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Mouse Behavioral Phenotyping Core

The Mouse Behavior Core provides investigators within the CIDD and throughout the UNC research community with a wide variety of behavioral tasks for studies in genetic, environmental, and pharmacological models of human disorders, and for preclinical efficacy testing of novel therapeutic agents. The Core includes a state-of-the-art laboratory for the measurement of mouse phenotypes, and offers training and consultation regarding the utilization of rodent models. Available testing regimens include a standardized battery for measures of general health and neurological reflexes, procedures for sensory and motor abilities, and evaluations of social interaction, sensorimotor gating, cognitive function, and abnormal repetitive behavior. The Core can also determine behavioral profiles in neonatal mouse pups. Investigators interested in using the facility are encouraged to meet with the Director to discuss project aims and the appropriate constellation of behavioral assays to address scientific hypotheses.
mouse_social_sniffing


Core Personnel

Director: Sheryl Moy, Ph.D.
Core manager: Lorinda Baker, B.A.
Research specialists: Kara Agster, Ph.D., Viktoriya Nikolova, B.S.
Consultant for ultrasonic vocalization studies: Philip “Sandy” Zeskind, Ph.D.
Dr. Zeskind, a Professor in the Department of Pediatrics at the Levine Children’s Hospital at Carolinas Medical Center, Charlotte, NC, is an expert in both human infant vocalization and rodent models (see Zeskind et al. (2011) Development of Translational Methods in Spectral Analysis of Human Infant Crying and Rat Pup Ultrasonic Vocalizations for Early Neurobehavioral Assessment. Frontiers in Neuroscience 2:56).


Behavioral Tests

All behavioral testing procedures are conducted in strict compliance with the policies on animal welfare of the National Institutes of Health (stated in the “Guide for the Care and Use of Laboratory Animals,” Institute of Laboratory Animal Resources, National Research Council, 1996 edition), and approved by the University of North Carolina Institutional Animal Care and Use Committee.

Measures of general health: The Core provides a preliminary assessment of general health and signs of gross physical impairment. Observations are taken of body weight, the appearance of the fur, body posture, and normality of gait. These initial evaluations ensure that mice are in good health for further behavioral testing.

Home cage behavior: Assessment of home cage behavior is usually conducted in the first week of testing. Observations are taken of nestlet shredding, nest building, sleeping in huddles, activity, fighting, and any aberrant behaviors, such as tremor or seizures. Changes in home cage behavior, such as constant locomotion or a failure to huddle together, may inform the choice of complex behavioral tests in characterizing a new mouse model.

Neurobehavioral reflexes: The Core assesses reflexive motor and sensory responses to a variety of stimuli, including:
* Tactile stimuli: head turn to a touch by a sterile cotton swab on the whiskers of the mouse.
* Visual stimuli: eye blink to the approach of a sterile cotton swab to the eyes.
* Acoustic stimuli: whole body flinch to the sound from a metal clicker (Preyer reflex).
Motor function
* Open field activity and exploration. Locomotion, fine movements, rearing, and center time are measured using automated activity systems (Fusion and VersaMax Systems, AccuScan Instruments). These data can be used to quantitate hyper- or hypo- activity, anxiety-like behavior, and stimulant or sedative drug effects.
Mouse in open field Activity System















* Motor coordination and balance on a beam or climbing pole, and grip strength in a wire hang test.
Mouse on balance beam
* Accelerating rotarod: Mice are placed on a cylinder which slowly accelerates to a constant rotating speed. Normal mice readily learn to walk forward as the drum turns.
Mouse on rotarod
* Stride and gait test: This test involves painting the paws to obtain a footprint pattern for walking or running.

* Swimming: A video tracking system (Ethovision, Noldus) is used to measure swimming ability in a water maze.

Sensory tasks
* Olfaction is assayed by scoring the retrieval of a buried food.
* Hearing is tested using an automated acoustic startle procedure (SR-Lab system, San Diego Instruments).
* Vision is tested with the visible platform task in a water maze or by a visual cliff procedure.
* Thermal sensitivity is tested with a hot plate/cold plate apparatus (IITC).

Anxiety- and depression- related behavior
The Core uses complementary tasks to provide an assessment of anxiety-like behavior. These anxiety measures are conflict tests based on a natural tendency of mice to actively explore a novel environment, versus a fear of being in a brightly-lit open area. In addition to the open field, the Core offers:

* Elevated plus maze or zero maze: mice are given a choice between staying within the safety of two walled areas, versus exploring two open areas.
Elevated plus maze
* Light/dark exploration: mice are given a choice between staying in the dark side of a chamber, or entering the lighted side (Versamax, Accuscan).

The Core uses two standard tasks for depression: the forced swim test and sucrose preference in a two-bottle choice task.

3-chamber social approach test
The laboratory has developed a test for social behavior in mice, which allows assessment of both social approach and avoidance. The test has 3 10-minute components:

* Habituation: an acclimation period which provides measures of general expiration.
* Sociability test: mice are given a choice between spending time in the proximity of another mouse, versus staying alone.
* Preference for social novelty: mice are given a choice between spending time in the proximity of an unfamiliar mouse, versus an already-investigated mouse.
Social test box
Learning and memory tasks

*Morris water maze: This is a standard assay for acquisition of spatial learning and cognitive flexibility during reversal learning.
Morris Water Maze
*Barnes maze: This apparatus provides indices of spatial and reversal learning similar to the water maze, but without the physical demands of swimming.
Barnes Maze
*T-maze: Spatial learning, alternation, and reversal can be tested in a T-maze, using food or liquid reinforcers. A delayed non-match-to-sample procedure can be utilized to demonstrate working memory deficits.
T-Maze
*Conditioned fear and avoidance tests: The Core uses a Near-Infrared Video Fear Conditioning system (Med Associates) for evaluating contextual or cue-dependent learning. A Gemini system (San Diego Instruments) is available for evaluating active or passive avoidance.

