval), ventricular excitation (QRS complex), and ventricular repolarization (T wave). There are great similarities in ECG and action potential measures across many mammals&#160;including humans, rabbits, dogs, guinea pigs, pigs, goats, and horses1,2,3.
Rabbits are an ideal model for cardiac translational research. The rabbit heart is similar to the human heart in terms of ion channel composition, and action potential properties2,4,5. Rabbits have been used for the generation of genetic, acquired, and drug-induced models of heart disease2,4,6,7,8. There are great similarities in the cardiac ECG and action potential response to drugs in humans and rabbits7,10,11.
The heart rate and cardiac electrical activation-recovery process is very different in rodents, as compared to rabbits, humans, and other larger mammals12,13,14.&#160;The rodent heart beats ~10 times as fast as humans. In contrast, to the iso-electric ST segment in human&#160;and rabbit ECGs, there is no ST segment in rodents14,15,16. Also, rodents have a QRS-r&#39; waveform with an inverted T wave14,15,16. Measurements of the QT interval are very different in rodents vs. humans and rabbits14,15,16. Furthermore, normal ECG values are very different in humans vs. rodents12,15,16. These differences in the ECG waveforms can be attributed to differences in the action potential morphology and the ion channels that drive cardiac repolarization9,14. While the transient outward potassium current is the major repolarizing current in the short (non-dome) cardiac action potential morphology in rodents, in humans and rabbits there is a large phase-2 dome on the action potential, and the delayed rectifier potassium currents (IKr&#160;and IKs) are the major repolarizing currents in humans and rabbits4,9,13,17. Importantly, the expression of IKr and IKs is absent/minimal in rodents, and due to the temporal activation kinetics of IKr and IKs it does not have a role in the cardiac action potential morphology9,13. Thus, rabbits provide a more translational model for assessing the mechanisms for drug-induced, acquired, and inherited ECG abnormalities and arrhythmias4,7,13. Next, as numerous studies have shown the presence of both neuronal and cardiac electrical abnormalities in primary cardiac (Long QT Syndrome18,19,20) or neuronal diseases (epilepsy21,22,23,24), it is important to study the underlying mechanisms in an animal model that closely reproduces human physiology. While rodents may be sufficient to model the human brain, rodents are not an ideal model of human cardiac physiology7.
Electroencephalography (EEG) uses electrodes, usually placed on the scalp or intracranially, to record cortical electrical function. These electrodes can detect changes in the firing rate and synchronicity of groups of nearby pyramidal neurons in the cerebral cortex25. This information can be used to assess cerebral function and awake/sleep state. Also, EEGs are useful to localize epileptiform activity, and distinguish epileptic seizures from non-epileptic events (e.g., psychogenic non-epileptiform activity and cardiogenic events). In order to diagnose epilepsy type, provoking factors, and origin of the seizure, epilepsy patients are subjected to various maneuvers&#160;which may bring on a seizure. Various methods include hyperventilation, photic stimulation, and sleep deprivation. This protocol demonstrates the use of photic stimulation to induce EEG aberrations and seizures in rabbits26,27,28,29.
Simultaneous video-EEG-ECG recordings have been extensively used in humans and rodents to assess behavioral, neuronal, and cardiac activity during the pre-ictal, ictal, and post-ictal states30. While several studies have conducted EEG and ECG recordings separately in rabbits4,31,32,33, a system for acquiring and analyzing simultaneous video-EEG-ECG in the conscious restrained rabbit is not well established34. This paper describes the design and implementation of a protocol that can record simultaneous video-EEG-ECG&#160;-capnography-oximetry data in conscious rabbits in order to assess neuro-cardiac electrical and respiratory function. Results gathered from this method can indicate the susceptibility, triggers, dynamics&#160;and concordance between arrhythmias, seizures, respiratory disturbances,&#160;and physical manifestations. An advantage of our experimental system is that we acquire conscious recordings without the need of a sedative. The rabbits remain in the restrainers for &#8805;5 h, with minimal movement. As anesthetics perturb neuronal, cardiac, respiratory, and autonomic function, recordings during the conscious state provide the most physiological data.
This recording system may ultimately provide detailed insights to advance the understanding of the neurologic, cardiac and respiratory mechanisms for sudden unexpected death in epilepsy (SUDEP). In addition to neurologic and cardiac monitoring above, recent evidence has also supported the role of respiratory failure as a potential contribution to sudden death after a seizure35,36. To monitor the respiratory status of the rabbits, oximetry and capnography were implemented to evaluate the status of the respiratory system before, during and after a seizure. The protocol presented here was designed with the purpose of assessing the threshold for pharmacologically and photic-stimuli induced rabbit seizures. This protocol can detect subtle EEG and ECG abnormalities that may not result in physical manifestations. In addition, this method can be used for cardiac safety and anti-arrhythmic efficacy testing of novel drugs and devices.&#160;

