We thank Mr. Zhengyang Wang for reshaping the scripts, shooting and editing the video, and Mr. Ziyuan Ye for editing the video. This study got support from CIT Endowment &#38; National Science Foundation (to JCD),&#160;Boswell fellowship (to QL) and High-level University Fund (No. G02386301, G02386401), Guangdong Natural Science Foundation Joint Fund (No. 2019A1515111038).&#160;

The development and application of the protocol were approved by the California Institute of Technology Institutional Review Board (IRB) and the Southern University of Science and Technology IRB. The subject provided informed consent prior to any procedures being performed.
1. System preparation and setup
<ol>
	<li>The recommended basic hardware is a&#160;2 GHz dual-core processor and 4 GB of system memory.</li>
	<li>Build the gaming platform under the Unity platform, while using C# programing language. The Logitech gaming wheel driver and Logitech Steering Wheel SDK are needed for gaming platform development.</li>
	<li>The gaming platform executable files only support Windows 10 Operating System (OS). Therefore, on a PC running Windows 10, download and install the corresponding racing wheel driver. Then download the compressed WheelCon software (https://github.com/Doyle-Lab/WheelCon/archive/master.zip) and extract the files to the local hard drive.</li>
	<li>Mount the racing wheel securely at the sitting level in front of a monitor, and then connect the wheel&#39;s USB cable to the PC and the power adapter to an outlet.</li>
	<li>Start the driver GUI to test for correct input readout and force feedback. Importantly, keep the driver GUI running in the background during the test.</li>
	<li>To start the program, double-click on WheelCon.exe in the &#39;\WheelCon-master\Executable &#38; Output Files\&#39; directory.</li>
	<li>On the configuration screen, choose settings for monitor and click Play! (Figure 2a). The main menu will appear. Make sure the display size and location are as specified. 
	NOTE: The &#39;Wheel Sensitivity&#39; value, defining cursor speed, ranges from 0 to 1, and defaults to 0.5. In case the range of motion afforded by the racing wheel does not suit specific task parameters, adjust this value. For example, decrease the sensitivity for the aging population. However, for comparing between tasks, it is necessary to keep this value constant for the battery and across groups.</li>
</ol>
2. Task implementation
<ol>
	<li>Fitts&#39; law reaching game 
	NOTE: The Fitts&#8217; law reaching game simulates the reaching process. The subject requires to turn the wheel to place the vertical line into the desired region (Figure 2d).
	<ol>
		<li>Seat the subject comfortably behind the wheels. Adjust the wheel height if necessary.</li>
		<li>On the main menu, click Fitts&#39; Law Task (Figure 2b) and type in a name for the output file indicating subject identification and task information on the textbox.</li>
		<li>Click on Select File, choose&#160;Fitt&#39;s Law.txt in the &#39;\WheelCon-master\ Demo Input Files\&#39; directory, and then click Begin Game.</li>
		<li>Instruct the subject to move the green vertical line with the wheel to place it within the gray zone. This task serves to familiarize the subject with maneuvering the wheel, as well as with the color convention used throughout different tasks.</li>
	</ol>
	</li>
	<li>Mountain bike tasks 
	NOTE: The mountain bike task is a combination of pursuit and compensatory tracking task. It simulates riding a mountain bike down a steep, twisted and bumpy trail. The subject can see the trail and turn the wheel to track it, while a motor can torque the wheel to mimic invisible bumps in the trial (Figure 2e).
	<ol>
		<li>Game 1: Testing the effect of the visual delay 
		NOTE: In this game, the length of the look-ahead window (advanced warning vs. delay) is manipulated.
		<ol>
			<li>On the main menu, click Mountain Bike Task (Figure 2c) and type in a name for the output file indicating subject identification and task information on the textbox.</li>
			<li>Click on Select File, choose Vision_Delay.txt in the &#39;\WheelCon-master\ Demo Input Files\&#39; directory, and then click on Begin Game.</li>