Sensorimotor gating
The acoustic startle system used to assess auditory function can also provide an evaluation of sensorimotor gating. The test is based on the measurement of the reflexive whole-body flinch, or startle response, that follows exposure to a sudden noise. In normal animals, the addition of a softer noise, or prepulse, immediately before the loud startle stimulus, can lead to a significant inhibition of the subsequent startle response. Deficits in prepulse inhibition are associated with schizophrenia, autism, and other neuropsychiatric disorders.
Acoustic Startle Box
Repetitive behavior
The Core can assess abnormal repetitive behavior, restricted interests, and stereotypy using several different approaches, including reversal learning in the water maze, digging in a marble-burying task, rates of grooming, jumping, or other behaviors (scored using Observer software, Noldus), and exploration during an automated nose-poke task (Pokeman, Accuscan Instruments).
Marble Burying Test

Neonatal assessment
Young mice can be evaluated with measures of ultrasonic vocalization (UltraVox, Noldus, or Avisoft recording system), activity in a Phenotyper (Ethovision, Noldus), prepulse inhibition of acoustic startle responses, and social approach, coded using Observer software (Noldus).

Core Behavioral Studies



For many projects, a set of mice is transferred to the Core for testing by our personnel. Study designs often include evaluating mice with an extensive phenotyping regimen across several weeks, with one or two tests per week.

Project initiation. UNC investigators wishing to utilize the Core are advised to contact the Director, Dr. Sheryl Moy, ssmoy@med.unc.edu, to discuss optimal study designs, feasibility for core use, and costs of testing. Most projects are conducted as scientific collaborations, rather than on a fee-for-service basis. Publications generally include relevant members of the Mouse Behavioral Phenotyping Laboratory as co-authors. The Core can provide, without charge, initial pilot experiments for IDDRC investigators. Support for subsequent experiments is contributed by Pis. Core charges are based on personnel effort for conducting studies.

IACUC approval. All projects utilizing the Core must be approved by the UNC Institutional Animal Care and Use Committee (IACUC) before initiation. The Director can provide drafts of amendments or sections to include behavioral testing in animal protocols. In addition, an Animal Services Form, describing use of core services, must be submitted to the IACUC. Both the project PI and the Core Director will need to sign this form.

Subjects. Typical mouse behavior studies require 8 to 12 subjects per experimental group for adequate power in the statistical analyses. Thus, for a line of genetic mutants, an N of approximately 10 wild type and 10 mutant littermates is required. To evaluate effects of both sex and genotype, approximately 10 males and 10 females of each genotype will be required.

Behavioral results are highly sensitive to environmental effects such as home cage environment and parental care. Therefore, in studies with genetically-altered mouse lines, it is essential to use littermate wild type and mutant mice, usually obtained from heterozygous breeding pairs. In order to obtain adequate subject numbers, the Core can test 2 or 3 separate, age-matched cohort groups. In this case, each cohort should include mice of each genotype (i.e. no separate group of only control mice). It is not appropriate to compare behavioral profiles in mutant mice bred in a UNC animal facility with wild type mice ordered directly from a commercial vendor.
Mouse on Barnes Maze

Transfer of subjects to the core facility. The Mouse Behavior Core is located in the Medical Biomolecular Research Building (MBRB), inside the Division of Laboratory Animal Medicine (DLAM) animal vivarium. The laboratory consists of 6 behavioral testing rooms, and an adjacent mouse housing room (1339 MBRB). All transfers of mice to the Core must first be approved by DLAM. Because the MBRB vivarium is a closed animal facility that maintains maximal cleanliness, only mice from other UNC facilities at a similar health status, or from commercial sources such as Jackson Laboratory, may be transferred to core housing. Rederivation may be required for mice that do not meet the DLAM health standards for the MBRB vivarium. Mice imported from other academic institutes with high health standards must first undergo a 6-9 week quarantine period before transfer to the Core, dependent upon DLAM approval.

MBRB

The Core Director can provide a DLAM Transfer Approval Form. For each transfer group, the Director will need an Excel spreadsheet with information about the mice, including subject ID, genotype, sex, DOB, and cage number. Because single housing is stressful for mice, the Core asks that each cage contain from 2-4 mice, separated by sex. For most projects, a maximum of 24 mice can be transferred to the Core at one time.

To be considered for membership in the CIDD and to gain access to core resources of the UNC IDDRC, please visit the Membership and Access Information page.

Membership and Access Information



Mouse Behavioral Phenotyping Core Contact Information

Sheryl Moy, Director
Phone: (919) 966-3082
Email:sheryl_moy@med.unc.edu
FAX: (919) 966-5657

Mouse Behavior Laboratory
Phone: (919) 966-8651
Email
Lorinda Baker lorinda@med.unc.edu
Kara Agster agster@email.unc.edu
Viktoriya Nikolova Viktoriya_Nikolova@med.un

Office Address
4200 Medical Biomolecular Research Building (MBRB)
111 Mason Farm Road
Campus Box 7146
UNC-CH
Chapel Hill, NC 27599
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