<table><tbody><tr><td>0.9% Sodium Chloride Irrigation, USP - Flexible Container</td><td>PFIZER (HOSPIRA)</td><td>7983-09</td><td>Dilutant</td></tr><tr><td>10cc Luer Lock syringe with 20G x 1&quot; Needle</td><td>Sur-Vet</td><td>SS-10L2025</td><td>Used as a flush after drug injection</td></tr><tr><td>4x4 gauze sponges</td><td>Fisher Scientific</td><td>22-415-469</td><td>Rolled in a tube to splint ear with angiocatheter</td></tr><tr><td>Apple Sauce</td><td>Kirkland</td><td>897971</td><td>Vehicle for oral medications</td></tr><tr><td>Computer</td><td>Dell</td><td>Optiplex 5040</td><td>Acquisition computer</td></tr><tr><td>E-4031</td><td>Tocris</td><td>1808</td><td>Agent known to prolong the QT interval</td></tr><tr><td>ECG Electrode</td><td>RhythmLink</td><td>RLSND116-2.5</td><td>13mm 35-degree bent (0.4 mm diameter) subdermal pin electrodes</td></tr><tr><td>EEG Electrode</td><td>RhythmLink</td><td>RLSP513</td><td>5-twist 13mm straight (0.4mm diameter) subdermal pin electrodes</td></tr><tr><td>EEGLAB (2020)</td><td>Swartz Center for Computational Neuroscience</td><td>Open Access</td><td>Can perform spectral analysis of EEG</td></tr><tr><td>Ethernet-to-ethernet adapter</td><td>Linksys</td><td>USB3G16</td><td>Adapter for connecting the camera to the computer</td></tr><tr><td>Euthanasia-III Solution</td><td>Med-Pharmex</td><td>ANADA 200-280</td><td>Contains pentobarbital sodium and phenytoin sodium, controlled substance</td></tr><tr><td>Foam padding</td><td>Generic</td><td>N/A</td><td>Reduces pressure applied to the neck of small rabbits by the restrainer in order to prevent the adverse cardiorespiratory effects of neck compression</td></tr><tr><td>Heparin Lock Flush</td><td>Medline</td><td>EMZ50051240</td><td>To maintain patency of angiocatheter</td></tr><tr><td>IR Light</td><td>Bosch</td><td>EX12LED-3BD-8W</td><td>Facilitates recordings in the dark</td></tr><tr><td>LabChart Pro (2019, Version 8.1.16)</td><td>ADInstruments</td><td>N/A</td><td>ECG Analysis</td></tr><tr><td>JELCO PROTECTIV Safety I.V. Catheters, 25 gauge</td><td>Smiths Medical</td><td>3060</td><td>Used to catherize marginal ear vein</td></tr><tr><td>MATLAB (R2019b, Update 5)</td><td>MathWorks</td><td>N/A</td><td>Required to run EEGLAB</td></tr><tr><td>Microphone</td><td>Sony Stereo</td><td>ECM-D570P</td><td>Recording of audible manifestions of seizures</td></tr><tr><td>Micropore Medical Tape, Paper, White</td><td>3M</td><td>1530-1</td><td>Used to secure wires and create ear splint</td></tr><tr><td>Natus NeuroWorks</td><td>Natus</td><td>LC101-8</td><td>Acquisition and review software</td></tr><tr><td>Pentylenetetrazol (1 - 10 mg/kg always in 1mL volume)</td><td>Sigma-Aldrich</td><td>88580</td><td>Dilutions prepared in saline</td></tr><tr><td>Photic Stimulator</td><td>Grass</td><td>PS22</td><td>Stimulator to control frequency, delay, duration, intensity of the light pulses</td></tr><tr><td>Plastic wire organizer / bundler</td><td>12Vwire.com</td><td>LM-12-100-BLK</td><td>Bundle wires to cut down on noise</td></tr><tr><td>PS 22 Photic Stimulator</td><td>Grass Instruments</td><td>BZA641035</td><td>Strobe light with adjustable flash frequency, delay, and intensity</td></tr><tr><td>PVC pipe</td><td>Generic</td><td>N/A</td><td>Prevents small rabbits from kicking their hind legs and causing spinal injury</td></tr><tr><td>Quantum Amplifier</td><td>Natus</td><td>13926</td><td>Amplifier / digitizer</td></tr><tr><td>Quantum HeadBox Amplifier</td><td>Natus</td><td>22134</td><td>64-pin breakout box</td></tr><tr><td>Rabbit Restrainer</td><td>Plas-Labs</td><td>501-TC</td><td>Various size rabbit restrainers are available. 6&quot; x 18&quot; x 6&quot; in this study.</td></tr><tr><td>Rubber pad (booster)</td><td>Generic</td><td>N/A</td><td>Raises small rabbits up in the restrainer to prevent neck compression</td></tr><tr><td>SpO2 ear clip</td><td>NONIN</td><td>61000</td><td>PureSAT/SpO2</td></tr><tr><td>SpO2 sensor adapter</td><td>NONIN</td><td>13931</td><td>XPOD PureSAT/SpO2</td></tr><tr><td>SRG-X120 1080p PTZ Camera with HDMI, IP &amp;amp; 3G-SDI Output</td><td>Sony</td><td>SRG-X120</td><td>Impela Camera</td></tr><tr><td>Terumo Sur-Vet Tuberculin Syringe 1cc 25G X 5/8&quot; Regular Luer</td><td>Sur-Vet</td><td>13882</td><td>Used to inject intravenous medications</td></tr><tr><td>Veterinary Injection Plug Luer Lock</td><td>Sur-Vet</td><td>SRIP2V</td><td>Injection plug for inserting the needle for intravenous medication</td></tr><tr><td>Webcol Alcohol Prep, Sterile, Large, 2-ply</td><td>Covidien</td><td>5110</td><td>To prepare ear vein before catheterization</td></tr></tbody></table>

