MSC Directors will meet with first-time users to direct them to appropriate services. Besides providing a general description of MSC services, they may offer referrals to the MSC Unit/Subunit Leaders for consultation on specific procedures, IDDRC scientific liaisons, and other WU facilities that offer services not provided by the MSC.  The MSC itself offers a wide range of core services pertaining to model systems of IDD.

UNITSERVICECOST / UNIT
AAU-ABSConsultation: Study Planning, Resources and ServicesNo Cost
AAU-ABSBehavioral Phenotyping90 / Hour
AAU-ABSStatistical and Graphical Analyses90 / Hour
AAU-ABSBehavioral Phenotyping Training90 / Hour
AAU-ABSEquipment and Space Reservation45 / Hour
AAU-ABSHome-cage Device Rental (Kravitz, Creed)Custom
AAU-ABSTelemetric Biobehavioral Sensor SystemCustom
AAU-NPSConsultation (Study Design, Protocols, Analysis)Free Initial 2-Hour Consultation
AAU-NPSNeurohistopathological assessment45 / Hour
NphysSConsultation (Study Design, Protocols, Analysis)No Cost
NphysSVideo-EEG studies25 / Hour
NphysSSleep studies25 / Hour
NphysSCellular physiologyCustom
CMUHuman pluripotent stem cell (hPSC) line derivation from patient biomaterialsCustom
CMUhPSC model quality controls (pluripotency, karyotyping, STR profiling, Myco test)Custom
CMUScale up, store, and deposit models in public repositoryCustom
CMUhPSC differentiation (e.g. developmental patterning or reprogramming-derived cortical excitatory, inhibitory neurons, glia)Custom
CMUCellular, physiological, and developmental phenotyping of human cellular models of IDDsCustom
CMUMolecular (e.g. Transcriptomic and epigenomic) analysis of neuronal and glial IDD models Custom
CMUMorphological analysis of IDD-model derived neuronsCustom
CMUFunctional analysis of IDD hPSC-derived neuronal network function (high density multi-electrode array, calcium imaging)Custom
CMUCollaboration with patient advisory groups, PreMIER/ICTS/IDDRC (Clinical Translational Core and Brain Gene Registry)Custom
Detailed service descriptions are provided in the drop down menu below.
For more information about the services of the Model Systems Core, please contact:

General Core Information
Karen O’Malley: omalleyk@wustl.edu; 314-362-7087
Susan Maloney: maloneys@wustl.edu; 314-362-7723

Cellular Models Core
Kristen Kroll: kkroll@wustl.edu; 314-362-7045

Animal Assessments Subunits
Animal Behavior (AAU-ABS): Susan Maloney: maloneys@wustl.edu; 314-362-7723
Neuropathology (AAU-NPS): Kevin Noguchi: noguchik@wustl.edu; 314-362-7007
Neurophysiology (NphysS): Michael Wong: wong_m@wustl.edu; 314-362-8713

Cellular Models Unit

The CMU represents a unique institutional platform, embedded in the IDDRC@WUSTL, with a mission of performing in-depth mechanistic studies of IDD in human cellular models. Development of IDD models leverages patient registries of the IDDRC’s Clinical-Translational Core and its interactions with the Brain Gene Registry and Autism Center of Excellence Network in gene discovery. Major goals are to link genetic alterations with disease mechanisms and phenotypes and to identify intermediate phenotypes and targets that can be used to develop potential interventions.

Deriving human pluripotent stem cell models of IDDs

Sets of human IDD cellular models are derived for each project by reprogramming patient-derived biomaterials to generate human pluripotent stem cell (hPSC) lines, and by genome engineering of both control and IDD subject-derived hPSCs. The IDDRC Clinical Translational Core (CTC) and their Biomaterials Acquisition Program work with investigators to recruit subjects and obtain deidentified biomaterials, which are provided to the CMU for this purpose. Reprogramming and genome engineering is either performed by the CMU or through collaboration with the Genome Engineering and Stem Cell Center @WUSTL. The CMU also derives molecular tools to manipulate the activity of IDD genes, which are used in combination with these hPSC models.

hPSC models are differentiated or reprogrammed to generate a range of IDD-relevant neuronal, glial, and organoid types and used to perform cellular and molecular phenotyping, including assessment of:

  • cellular physiology, including altered proliferative and apoptotic indices, ER or oxidative stress, and/or cellular metabolism.
  • neural progenitor specification, maintenance, and progenitor cell type identity.
  • neuronal differentiation, organoid patterning, neuronal cell type identity, and maturation.
  • neuronal morphology, neurite extension, synaptogenesis, and migration.
  • neuronal function, assessed using electrophysiology, calcium imaging and/or high density multi-electrode array (HD-MEA), in pure neuronal populations, organoids, or co-cultures, is performed in collaboration with Dr. Huettner in the NPhyS.
  • Genome-wide transcriptomic and/or epigenomic analyses are used to define molecular mechanisms, pathways, and processes altered in IDD models, including acute effects and direct targets. RNA or chromatin sample preparation is performed by the CMU, with sample sequencing performed through the MGI Genome Technology Access Center @WUSTL.
  • Targeted or high-throughput screening and other applications.