			<li>Instruct the subject to move the green vertical line with the wheel in order to track the part of the gray trail that intersects the purple horizontal line.</li>
		</ol>
		</li>
		<li>Game 2: Testing the effect of action delay 
		NOTE: In this game, a delay of various lengths is added between wheel movement and action output.
		<ol>
			<li>On the main menu, click on Mountain Bike Task and type in a name for the output file indicating subject identification and task information on the textbox.</li>
			<li>Click on Select File, choose Action_Delay.txt in the &#39;\WheelCon-master\ Demo Input Files\&#39; directory, and then click Begin Game.</li>
			<li>Instruct the subject to move the green vertical line with the wheel in order to track the part of the gray trail that intersects the purple horizontal line.</li>
		</ol>
		</li>
		<li>Game 3: Testing the effect of visual quantization 
		NOTE: In this game, visual input is quantized to limit the data rate.
		<ol>
			<li>On the main menu, click on Mountain Bike Task and type in a name for the output file indicating subject identification and task information on the textbox.</li>
			<li>Click on Select File, choose Vision Quantization.txt in the &#39;\WheelCon-master\ Demo Input Files\&#39; directory, and then click Begin Game.</li>
			<li>Instruct the subject to move the green vertical line with the wheel in order to track the part of the gray trail that intersects the purple horizontal line.</li>
		</ol>
		</li>
		<li>Game 4: Testing the effect of action quantization 
		NOTE: In this game, action output is quantized to limit the data rate.
		<ol>
			<li>On the main menu, click on Mountain Bike Task and type in a name for the output file indicating subject identification and task information on the textbox.</li>
			<li>Click on Select File, choose Action Quantization.txt in the &#39;\WheelCon-master\ Demo Input Files\&#39; directory, and then click Begin Game.</li>
			<li>Instruct the subject to move the green vertical line with the wheel in order to track the part of the gray trail that intersects the purple horizontal line.</li>
		</ol>
		</li>
		<li>Game 5: Testing the effect of bump and trail disturbance 
		NOTE: This task consists of three scenarios: 
		a) &#34;Bumps&#34;, tracking a constant trail subject despite torque disturbances on the wheel that mimic hitting bumps when riding a mountain bike; 
		b) &#34;Trail&#34;, tracking a moving trail with random turns but without bumps; 
		c) &#34;Trail with Bumps&#34;, tracking a moving trail with random turns and bumps.
		<ol>
			<li>On the main menu, click on Mountain Bike Task and type in a name for the output file indicating subject identification and task information on the textbox.</li>
			<li>Click on Select File, choose Bump &#38; Trail.txt in the &#39;\WheelCon-master\ Demo Input Files\&#39; directory, and then click Begin Game.</li>
			<li>Instruct the subject to move the green vertical line with the wheel in order to track the part of the gray trail that intersects the purple horizontal line.</li>
		</ol>
		</li>
	</ol>
	</li>
</ol>
3. Data output
<ol>
	<li>Locate the TXT output file in the &#39;\WheelCon-master\Executable &#38; Output Files\MountainBikeData\&#39; directory, and then open with Matlab&#39; WheelCon Data Analysis Code.m&#39; in the &#39;\WheelCon-master\Source Code&#39; directory.</li>
	<li>Specify in the MATLAB script the folder and file_names variables according to the output file directory, and then run the script (Ctrl + Enter), and the output variables will be saved as column vectors to the Workspace. The error and control policy will be exported for each sampling time. See Table 2 for the detailed description.</li>
</ol>
4. Input file development
<ol>
	<li>Open &#39;WheelCon Mntn Bike Trail Design Code.m&#39; in the &#39;\WheelCon-master\Source Code\&#39; directory.</li>
	<li>Uncomment (Ctrl + T) the section for the desired game parameters and run the script (Ctrl + Enter). The input file will be saved in the &#39;\WheelCon-master\Source Code\&#39; directory&#39; in .txt format. Each column in the input files is one control variable. Refer to Table 1 for the list of control variables.</li>
</ol>