multi-system monitoring for identification of seizures, arrhythmias and apnea in conscious restrained rabbits

Patients with ion channelopathies are at a high risk of developing seizures and fatal cardiac arrhythmias. There is a higher prevalence of heart disease and arrhythmias in people with epilepsy (i.e., epileptic heart.) Additionally, cardiac and autonomic disturbances have been reported surrounding seizures. 1:1,000 epilepsy patients/year die of sudden unexpected death in epilepsy (SUDEP). The mechanisms for SUDEP remain incompletely understood. Electroencephalograms (EEG) and electrocardiograms (ECG) are two techniques routinely used in the clinical setting to detect and study the substrates/triggers for seizures and arrhythmias. While many studies and descriptions of this methodology are in rodents, their cardiac electrical activity differs significantly from humans. This article provides a description of a non-invasive method for recording simultaneous video-EEG-ECG-oximetry-capnography in conscious rabbits. As cardiac electrical function is similar in rabbits and humans, rabbits provide an excellent model of translational diagnostic and therapeutic studies. In addition to outlining the methodology for data acquisition, we discuss the analytical approaches for examining neuro-cardiac electrical function and pathology in rabbits. This includes arrhythmia detection, spectral analysis of EEG and a seizure scale developed for restrained rabbits.

Watch this Scientific Journal Video about Multi-system Monitoring for Identification of Seizures, Arrhythmias and Apnea in Conscious Restrained Rabbits at JoVE.com

Multi-system Monitoring for Identification of Seizures, Arrhythmias and Apnea in Conscious Restrained Rabbits

Using simultaneous video-EEG-ECG-oximetry-capnography, we developed a methodology to evaluate the susceptibility of rabbit models to develop provoked arrhythmias and seizures. This novel recording system establishes a platform to test the efficacy and safety of therapeutics and can capture the complex cascade of multi-system events that culminate in sudden death.