The workflow above defines cell autonomous phenotypes that serve as proxies for aspects of IDD clinical presentation (e.g. neuronal network functional disruptions).  These phenotypes are useful for gene and pathway targeted molecular and pharmacological screening to identify leads for developing interventions for IDD. The CMU performs some of this screening in collaboration with the High-Throughput Screening Core @WUSTL. These models can also be used for many other applications, such as high throughput annotation of variant pathogenicity by complementation assay, to compare phenotypes resulting from many variants of uncertain pathogenicity in an IDD gene.

Cross-IDDRC Calibration of Methods

The directors of the CMUs at WUSTL and University of Wisconsin, Drs. Kroll and Anita Bhattacharyya, co-lead the Cross-IDDRC Human Cellular Models Consortium. This group engages CMUs at all US IDDRCs in collaborative projects, some of which focus on cross-IDDRC calibration, benchmarking, and standardization of methods for IDD cellular phenotyping, to ensure reproducibility and enable data meta-analysis across the network. The Cellular Models Group is also building both a biorepository and a data repository for IDD cellular models under study at all IDDRCs. These repositories will enable access to IDD models generated by CMUs throughout the network, and will link these models with accompanying genomic, transcriptomic, and epigenomic data. Banking of these IDD models and data will utilize cross-IDDRC calibrated methods, making these repositories valuable for data meta-analyses and model resource sharing. Such meta-analyses can be informative in defining convergent mechanisms that contribute to IDDs involving many different genetic contributors to patient risk.

CMU Projects

Additional information about the CMU is accessible via this link.


Animal Assessments Unit: Animal Behavior Subunit (ABS)

The ABS offers comprehensive services regarding the behavioral testing of rodent models with a focus on conducting an array of standard and IDD-specific behavioral tests for mice and rats. The Subunit also provides pre-study consultation with investigators to discuss all aspects of experimental design. Training on our state-of-the-art equipment and updated protocols can also be provided by the ABS for investigators and their teams.

Behavioral Tests

The ABS offers over 50 individual mouse behavioral tests within the following categories:

  1. Approach/Avoidance (Anxiety-Like)
  2. Circadian Rhythm
  3. Developmental Trajectories
  4. Feeding Behavior
  5. Learning and Memory (spatial and non-spatial)
  6. Repetitive, Restricted Behaviors
  7. Reward Behavior
  8. Sensory/Motor Functions
  9. Social Behaviors

For rats, we offer behavioral tests within the following categories:

  1. Approach/Avoidance (Anxiety-Like)
  2. Learning and Memory (spatial and non-spatial)
  3. Sensory/Motor Function
  4. Social Behaviors
Consultations

Our team of animal behavior experts can provide consultation on experimental issues such as sex effects, background strain, littermate controls, non-behavioral influences on performance, and statistical power. Consultation will include recommending certain tests for specific models and cost estimates for the work involved, as well as referrals to other relevant cores.

Equipment

The ABS has acquired a wide range of instrumentation to better characterize phenotypes and treatment effects including:

  1. DigiGait and CatWalk gait analysis systems
  2. Mouse and Rat Morris Water Maze Pools
  3. Force-plate Actometers
  4. Accoustic Startle/Prepulse Inhibition Chambers and Program
  5. Fear Conditioning Chambers and Program
  6. Behavior Sound- and Scent-Attenuating Chambers for various tests

And more!

Training on our equipment and protocols can be provided as a service if requested.

Ongoing Test Development

The ABS is currently developing and integrating machine learning into our behavioral tests and analyses with the goal of allowing us to offer streamlined access to high-throughput machine learning tools for IDD researchers.  Machine learning techniques will allow for the automated acquisition and precise processing of subtle behaviors during testing through the use of computer vision applications, which will expand our phenotyping capabilities.

We are excitedly building the necessary infrastructure required for high-throughput computer vision and machine learning behavior quantification, including:

1) Building new custom behavioral data acquisition systems designed specifically for the advanced video acquisition required for computer vision platforms.