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The authors disclose that they have no conflicts of interest.

In this paper, we have presented a free, open-source gaming platform, WheelCon, for studying the effects of delay, quantization, disturbance, and layered feedback loops in human sensorimotor control. We have shown the hardware, the software, and the GUI. The settings of a single sensorimotor control loop with delay and quantization have been implemented, which allows us to measure the effects of delay, quantization, and disturbance in sensorimotor control. The experimental results are well in line with the prediction fro...

The human sensorimotor control system is extremely robust1, although the sensing is distributed, variable, sparse, quantized, noisy and delayed2,3,4; the computing in the central nervous system is slow5,6,7; and the muscle actuation fatigues and saturates8. Many computational theoretical models have been proposed to explain the complicated human sensorimotor control process4,9,10,11,12,13,14, which is a tradeoff process in human reach and response15,16. For example, feedback control theory predicts the optimal control policy12, Bayesian theory models sensorimotor learning17,18,19 and information theory sensorimotor foundation20,21. In contrast to the abundance of theoretical models, experimental platforms capable of manipulating important components of multiple feedback loops lack development. This is in part due to the fact that designing a platform to bridge and test these aspects of sensorimotor control requires a diverse range of expertise, extending from motor control theory, signal processing, and interaction, all the way to computer graphics and programming. Researchers often develop their own custom hardware/software systems to characterize human sensorimotor control performance, which can limit the ability to compare/contrast and integrate datasets across research groups. The development of an easy-to-use and validated system could broaden the quantitative characterization of sensorimotor control.
In this paper, we present the WheelCon platform, a novel, free and open-source platform to design video games for a virtual environment that noninvasively simulates a Fitts&#8217; Law reaching game and a mountain bike task with downing a steep, twisting and bumpy trail. The Fitts&#8217; law for reaching task quantifies the tradeoff between speed and accuracy in which the time required for reaching a target of width at distance scales as22,23. The &#39;mountain-bike task&#39; is a combination of a pursuit and compensatory tracking task, which are two classic components of research on human sensorimotor performance, especially in terms of studying feedback loops.
WheelCon contains the highly demanded basic components presented in each theory: delay, quantization, noise, disturbance, and multiple feedback loops. It is a potential tool for studying the following diverse questions in human sensorimotor control:
&#8226; How the human sensorimotor system deals with the delay and quantization in neural signaling, which is fundamentally constrained by the limited resources (such as the space and metabolic costs) in the brain24,25; &#8226; How neural correlation in the human cortex with sensorimotor control26; &#8226; How humans handle the unpredictable, external disturbances in sensorimotor control27; &#8226; How the hierarchical control loops layered and integrated within human sensorimotor system16,28,29; &#8226; The consequence of the delay and quantization in human visual feedback30 and reflex feedback31 in sensorimotor control; &#8226; The optimal policy and strategy for sensorimotor learning under delay and quantization16,17,24,29.
WheelCon integrates with a steering wheel and can simulate game conditions that manipulate the variables in these questions, such as signaling delay, quantization, noise, and disturbance, while recording the dynamic control policy and system errors. It also allows researchers to study the layered architecture in sensorimotor control. In the example of riding a mountain bike, two control layers are involved in this task: the high-layer plan and the low-layer reflex. For visible disturbances (i.e., the trail), we plan before the disturbance arrives. For disturbances unknown in advance (i.e., small bumps), the control relies on delayed reflexes. Feedback control theory proposes that effective layered architectures can integrate the higher layers&#39; goals, plans, decisions with the lower layers&#39; sensing, reflex, and action24. WheelCon provides experimental tools to induce distinctive disturbances in the plan and reflex layers separately for testing such a layered architecture (Figure 1).
We provide a cheap, easy to use and flexible to program platform, WheelCon that bridges the gap between theoretical and experimental studies on neuroscience. To be specific, it can be used for examining the effects of delay, quantization, disturbance, potentially speed-accuracy tradeoffs. The variables that can be manipulated in control loops are shown in Table 1. It can also be applied for studying decision making and multiplexing ability across different control layers in human sensorimotor control. Moreover, WheelCon is compatible with noninvasive neural recordings, such as electroencephalography (EEG), to measure the neural response during sensorimotor control32,33,34,35, and the non-invasive brain stimulation techniques, such as Transcranial Electrical Stimulation (tES) and Transcranial Magnetic Stimulation (TMS), to manipulate the neural activity36,37.