Patients with ion channelopathies are at a high risk of developing seizures and fatal cardiac arrhythmias. There is a higher prevalence of heart disease ...

multi-system-monitoring-for-identification-seizures-arrhythmias-apnea

Nanyang Technological University

Research

JoVE Journal

Medicine

5.9K Views.  Upstate Medical University. Hart- en ademhalingsstoornissen dragen bij aan plotselinge dood na een aanval. Daarom werd om dit fenomeen te bestuderen, een multi-systeembenadering toegepast op een konijnenmodel. Deze techniek maakt gelijktijdige monitoring en latere analyse van de neurologische, cardiale en ademhalingsfunctie van meerdere konijnen mogelijk rond aanvallen, hartritmestoornissen en voorafgaande dood.Hoewel een ziekte voornamelijk neuronaal of hart kan zijn, kan het elektrische storingen in zowel de he...

Video: Multi-system Monitoring for Identification of Seizures, Arrhythmias and Apnea in Conscious Restrained Rabbits

Hyperinsulinemic-Euglycemic Clamp in the Conscious Rat

Type 2 diabetes (T2D) is rapidly rising in prevalence. Characterized by either inadequate insulin production or the inability to utilize insulin produced, T2D results in elevated blood glucose levels. The "gold-standard" in assessing insulin sensitivity is a hyperinsulinemic-euglycemic clamp or insulin clamp. In this procedure, insulin is infused at a constant rate resulting in a drop in blood glucose. To maintain blood glucose at a constant level, exogenous glucose (D50) is infused into the venous circulation. The amount of glucose infused to maintain homeostasis is indicative of insulin sensitivity. Here, we show the basic clamp procedure in the chronically catheterized, unrestrained, conscious rat. This model allows blood to be collected with minimal stress to the animal. Following the induction of anesthesia, a midline incision is made and the left common carotid artery and right jugular vein are catheterized. Inserted catheters are flushed with heparinized saline, then exteriorized and secured. Animals are allowed to recover for 4-5 days prior to experiments, with weight gain monitored daily. Only those animals who regain weight to pre-surgery levels are used for experiments. On the day of the experiment, rats are fasted and connected to pumps containing insulin and D50. Baseline glucose is assessed from the arterial line and used a benchmark throughout the experiment (euglycemia). Following this, insulin is infused at a constant rate into the venous circulation. To match the drop in blood glucose, D50 is infused. If the rate of D50 infusion is greater than the rate of uptake, a rise in glucose will occur. Similarly, if the rate is insufficient to match whole body glucose uptake, a drop will occur. Titration of glucose continues until stable glucose readings are achieved. Glucose levels and glucose infusion rates during this stable period are recorded and reported. Results provide an index of whole body insulin sensitivity. The technique can be refined to meet specific experimental requirements. It is further enhanced by the use of radioactive tracers that can determine tissue specific insulin-stimulated glucose uptake as well as whole body glucose turnover.

The hyperinsulinemic-euglycemic clamp is the "gold standard" for the assessment of insulin action. Insulin is infused at a constant rate stimulating glucose uptake. The amount of exogenous glucose infused to counter this drop is indicative of insulin sensitivity. Here the procedure is performed on a conscious, unrestrained rat.

Type 2 diabetes (T2D) is rapidly rising in prevalence. Characterized by either inadequate insulin production or the inability to utilize insulin produced, ...

Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice

Type 2 diabetes is characterized by a defect in insulin action. The hyperinsulinemic-euglycemic clamp, or insulin clamp, is widely considered the "gold standard" method for assessing insulin action in vivo. During an insulin clamp, hyperinsulinemia is achieved by a constant insulin infusion. Euglycemia is maintained via a concomitant glucose infusion at a variable rate. This variable glucose infusion rate (GIR) is determined by measuring blood glucose at brief intervals throughout the experiment and adjusting the GIR accordingly. The GIR is indicative of whole-body insulin action, as mice with enhanced insulin action require a greater GIR. The insulin clamp can incorporate administration of isotopic 2[14C]deoxyglucose to assess tissue-specific glucose uptake and [3-3H]glucose to assess the ability of insulin to suppress the rate of endogenous glucose appearance (endoRa), a marker of hepatic glucose production, and to stimulate the rate of whole-body glucose disappearance (Rd).
The miniaturization of the insulin clamp for use in genetic mouse models of metabolic disease has led to significant advances in diabetes research. Methods for performing insulin clamps vary between laboratories. It is important to note that the manner in which an insulin clamp is performed can significantly affect the results obtained. We have published a comprehensive assessment of different approaches to performing insulin clamps in conscious mice1 as well as an evaluation of the metabolic response of four commonly used inbred mouse strains using various clamp techniques2. Here we present a protocol for performing insulin clamps on conscious, unrestrained mice developed by the Vanderbilt Mouse Metabolic Phenotyping Center (MMPC; URL: www.mc.vanderbilt.edu/mmpc). This includes a description of the method for implanting catheters used during the insulin clamp. The protocol employed by the Vanderbilt MMPC utilizes a unique two-catheter system3. One catheter is inserted into the jugular vein for infusions. A second catheter is inserted into the carotid artery, which allows for blood sampling without the need to restrain or handle the mouse. This technique provides a significant advantage to the most common method for obtaining blood samples during insulin clamps which is to sample from the severed tip of the tail. Unlike this latter method, sampling from an arterial catheter is not stressful to the mouse1. We also describe methods for using isotopic tracer infusions to assess tissue-specific insulin action. We also provide guidelines for the appropriate presentation of results obtained from insulin clamps.

The hyperinsulinemic-euglycemic clamp, or insulin clamp, is the gold standard for assessing insulin action in vivo. A method for performing insulin clamps in mice is described. This includes a method for arterial catheterization that permits experiments to be performed in conscious, unrestrained mice with minimal stress.

Type 2 diabetes is characterized by a defect in insulin action. The hyperinsulinemic-euglycemic clamp, or insulin clamp, is widely considered the "gold ...

Production of Apolipoprotein C-III Knockout Rabbits using Zinc Finger Nucleases

Apolipoprotein (Apo) C-III (ApoCIII) resides on the surface of plasma chylomicron (CM), very low density lipoprotein (VLDL) and high density lipoproteins (HDL). It has been recognized that high levels of plasma ApoCIII constitutea risk factor for cardiovascular diseases (CVD). Elevated plasma ApoCIII level often correlates with insulin resistance, obesity, and hypertriglyceridemia. Invaluable knowledge on the roles of ApoCIIIin lipid metabolisms and CVD has been obtained from transgenic mouse models including ApoCIII knockout (KO) mice; however, it is noted that the metabolism of lipoprotein in mice is different from that of humans in many aspects. It is not known until now whether elevated plasma ApoCIII is directly atherogenic. We worked to develop ApoCIII KO rabbits in the present study based on the hypothesis that rabbits can serve as a reasonablemodelfor studying human lipid metabolism and atherosclerosis. Zinc finger nuclease (ZFN) sets targeting rabbit ApoCIIIgene were subjected to in vitro validation prior to embryo microinjection. The mRNA was injected to the cytoplasm of 35 rabbit pronuclear stage embryos, and evaluated the mutation rates at the blastocyst state. Of sixteen blastocysts that were assayed, a satisfactory 50% mutation rate (8/16) at the targeting site was achieved, supporting the use of Set 1 for in vivo experiments. Next, we microinjected 145 embryos with Set 1 mRNA, and transferred these embryos to 7 recipient rabbits. After 30 days gestation, 21 kits were born, out of which five were confirmed as ApoCIII KO rabbits after PCR sequencing assays. The KO animal rate (#KO kits/total born) was 23.8%. The overall production efficiency is 3.4% (5 kits/145 embryos transferred). The present work demonstrated that ZFN is a highly efficient method to produce KO rabbits. These ApoCIII KO rabbits are novel resources to study the roles of ApoCIII in lipid metabolisms.

Recent development in gene targeting tools makes production of knockout (KO) rabbits possible. In the present work, we generated five Apolipoprotein (Apo) C-III KO rabbits using Zinc Finger Nucleases (ZFN). This work demonstrated that ZFN is a highly efficient method to produce KO rabbits.

Apolipoprotein (Apo) C-III (ApoCIII) resides on the surface of plasma chylomicron (CM), very low density lipoprotein (VLDL) and high density lipoproteins ...

