Agenesis of the corpus callosum and voluntary wheel running in mice

Humans born without a corpus callosum (CC) are often comparatively slow and clumsy on tasks requiring bilateral motor coordination. In this study, we attempted to identify correlates of CC agenesis in mice by examining an ecologically valid motor behavior: running-wheel performance. Mice with varying degrees of congenital CC deficits were tested on a running wheel apparatus for 7 consecutive days. The mice became more proficient at running with experience (i.e., rotations, time spent running, length of running bouts, and maximum and modal running speeds increased while variability of rotation times decreased). Multiple regression analysis suggested that CC deficiency may be related to 2 out of 20 measurements of running (decreased variability of rotation times and shorter maximum running bout duration), but at levels below the traditional criteria for significance. Although these variables predicted CC deficiency at a level significantly greater than chance (71% correct) in a discriminant analysis, examination of the meaning of their relationship with CC size suggested that any connection may be spurious. Article: Axons of the corpus callosum (CC) connect the cerebral hemispheres in placental mammals. Agenesis of the CC occurs in the embryo when axons are unable to cross the cerebral midline but instead grow longitudinally in the novel Probst bundle (Ozaki, Murakami, Toyoshima, & Shimada, 1987; Ozaki & Shimada, 1988) and soon return to the ipsilateral cerebral cortex (Ozaki & Wahlsten, 1993). In humans, the incidence of callosal agenesis is estimated to be 0.0005%-0.7% (Wisniewski & Jeret, 1994), and its occurrence is often associated with other neurological deficits (Aicardi & Chevrie, 1994; Andermann & Andermann, 1994). It is paradoxical that humans born without a CC exhibit comparatively few behavioral or performance deficits, especially in comparison with patients who have had their CC surgically split (Sauerwein & Lassonde, 1994; Sperry, 1982). Unlike callosotomy patients, acallosals can transfer information from one hemisphere to another, suggesting that plasticity exists in the formation of forebrain cortical connections. The most consistent functional finding is that acallosals often exhibit deficits on motor tasks requiring bimanual coordination, especially under speed stress (Silver & Jeeves, 1994). Four strains of mice (BALB/c, 1/LnJ, 129, and ddN) frequently exhibit congenital agenesis of the CC to varying degrees. Several recent studies utilizing the transgenic knockout method in mice have also reported a high frequency of absent CC (Müller et al., 1994; Qiu, Anderson, Meneses, Pedersen, & Rubenstein, 1995; Stumpo, Bock, Tuttle, & Blackshear, 1995). However, the 129/SvJ substrain is widely utilized as the source of embryonic stem cells in this method, and there is uncertainty about whether the targeted genes or additional portions of the 129 genome are responsible for the acallosal phenotype. Much is known about the anatomical and genetic etiology of CC agenesis in mice (Wahlsten & Ozaki, 1994). Tests of bilateral motor coordination suggest subtle problems in limb coordination. I/Ln mice, which always exhibit complete CC agenesis, have been observed circling during swimming navigation (Lipp & Waanders, )990; Lipp & Wahlsten, 1992). 1/Lo animals are known for their high activity (McClearn, Wilson, & Meredith, 1970), and fast moving animals often show bouts of uncontrolled circling which alternate with straight running. On a task requiring mice to walk along a notched bar, a clear strain correlation was found between size of the CC and the number of hind-paw slips, the acallosal PLn mice having the greatest mean number of slips (Lipp & Wah)sten, 1992). However, no correlation between CC size and platform slips was observed within strains [129/J, BALB/c, (C57BL/6 × I/Ln) × I/Ln backcrosses]. Completely acallosal I/Ln mice are relatively ambi lateral in comparison with strains with normal CCs and strong paw preferences (Gruber, Waanders, Collins, Wolfer, & Lipp, 1991). However, in a sample of backcrossed hybrids [(C57BL/6 × I/Ln) × I/Lnl no correlation between CC size and degree of paw lateralization was observed (Lipp, Bechel, Wolfer, & Scheffran, 1991). Although a significant correlation was reported in a small sample of 129/J mice but not in a sample of BALB/c mice (Ward, Tremblay, & Lassonde, 1987), larger studies have confirmed the lack of relationship between CC size and degree of paw preference lateralization in BALB/c mice (Bulman-Fleming, Wainwright, & Collins, 1992; Schmidt, Manhaes, & de Monies, 1991). In the present study, we assessed the impact of CC agenesis on mouse running-wheel performance, a task involving high-speed running and relying on the intrinsic motivation of mice to run. Wheel running was examined in mice obtained by inbreeding different family lines from an F2 cross between BALB/cWahl and 129/ ReJ (Wahlsten & Sparks, 1995), This method yielded many animals with total absence of the CC. It was hypothesized that mice with absent CC would run more slowly and clumsily (i.e., stumble more often at high speeds) than mice with an intact CC, because the acallosal mice rely on indirect cortical pathways with lower speed and capacity for transmitting information between the hemispheres.