<table>
	<tbody>
		<tr>
			<td>Gaming Wheel</td>
			<td>Logitech</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Windows 10 OS</td>
			<td>Microsoft</td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

wheelcon: a wheel control-based gaming platform for studying human sensorimotor control

Feedback control theory has been extensively implemented to theoretically model human sensorimotor control. However, experimental platforms capable of manipulating important components of multiple feedback loops lack development. This paper describes WheelCon, an open-source platform aimed at resolving such insufficiencies. Using only a computer, a standard display, and inexpensive gaming steering wheel equipped with a force feedback motor, WheelCon safely simulates the canonical sensorimotor task of riding a mountain bike down a steep, twisting, bumpy trail. The platform provides flexibility, as will be demonstrated in the demos provided, so that researchers may manipulate the disturbances, delay, and quantization (data rate) in the layered feedback loops, including a high-level advanced plan layer and a low-level delayed reflex layer. In this paper, we illustrate WheelCon&#39;s graphical user interface (GUI), the input and output of existing demos, and how to design new games. In addition, we present the basic feedback model and the experimental results from the demo games, which align well with the model&#39;s prediction. The WheelCon platform can be downloaded at https://github.com/Doyle-Lab/WheelCon. In short, the platform is featured to be cheap, simple to use, and flexible to program for effective sensorimotor neuroscience research and control engineering education.

Modelling Feedback Control
We show a simplified feedback control model shown in Figure 1. The system dynamics is given by:
<img alt="Equation 1" src="/files/ftp_upload/61092/61092equ01.jpg" />
where x(t) is the error at time t, r(t) is the trail disturbance w(t), is the bump disturbance, and u(...

Watch this Scientific Journal Video about WheelCon: A Wheel Control-Based Gaming Platform for Studying Human Sensorimotor Control at JoVE.com

WheelCon: A Wheel Control-Based Gaming Platform for Studying Human Sensorimotor Control

WheelCon is a novel, free and open-source platform to design video games that noninvasively simulates mountain biking down a steep, twisting, bumpy trail. It contains components presenting in human sensorimotor control (delay, quantization, noise, disturbance, and multiple feedback loops) and allows researchers to study the layered architecture in sensorimotor control.

Feedback control theory has been extensively implemented to theoretically model human sensorimotor control. However, experimental platforms capable of ...

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Research

JoVE Journal

Neuroscience

4.9K Views.  Southern University of Science and Technology. Menselijke sensorische motor controle systeem is zeer robuust, hoewel de detectie is verdeeld, schaars, gekwantificeerd, lawaaierig, en vertraagd. Het computergebruik in het centrale zenuwstelsel is traag, de spieractuatie vermoeien en verzadigt. Om deze oorzakelijke factoren en de gevolgen daarvan voor de systeemprestaties van sensorische motorbesturing te bestuderen, is het belangrijk om een gebruiksvriendelijk experimenteel platform te ontwikkelen dat deze factoren manipuleert en de presta...

Video: WheelCon: A Wheel Control-Based Gaming Platform for Studying Human Sensorimotor Control

A Procedure for Studying the Footshock-Induced Reinstatement of Cocaine Seeking in Laboratory Rats

The most insidious aspect of drug addiction is the high propensity for relapse. Animal models of relapse, known as reinstatement procedures, have been used extensively to study the neurobiology and phenomenology of relapse to drug use. Although procedural variations have emerged over the past several decades, the most conventional reinstatement procedures are based on the drug self-administration (SA) model. In this model, an animal is trained to perform an operant response to obtain drug. Subsequently, the behavior is extinguished by withholding response-contingent reinforcement. Reinstatement of drug seeking is then triggered by a discrete event, such as an injection of the training drug, re-exposure to drug-associated cues, or exposure to a stressor 1.
Reinstatement procedures were originally developed to study the ability of acute non-contingent exposure to the training drug to reinstate drug seeking in rats and monkeys 1, 2. Reinstatement procedures have since been modified to study the role of environmental stimuli, including drug-associated cues and exposure to various forms of stress, in relapse to drug seeking 1, 3, 4.
Over the past 15 years, a major focus of the reinstatement literature has been on the role of stress in drug relapse. One of the most commonly used forms of stress for studying this relationship is acute exposures to mild, intermittent, electric footshocks. The ability of footshock stress to induce reinstatement of drug seeking was originally demonstrated by Shaham and colleagues (1995) in rats with a history of intravenous heroin SA5. Subsequently, the effect was generalized to rats with histories of intravenous cocaine, methamphetamine, and nicotine SA, as well as oral ethanol SA 3, 6.
Although footshock-induced reinstatement of drug seeking can be achieved reliably and robustly, it is an effect that tends to be sensitive to certain parametrical variables. These include the arrangement of extinction and reinstatement test sessions, the intensity and duration of footshock stress, and the presence of drug-associated cues during extinction and testing for reinstatement. Here we present a protocol for footshock-induced reinstatement of cocaine seeking that we have used with consistent success to study the relationship between stress and cocaine seeking.

