The Multivariate Concentric Square Field Test Reveals Behavioral Profiles of Risk Taking, Exploration, and Cognitive Impairment in Mice Subjected to Traumatic Brain Injury

Abstract

There is a need for more efficient tests to evaluate functional outcome following experimental traumatic brain injury (TBI), reflecting deficits in cognitive, sensory, and motor functions that are seen in TBI patients. The Multivariate Concentric Square Field (MCSF) test is a relatively new behavioral model that measures exploration, risk taking, risk assessment, and shelter seeking, all of which are evolutionarily-conserved strategies for survival. The multivariate design enables scoring of different functional domains in a single test situation, with a free choice of optional environmental settings. Furthermore, repeated trials permits cognitive effects to be measured. In the present study, 11 anesthetized C57BL6 mice received controlled cortical injury (CCI) (0.5 mm and 3.3 m/sec) over the right parietal cerebral cortex or sham surgery (n = 12). Naïve mice (n = 12) not subjected to any surgical procedure were also included. The animals were evaluated in the MCSF test at 2 and 7 days post-surgery, and behavioral profiles were analyzed. The results revealed differences in risk taking and explorative behavior between the sham animals and the animals subjected to trauma. Animals subjected to trauma were characterized by taking more risks and had a higher level of exploration activity, but they sought less shelter. Repeated exposure to the MCSF caused a general decrease in activity in the naïve and sham group, while a more specific behavioral impairment was seen in injured mice, suggesting cognitive dysfunction. We submit that the MCSF test is a useful complementary tool for functional outcome evaluation in experimental TBI.

Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes

“…The test has been developed as a multidimensional assessment of distinct behavioral phenotypes in a complex environment that is rich with alternatives, in which animals are free to move around and explore among various compartments and areas [51]. The MCSF can enhance sensitivity to treatments such as brain injury or developmental manipulations that may produce changes in internal states that may be expressed as differences in behavioral patterning or profiles (e.g., in risk taking, risk assessment, shelter seeking, or exploration) [52–54, 56]. Our finding that EGCG treatment produces effects in opposite directions for risk taking behavior of trisomic and euploid mice raises the intriguing possibility that EGCG may improve the maladaptive behavior expressed in risk-related settings [51, 61], and may have similar selective effects on adaptive behavioral regulation in unfamiliar environments in individuals with DS [49].…”

“…The MCSF apparatus, adapted from Ekmark-Lewén [52], is a complex, multi-compartment novel environment in which animals may move around and explore freely among various compartments and areas, including ones that are open, elevated, or sheltered [see Supplemental Figure 1 for image]. The MCSF design consists of an outer square field [70 cm × 70 cm × 26 cm (high)] that encloses a smaller interior center square field [41 cm × 41 cm × 25 cm (high)] centered within the larger field.…”

“…The current study was also the first to employ the Multivariate Concentric Square Field (MCSF) in mouse models of DS, a behavioral task originally developed by Meyerson and colleagues that assesses patterns of activity and exploration in a complex novel environment, and has been shown to identify distinct behavioral phenotypes in rodent models, quantify locomotor activity, exploratory behavior, risk-taking, risk assessment, and shelter seeking, [51]. MCSF appears to be well suited to study behavioral phenotypes associated with neurodevelopment disorders given prior results from various rat and mouse models indicating its sensitivity to effects of traumatic brain injury [52], early life maternal separation stress [53], and disparities in lines of rodents selectively bred for differences in voluntary alcohol drinking [54]. Another key goal of this study was to determine Dyrk1a protein levels using Western blot analysis and to quantify kinase activity using a modified HPLC-based assay that has been suggested to measure Dyrk1a-related activity [55].…”

Influence of Physical Exercise on Traumatic Brain Injury Deficits: Scaffolding Effect

“…Neurons and glial cells in proximity to the damaged region induce apoptotic cell death at the early post-TBI stage (Itoh et al 2009(Itoh et al , 2010, with accompanying cerebral dysfunction (Dressler and Vemuganti 2009). Experimental TBI reliably models the functional deficits, within cognitive, emotional, sensory, and motor domains that are observed in TBI patients (Ekmark-Lewén et al 2010;Sigurdardottir et al 2010) thereby providing analyses at all levels of TBI pathophysiology. The notion of 'age-at-injury' poses an important aspect of both clinical and experimental TBI since the immature brain may be particularly vulnerable to injury during critical periods of development (Serra-Grabulosa et al 2005), whereas considerable evidence indicates that outcomes from TBI are worse in elderly individuals (Marklund et al 2009;Onyszchuk et al 2008).…”

Structured evaluation of rodent behavioral tests used in drug discovery research

“…Another strategy is to use a test that does not measure a single behavioral trait in the animal, but instead determines a behavioral profile. An example of this strategy is the multivariate concentric square field test, which uses a complex arena to enable simultaneous evaluation of several aspects of rodent behavior and subsequent analysis of the results using multivariate statistics (Meyerson et al, 2006; Ekmark-Lewén et al, 2010). Another example is a modified version of the hole board test, which measure several behaviors related to anxiety-like behavior, cognition and social interactions (Ohl and Keck, 2003).…”