2) Acquiring high-powered machines necessary to build and process computer vision and machine learning models.

3) Generating computer vision and machine learning models for automated quantification of gait and motor behaviors, stereotypies and repetitive patterns of behavior, and social behaviors.

For more information about the Animal Behavior Subunit or to schedule a consultation/start a study with us, click here!


Animal Assessments Unit: Neuropathology Subunit (NPS)

The NPS provides consultation and services to investigators characterizing animal models of IDD in basic histopathology approaches, immunohistochemical methods, and quantitative tissue analysis. Additional NPS information is available on Dr. Noguchi’s lab site.

Histopathology Approaches

Basic histopathology approaches for light microscopic evaluation include perfusion fixation, embedding, sectioning and staining of CNS tissues.  The NPS also provides investigator training in these methods and in research design, data analysis and interpretation. Additional procedures offered include DeOlmos cupric silver staining, in situ hybridization, and western blotting.

Immunohistochemical Methods

The NPS has experience with a wide variety of immunohistochemical methods including: activated caspase-3, pERK, TUNEL, NeuN, GFAP, MBP, Ki-67, PCNA, Nestin, BrdU, NR1, GAD, calbindin, ChAT.  The NPS  will develop additional approaches as need arises. Previous work included the development of new methods to assess the developmental neuropathology produced by Zika virus infection, anesthetic drugs, and glucocorticoids

Quantitative Tissue Analysis

The NPS also conducts and/or assists investigators in quantitative tissue analyses using unbiased stereology and unbiased sampling of the brain or brain regions of interest. The NPS is equipped with digital imaging microscopes with electronically driven stages and Microbrightfield software specifically designed to facilitate unbiased stereological quantitative analysis. The NPS also provides ultrastructural analysis of pathological changes in the developing brain. Both Drs. Noguchi and Farber have many years of experience in using the electron microscope to investigate a variety of neuropathological phenomena including viral infection, excitoxicity, and apoptosis.


Animal Assessments Unit: Neurophysiology Subunit (NPhyS)

Drs. Wong and Thio offer consultation and services for a wide range of in vivo and in vitro electrophysiology assays of rodent models of IDD.

Assays

EEG: Numerous studies have documented the co-existence of seizures with disorders of IDD. In order to evaluate these and other paroxysmal behaviors, the NPhyS established and offers a rodent epilepsy monitoring unit with the capacity to monitor 36 mice using continuous video-EEG monitoring.  Using this technique, the NPhyS has characterized seizures in multiple models of IDD, such as in mouse models of tuberous sclerosis complex, neuronal ceroid lipofuscinosis, and other genetic IDDs.  The NPhyS also developed and offers technically innovative methods to allow serial video-EEG monitoring longitudinally in preweaning neonatal mice. In addition, NPhys performs both qualitative and quantitative (e.g., spike counts, spectral analysis) assessments of abnormalities in interictal background EEG activity, which provide a neurophysiological correlate of encephalopathy;

Seizure threshold testing: This is performed using convulsant drugs, such as pentylenetetrazol or kainate in rodents that do not have spontaneous seizures;

Polysomnograms: Sleep disorders are common in IDD and can exacerbate its symptoms. Using a combination of EEG and EMG, the NPhyS performs sleep studies that characterize the sleep-wake cycle, including the percentage of times in awake, non-REM, and REM states and power spectra analysis. The NPhyS has recently used these methods to identify sleep abnormalities in a mouse model of neurofibromatosis, tuberous sclerosis, and aging.

Somatosensory evoked potentials: Sensory abnormalities are also characteristic of some neurodevelopmental disorders. The NPhyS offers newly developed methods for stimulating median nerve in rodent forepaw and stably recording evoked potentials over somatosensory cortex with epidural electrodes;

Slice and Cellular Electrophysiology: Extracellular field potential recordings and single cell/intracellular recordings are powerful methods for assessing synaptic function and plasticity in neuronal networks and investigating the cellular basis and mechanisms of learning deficits and other brain dysfunction in IDDs.  The NPhyS offers consultation, training, and equipment use to investigators in several fully-equipped electrophysiology rigs available in the MSC for extracellular field potential recording in brain slices and whole-cell patch-clamp recording in slices and cultured cells.

Human PSCs:  Inasmuch as neurons derived from human PSCs are difficult to work with and characterize, Dr. Huettner, a noted expert in this field, works with Dr. Kroll of the Cellular Models Unit to assess IDD patient-derived pure neuronal populations, organoids, or co-cultures using electrophysiology and/or multi-electrode array.