Animal models of relapse, known as reinstatement procedures, have been used extensively to study the role of stress in relapse to drug seeking. Here, we report on a method for inducing the reinstatement of cocaine seeking in laboratory rats via acute exposures to mild, intermittent electric footshock.

The most insidious aspect of drug addiction is the high propensity for relapse.  Animal models of relapse, known as reinstatement procedures, have been ...

Measuring Circadian and Acute Light Responses in Mice using Wheel Running Activity

Circadian rhythms are physiological functions that cycle over a period of approximately 24 hours (circadian- circa: approximate and diem: day)1, 2. They are responsible for timing our sleep/wake cycles and hormone secretion. Since this timing is not precisely 24-hours, it is synchronized to the solar day by light input. This is accomplished via photic input from the retina to the suprachiasmatic nucleus (SCN) which serves as the master pacemaker synchronizing peripheral clocks in other regions of the brain and peripheral tissues to the environmental light dark cycle3-7. The alignment of rhythms to this environmental light dark cycle organizes particular physiological events to the correct temporal niche, which is crucial for survival8. For example, mice sleep during the day and are active at night. This ability to consolidate activity to either the light or dark portion of the day is referred to as circadian photoentrainment and requires light input to the circadian clock9. Activity of mice at night is robust particularly in the presence of a running wheel. Measuring this behavior is a minimally invasive method that can be used to evaluate the functionality of the circadian system as well as light input to this system. Methods that will covered here are used to examine the circadian clock, light input to this system, as well as the direct influence of light on wheel running behavior.

This article will review methods that can be used to determine circadian function and light responsiveness in mice.

Circadian rhythms are physiological functions that cycle over a period of approximately 24 hours (circadian- circa: approximate and diem: day)1, 2.  They ...

Three Dimensional Vestibular Ocular Reflex Testing Using a Six Degrees of Freedom Motion Platform

The vestibular organ is a sensor that measures angular and linear accelerations with six degrees of freedom (6DF). Complete or partial defects in the vestibular organ results in mild to severe equilibrium problems, such as vertigo, dizziness, oscillopsia, gait unsteadiness nausea and/or vomiting. A good and frequently used measure to quantify gaze stabilization is the gain, which is defined as the magnitude of compensatory eye movements with respect to imposed head movements. To test vestibular function more fully one has to realize that 3D VOR ideally generates compensatory ocular rotations not only with a magnitude (gain) equal and opposite to the head rotation but also about an axis that is co-linear with the head rotation axis (alignment). Abnormal vestibular function thus results in changes in gain and changes in alignment of the 3D VOR response.
Here we describe a method to measure 3D VOR using whole body rotation on a 6DF motion platform. Although the method also allows testing translation VOR responses 1, we limit ourselves to a discussion of the method to measure 3D angular VOR. In addition, we restrict ourselves here to description of data collected in healthy subjects in response to angular sinusoidal and impulse stimulation.
Subjects are sitting upright and receive whole-body small amplitude sinusoidal and constant acceleration impulses. Sinusoidal stimuli (f = 1 Hz, A = 4&deg;) were delivered about the vertical axis and about axes in the horizontal plane varying between roll and pitch at increments of 22.5&deg; in azimuth. Impulses were delivered in yaw, roll and pitch and in the vertical canal planes. Eye movements were measured using the scleral search coil technique 2. Search coil signals were sampled at a frequency of 1 kHz.
The input-output ratio (gain) and misalignment (co-linearity) of the 3D VOR were calculated from the eye coil signals 3.
Gain and co-linearity of 3D VOR depended on the orientation of the stimulus axis. Systematic deviations were found in particular during horizontal axis stimulation. In the light the eye rotation axis was properly aligned with the stimulus axis at orientations 0&deg; and 90&deg; azimuth, but gradually deviated more and more towards 45&deg; azimuth.
The systematic deviations in misalignment for intermediate axes can be explained by a low gain for torsion (X-axis or roll-axis rotation) and a high gain for vertical eye movements (Y-axis or pitch-axis rotation (see Figure 2). Because intermediate axis stimulation leads a compensatory response based on vector summation of the individual eye rotation components, the net response axis will deviate because the gain for X- and Y-axis are different.
In darkness the gain of all eye rotation components had lower values. The result was that the misalignment in darkness and for impulses had different peaks and troughs than in the light: its minimum value was reached for pitch axis stimulation and its maximum for roll axis stimulation.
Case Presentation
Nine subjects participated in the experiment. All subjects gave their informed consent. The experimental procedure was approved by the Medical Ethics Committee of Erasmus University Medical Center and adhered to the Declaration of Helsinki for research involving human subjects.
Six subjects served as controls. Three subjects had a unilateral vestibular impairment due to a vestibular schwannoma. The age of control subjects (six males and three females) ranged from 22 to 55 years. None of the controls had visual or vestibular complaints due to neurological, cardio vascular and ophthalmic disorders.
The age of the patients with schwannoma varied between 44 and 64 years (two males and one female). All schwannoma subjects were under medical surveillance and/or had received treatment by a multidisciplinary team consisting of an othorhinolaryngologist and a neurosurgeon of the Erasmus University Medical Center. Tested patients all had a right side vestibular schwannoma and underwent a wait and watch policy (Table 1; subjects N1-N3) after being diagnosed with vestibular schwannoma. Their tumors had been stabile for over 8-10 years on magnetic resonance imaging.

