Assessment of Behavioral Characteristics With Procedures of Minimal Human Interference in the mdx Mouse Model for Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a severe, progressive neuromuscular disorder caused by mutations in the DMD gene resulting in loss of functional dystrophin protein. The muscle dystrophin isoform is essential to protect muscles from contraction-induced damage. However, most dystrophin isoforms are expressed in the brain. In addition to progressive muscle weakness, many DMD patients therefore also exhibit intellectual and behavioral abnormalities. The most commonly used mouse model for DMD, the mdx mouse, lacks only the full-length dystrophin isoforms and has been extensively characterized for muscle pathology. In this study, we assessed behavioral effects of a lack of full-length dystrophins on spontaneous behavior, discrimination and reversal learning, anxiety, and short-term spatial memory and compared performance between male and female mdx mice. In contrast to our previous study using only female mdx mice, we could not reproduce the earlier observed reversal learning deficit. However, we did notice small differences in the number of visits made during the Y-maze and dark-light box. Results indicate that it is advisable to establish standard operating procedures specific to behavioral testing in mdx mice to allow the detection of the subtle phenotypic differences and to eliminate inter and intra laboratory variance.

Long-Term Effects of Low-Intensity Blast Non-Inertial Brain Injury on Anxiety-Like Behaviors in Mice: Home-Cage Monitoring Assessments

“…The short shelter visit threshold defines the upper limit of a short visit. 26 The short shelter visit threshold was significantly lower in LIB-exposed mice compared to sham controls by 7% ( p = 0.0349; Fig. 4A ).…”

“… 40 To optimize behavioral resolution, sheltering behaviors in this study were further classified according to a previous study. 19 , 26 Long shelter visits were used to indicate behaviors of resting or sleeping (for hours), whereas passing through shelters during activity bouts was defined as short shelter visits (for seconds).…”

“…Spontaneous behaviors were assessed in sham controls ( n = 23) and LIB-exposed ( n = 29) mice at 3 months post-LIB exposure with the PhenoTyper home cages (Model 3000; Noldus Information Technology, Wageningen, The Netherlands), as previously described. 19 , 25 , 26 Briefly, home cages (L = 30 × W = 30 × H = 35 cm) were composed of a top control unit, four semitransparent Perspex walls, an opaque Perspex floor, a shelter, and food and water stations. Mice were housed individually with bedding (Bed-o'Cobs ® , Laboratory Animal Bedding; The Andersons Laboratory Animal Bedding, Maumee, OH) and provided food and water ad libitum ( Fig.…”

“…The spontaneous behavioral parameters in six categories were activity bouts, kinematics, sheltering, dark-light index, habituation, and light/dark phase transition. 19 , 25 , 26 Briefly, movements were classified into short movements , as turning or rearing against the wall, and long movements , as traveling from one location to the next. Activity bouts stopped at the encounter of a long arrest segment or a shelter visit that exceeded the short shelter visit threshold.…”

Characterization of Alzheimer's disease‐like neuropathology in Duchenne's muscular dystrophy using the DBA/2J mdx mouse model

“…The mdx mouse is the traditional model for DMD, and studies in these mice have demonstrated impairments in passive avoidance learning [ 29 ], retention in a T‐maze and in long‐term consolidation [ 30 ], object recognition and spatial memory [ 31 ]. However, as with human patients with DMD, there is some discrepancy in the field and a recent study did not find any differences in cognitive flexibility in mdx mice compared with wild‐type (WT) controls [ 32 ]. These previous studies have all utilized the mdx mouse on a C57BL/10 (C57) background, which despite being the most commonly used mdx model is known to have a mild dystrophic phenotype compared with human DMD.…”