Transcutaneous Assessment of Renal Function in Conscious Rodents

Glomerular filtration rate (GFR) is the gold standard to assess overall kidney function. However, traditional methods to evaluate GFR are cumbersome and time-consuming. In addition, serial blood or urine samples are required, with the associated stress for the experimental animals. A recent technique significantly reduces the investment in time and resources, minimizing the invasiveness and the animal stress, but being equally valid as the traditional approaches. The method measures transcutaneously renal function. Using an optical device and the exogenous renal marker fluorescein isothiocyanate (FITC)-sinistrin, this technique is capable of measuring the elimination kinetics of the marker through the skin. With neither blood nor urine samples nor the associated laboratory assays needed, the results of the transcutaneous measurement are almost instantaneously available. The method has been already validated in different species and successfully applied in several models of renal pathology. Moreover, due to its minimally invasive characteristics, it is suitable for sequential measurements within the same animal. Here is provided a detailed protocol to carry out the transcutaneous assessment of renal function in rodents.

Determination of glomerular filtration rate (GFR) is the gold standard to assess overall kidney function. However, traditional procedures to measure this parameter are cumbersome and require a large investment of time. Here we describe a faster and minimally invasive method to determinate GFR transcutaneously.

Glomerular filtration rate (GFR) is the gold standard to assess overall kidney function. However, traditional methods to evaluate GFR are cumbersome and ...

Continuous EEG/ECG Recordings in Rabbits Using Subdermal Electrode Placement

Surgical Implant Procedure and Wiring Configuration for Continuous Long-Term EEG/ECG Monitoring in Rabbits

A multi-system approach that includes the continuous collection of electroencephalogram (EEG) and electrocardiogram (ECG) recordings facilitates a comprehensive assessment of electrical activity in the brain and heart, particularly leading up to and surrounding episodic events. Building on our previous protocol that facilitates the collection of intermittent EEG/ECG recordings from conscious restrained rabbits, we developed a protocol for the collection of continuous EEG/ECG recordings from unrestrained rabbits. This new method enables high-quality 24/7 recordings in the housing cage, which captures the normal range of physiological states and enables the rabbits to move, eat, drink, and sleep freely. It enables comprehensive assessments of the prevalence, incidence, and susceptibility to EEG/ECG abnormalities, seizures, arrhythmias, and sudden death. This procedure involves the surgical placement of subdermal electrodes and the design and manufacturing of a robust wiring system that is impervious to damage by the rabbits. The surgical procedure includes two incisions and the sub-dermal tunneling of nine electrodes and wires that exit through a custom-made port. The external connector attaches to a wire harness that includes an electrical swivel, which allows for&#160;free range of rabbit motion throughout its cage. Additionally, the wires are enclosed in a metal sheath suspended by a retractor cable from the ceiling of the rabbit&#39;s cage. The wires are then connected to an amplifier/digitizer for the acquisition of high-quality continuous EEG/ECG recordings.

The study outlines a protocol for the design, manufacturing, and placement of a novel continuous EEG/ECG recording system in rabbits. This hard-wired system allows for continuous EEG/ECG recordings from nine distinct electrodes on the head and chest, which facilitates comprehensive assessments of electrical activity in the brain and heart.

A multi-system approach that includes the continuous collection of electroencephalogram (EEG) and electrocardiogram (ECG) recordings facilitates a ...

Implantation of Electroencephalogram and Electrocardiogram Telemetry Devices in Neonatal Rabbit Kits

Pathogenic variants in ion channel genes are associated with a high rate of sudden unexpected death in epilepsy (SUDEP). Mechanisms of SUDEP are poorly understood but may involve autonomic dysfunction and cardiac arrhythmias in addition to seizures. Some ion-channel genes are expressed in both the brain and the heart, potentially increasing the risk of SUDEP in patients with ion-channelopathies associated with epilepsy and cardiac arrhythmias. Transgenic rabbits expressing epilepsy variants provide a whole organism to study the complex physiology of SUDEP. Importantly, rabbits more closely replicate human cardiac physiology than do mouse models. However, rabbit models have additional health and anesthesia considerations when undergoing invasive monitoring procedures. We have developed a novel method to surgically implant a telemetry device for long-term simultaneous electroencephalogram (EEG) and electrocardiogram (ECG) monitoring in neonatal rabbit kits. Here, we demonstrate surgical methods to implant a telemetry device in P14 (weight range 175-250 g) kits with detailed attention to surgical approach, appropriate anesthesia and monitoring, and postoperative care, resulting in a low complication rate. This method allows for continuous monitoring of neural and cardiac electrophysiology during critical points in the development of cardiac arrhythmias, seizures, and potential SUDEP in rabbit models of genetic or acquired epilepsies.