A method is described to measure three-dimensional vestibulo ocular reflexes (3D VOR) in humans using a six degrees of freedom (6DF) motion simulator. The gain and misalignment of the 3D angular VOR provide a direct measure of the quality of vestibular function. Representative data on healthy subjects are provided

The vestibular organ is a sensor that measures angular and linear accelerations with six degrees of freedom (6DF). Complete or partial defects in the ...

Recording and Analysis of Circadian Rhythms in Running-wheel Activity in Rodents

When rodents have free access to a running wheel in their home cage, voluntary use of this wheel will depend on the time of day1-5. Nocturnal rodents, including rats, hamsters, and mice, are active during the night and relatively inactive during the day. Many other behavioral and physiological measures also exhibit daily rhythms, but in rodents, running-wheel activity serves as a particularly reliable and convenient measure of the output of the master circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus. In general, through a process called entrainment, the daily pattern of running-wheel activity will naturally align with the environmental light-dark cycle (LD cycle; e.g. 12 hr-light:12 hr-dark). However circadian rhythms are endogenously generated patterns in behavior that exhibit a ~24 hr period, and persist in constant darkness. Thus, in the absence of an LD cycle, the recording and analysis of running-wheel activity can be used to determine the subjective time-of-day. Because these rhythms are directed by the circadian clock the subjective time-of-day is referred to as the circadian time (CT). In contrast, when an LD cycle is present, the time-of-day that is determined by the environmental LD cycle is called the zeitgeber time (ZT).
Although circadian rhythms in running-wheel activity are typically linked to the SCN clock6-8, circadian oscillators in many other regions of the brain and body9-14 could also be involved in the regulation of daily activity rhythms. For instance, daily rhythms in food-anticipatory activity do not require the SCN15,16 and instead, are correlated with changes in the activity of extra-SCN oscillators17-20. Thus, running-wheel activity recordings can provide important behavioral information not only about the output of the master SCN clock, but also on the activity of extra-SCN oscillators. Below we describe the equipment and methods used to record, analyze and display circadian locomotor activity rhythms in laboratory rodents.

Circadian rhythms in voluntary wheel-running activity in mammals are tightly coupled to the molecular oscillations of a master clock in the brain. As such, these daily rhythms in behavior can be used to study the influence of genetic, pharmacological, and environmental factors on the functioning of this circadian clock.

When rodents have free access to a running wheel in their home cage, voluntary use of this wheel will depend on the time of day1-5. Nocturnal rodents, ...

Methods for Studying the Mechanisms of Action of Antipsychotic Drugs in Caenorhabditis elegans

Caenorhabditis elegans is a simple genetic organism amenable to large-scale forward and reverse genetic screens and chemical genetic screens. The C. elegans genome includes potential antipsychotic drug (APD) targets conserved in humans, including genes encoding proteins required for neurotransmitter synthesis and for synaptic structure and function. APD exposure produces developmental delay and/or lethality in nematodes in a concentration-dependent manner. These phenotypes are caused, in part, by APD-induced inhibition of pharyngeal pumping1,2. Thus, the developmental phenotype has a neuromuscular basis, making it useful for pharmacogenetic studies of neuroleptics. Here we demonstrate detailed procedures for testing APD effects on nematode development and pharyngeal pumping. For the developmental assay, synchronized embryos are placed on nematode growth medium (NGM) plates containing APDs, and the stages of developing animals are then scored daily. For the pharyngeal pumping rate assay, staged young adult animals are tested on NGM plates containing APDs. The number of pharyngeal pumps per unit time is recorded, and the pumping rate is calculated. These assays can be used for studying many other types of small molecules or even large molecules.

Methods for Studying the Mechanisms of Action of Antipsychotic Drugs in Caenorhabditis elegans

Approaches for testing the effects of antipsychotic drugs (APDs) in Caenorhabditis elegans are demonstrated. Assays are described for testing drug effects on development and viability and on pharyngeal pumping rate. These methods are also applicable for pharmacogenetic experiments with drug classes other than APDs.

Caenorhabditis elegans is a simple genetic organism amenable to  large-scale forward and reverse genetic screens and chemical genetic screens. The C.  ...

A Simplified Method for Ultra-Low Density, Long-Term Primary Hippocampal Neuron Culture

Culturing primary hippocampal neurons in vitro facilitates mechanistic interrogation of many aspects of neuronal development. Dissociated embryonic hippocampal neurons can often grow successfully on glass coverslips at high density under serum-free conditions, but low density cultures typically require a supply of trophic factors by co-culturing them with a glia feeder layer, preparation of which can be time-consuming and laborious. In addition, the presence of glia may confound interpretation of results and preclude studies on neuron-specific mechanisms. Here, a simplified method is presented for ultra-low density (~2,000 neurons/cm2), long-term (&#62;3 months) primary hippocampal neuron culture that is under serum free conditions and without glia cell support. Low density neurons are grown on poly-D-lysine coated coverslips, and flipped on high density neurons grown in a 24-well plate. Instead of using paraffin dots to create a space between the two neuronal layers, the experimenters can simply etch the plastic bottom of the well, on which the high density neurons reside, to create a microspace conducive to low density neuron growth. The co-culture can be easily maintained for &#62;3 months without significant loss of low density neurons, thus facilitating the morphological and physiological study of these neurons. To illustrate this successful culture condition, data are provided to show profuse synapse formation in low density cells after prolonged culture. This co-culture system also facilitates the survival of sparse individual neurons grown in islands of poly-D-lysine substrates and thus the formation of autaptic connections.

Low density cultures of primary hippocampal neurons usually require glia feeder layer to supply neurotrophic factors and sustain longevity. We describe here a simplified method to culture ultra-low density neurons on glass coverslips in the presence of a high density neuronal feeder layer, which facilitates investigation of specific neuronal-autonomous mechanisms.

Culturing primary hippocampal neurons in vitro facilitates mechanistic interrogation of many aspects of neuronal development. Dissociated embryonic ...

Fabrication of High Contact-Density, Flat-Interface Nerve Electrodes for Recording and Stimulation Applications

Many attempts have been made to manufacture multi-contact nerve cuff electrodes that are safe, robust and reliable for long term neuroprosthetic applications. This protocol describes a fabrication technique of a modified cylindrical nerve cuff electrode to meet these criteria. Minimum computer-aided design and manufacturing (CAD and CAM) skills are necessary to consistently produce cuffs with high precision (contact placement 0.51 &#177; 0.04 mm) and various cuff sizes. The precision in spatially distributing the contacts and the ability to retain a predefined geometry accomplished with this design are two criteria essential to optimize the cuff&#39;s interface for selective recording and stimulation. The presented design also maximizes the flexibility in the longitudinal direction while maintaining sufficient rigidity in the transverse direction to reshape the nerve by using materials with different elasticities. The expansion of the cuff&#39;s cross sectional area as a result of increasing the pressure inside the cuff was observed to be 25% at 67 mm Hg. This test demonstrates the flexibility of the cuff and its response to nerve swelling post-implant. The stability of the contacts&#39; interface and recording quality were also examined with contacts&#39; impedance and signal-to-noise ratio metrics from a chronically implanted cuff (7.5 months), and observed to be 2.55 &#177; 0.25 k&#8486; and 5.10 &#177; 0.81 dB respectively.