Mechanisms of sudden unexpected death in epilepsy (SUDEP) are poorly understood and challenging to translate from current models. Transgenic rabbits may offer insights into these mechanisms. We describe a method for long-term, continuous electroencephalography and electrocardiography recordings in transgenic rabbit kits to evaluate serious events that may lead to death.

Pathogenic variants in ion channel genes are associated with a high rate of sudden unexpected death in epilepsy (SUDEP). Mechanisms of SUDEP are poorly ...

Multisystem Monitoring in Rabbit Model: A Method to Assess Neuro-Cardiac and Respiratory Parameters to Study the Oral Drug-induced Triggers for  Arrhythmia and Seizures

Source: Bosinski, C., et al. <a href="https://www-jove-com.remotexs.ntu.edu.sg/v/62256">Multi-system Monitoring for Identification of Seizures, Arrhythmias and Apnea in Conscious Restrained Rabbits.</a> J. Vis. Exp. (2021).
In this video, we describe simultaneous recording of video, EEG, ECG and respiratory cues in a rabbit model in response to orally administered drug to understand the sequence of events leading to seizure. The model can be used for testing potential drugs for their neuro-cardiac safety.

Source: Bosinski, C., et al. Multi-system Monitoring for Identification of Seizures, Arrhythmias and Apnea in Conscious Restrained Rabbits. J. Vis. Exp. ...

JoVE Encyclopedia of Experiments

Biology

Large Animal Models

Leporine

Intermittent Photic Stimulation in Rabbit Model: A Technique to Induce Epileptic Seizures and Simultaneously Record Multisystem Parameters

Source: Bosinski, C., et al. <a href="https://www-jove-com.remotexs.ntu.edu.sg/v/62256">Multi-system Monitoring for Identification of Seizures, Arrhythmias and Apnea in Conscious Restrained Rabbits.</a> J. Vis. Exp. (2021).
In this video, we show a procedure for simultaneous recording of video-EEG-ECG-capnography-oximetry data generated by inducing seizures in a rabbit model.

Prepping Conscious Rabbit Model for Simultaneous Video-EEG-ECG-Oximetry-Capnography for Experimental Interventions: A Procedure to Implant EEE-ECG Electrodes and Attach Respiratory Probes in Rabbit Model

Source: Bosinski, C. et al., <a href="https://www-jove-com.remotexs.ntu.edu.sg/v/62256">Multi-system Monitoring for Identification of Seizures, Arrhythmias and Apnea in Conscious Restrained Rabbits.</a> J. Vis. Exp. (2021).
This video demonstrates the procedure to implant EEG-ECG electrodes and attach respiratory probes in a rabbit model for acquiring and analyzing records of its bio signals.

Source: Bosinski, C. et al., Multi-system Monitoring for Identification of Seizures, Arrhythmias and Apnea in Conscious Restrained Rabbits. J. Vis. Exp. ...

Multisystem Monitoring of Epileptic Abnormalities in Rabbit: A Method for Simultaneous Video EEG, ECG, Capnography, and Oximetry Recording During Induced Seizures

Source: Bosinski, C., et al. <a href="https://www-jove-com.remotexs.ntu.edu.sg/v/62256">Multi-system Monitoring for Identification of Seizures, Arrhythmias and Apnea in Conscious Restrained Rabbits.</a> J. Vis. Exp. (2021).
In this video, we demonstrate a multisystem monitoring method to evaluate neurological and cardiorespiratory abnormalities during intravenous injection of a seizure-inducing drug. The simultaneous monitoring of video EEG, ECG, oximetry, and capnography parameters helps to understand the real-time physiological changes associated with epileptic seizures.

Multi-system Monitoring for Identification of Seizures, Arrhythmias and Apnea in Conscious Restrained Rabbits

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