This article provides a detailed description on the fabrication process of a high contact-density flat interface nerve electrode (FINE). This electrode is optimized for recording and stimulating neural activity selectively within peripheral nerves.

Many attempts have been made to manufacture multi-contact nerve cuff electrodes that are safe, robust and reliable for long term neuroprosthetic ...

The Mouse Hindbrain As a Model for Studying Embryonic Neurogenesis

The mouse embryo forebrain is the most commonly employed system for studying mammalian neurogenesis during development. However, the highly folded forebrain neuroepithelium is not amenable to wholemount analysis to examine organ-wide neurogenesis patterns. Moreover, defining the mechanisms of forebrain neurogenesis is not necessarily predictive of neurogenesis in other parts of the brain; for example, due to the presence of forebrain-specific progenitor subtypes. The mouse hindbrain provides an alternative model for studying embryonic neurogenesis that is amenable to wholemount analysis, as well as tissue sections to observe the spatiotemporal distribution and behavior of neural progenitors. Moreover, it is easily dissected for other downstream applications, such as cell isolation or molecular biology analysis. As the mouse hindbrain can be readily analyzed in the vast number of cell lineage reporter and mutant mouse strains that have become available, it offers a powerful model for studying the cellular and molecular mechanisms of developmental neurogenesis in a mammalian organism. Here, we present a simple and quick method to use the mouse embryo hindbrain for analyzing mammalian neural progenitor cell (NPC) behavior in wholemount preparations and tissue sections.

This article demonstrates how the mouse embryonic hindbrain can be used as a model for studying developmental neurogenesis in both whole organ and tissue section preparations.

The mouse embryo forebrain is the most commonly employed system for studying mammalian neurogenesis during development. However, the highly folded ...

An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons

Aberrant aggregation of the protein tau is pathogenically involved in a number of neurodegenerative diseases, including Alzheimer&#8217;s disease (AD). Although mouse models of tauopathy have provided a valuable resource for investigating the neurotoxic mechanisms of aggregated tau, it is becoming increasingly apparent that, due to interspecies differences in neurophysiology, the mouse brain is unsuitable for modeling the human condition. Advances in cell culture methods have made human neuronal cultures accessible for experimental use in vitro and have aided in the development of neurotherapeutics. However, despite the adaptation of human neuronal cell cultures, in vitro models of human tauopathy are not yet widely available. This protocol describes a cellular model of tau aggregation in which human neurons are transduced with lentiviral-derived vectors that code for pathogenically mutated tau fused to a yellow fluorescent protein (YFP) reporter. Transduced cultures produce tau aggregates that stain positively for thioflavin and display markers of neurotoxicity, such as decreased axonal length and increased lysosomal volume. This procedure may be a useful and cost-effective model for studying human tauopathies.

This protocol details a procedure in which human neuronal cultures are transduced with lentiviral constructs coding for mutant human tau. Transduced cultures display tau aggregates and associated pathologies.

Aberrant aggregation of the protein tau is pathogenically involved in a number of neurodegenerative diseases, including Alzheimer&#8217;s disease (AD). ...

&#181;Tongue: A Microfluidics-Based Functional Imaging Platform for the Tongue In Vivo

Intravital fluorescence microscopy is a tool used widely to study multicellular dynamics in a live animal. However, it has not been successfully used in the taste sensory organ. By integrating microfluidics into the intravital tongue imaging window, the &#181;Tongue provides reliable functional images of taste cells in vivo under controlled exposure to multiple tastants. In this paper, a detailed step-by-step procedure to utilize the &#181;Tongue system is presented. There are five subsections: preparing of tastant solutions, setting up of a microfluidic module, sample mounting, acquiring functional image data, and data analysis. Some tips and techniques to solve the practical issues that may arise when using the &#181;Tongue are also presented.

 &#181;Tongue: A Microfluidics-Based Functional Imaging Platform for the Tongue In Vivo

The article introduces the &#181;Tongue (microfluidics-on-a-tongue) device for functional taste cell imaging in vivo by integrating microfluidics into an intravital imaging window on the tongue.

Intravital fluorescence microscopy is a tool used widely to study multicellular dynamics in a live animal. However, it has not been successfully used in ...

WheelCon: A Wheel Control-Based Gaming Platform for Studying Human Sensorimotor Control

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