January 10th, 2018
Animal Models Examining Neurobehavioral Disorders
Animal experiments aim to replicate observations noted in post-mortem assays of dyslexic brains, to elucidate the structure and physiology of implicated genes and possibly identify a causal relationship of defects in such genes to behavior (Galaburda et al. 1215). Abnormal behavior in neonatal rats has been suggested to be a result of induction of cortical malformations (Galaburda et al. 1215). For instance, most animal models have principally replicated focal mycrogyria and ectopias of the molecular layer (Galaburda et al. 1215). Successful replication of mycrogyria in female and male rats has been associated with changes in “cortico-cortical connectivity and changes of connectivity across the corpus callosum” (Galaburda et al. 1215). Additionally, such induction in male rats has been linked with thalamic changes that are similar to those occurring in dyslexic thalami but corresponding induction in female rats does not result to such thalamic changes (Galaburda et al. 1215). Such sex differences may help explain observations to the effect that more male rats become afflicted by developmental disorders than are female rats (Galaburda et al. 1215).
Thalamic changes that arise from induction of mycrogyria have been noted to contribute to the auditory impairment in males (Galaburda et al. 1215). One study has for instance found the existence of a link between cortical malformations and basic auditory processing in animal models (Peiffer et al. 2875- 2879). In this study, ectopic male NZB/BINJ mice “failed to detect short embedded tone durations of 2 and 5 [milliseconds; ms], but detected significantly longer durations” (Peiffer et al. 2877). Non-ectopic NZB/BINJ males did not show such impaired auditory processing, and despite ectopic-mice detecting tones at longer durations, such detection was not as accurate as that of the non-ectopic rats (Galaburda et al. 1215). Another factor noted to mediate the extent of impairment to the auditory processing is age with juvenile mice having heightened impairment when compared with adult mice (Galaburda et al. 1215). Additionally, such deficits are mediated by the cognitive demand of the task being assessed (Galaburda et al. 1215). Young animals with cortical malformations for instance exhibit deficits in processing even with low cognitive-demand (simple gap-detection) tasks, whereas for adult animals, such thresholds required for impaired processing to result are slightly higher – two-tone sequence thresholds (Galaburda et al. 1215).
Other behavioral deficits noted with rats with induced mycrogyria or those that have developed neocortical ectopias following mutations in their genomes, have been revealed in “non-spatial discrimination tests … [and] in a spatial water escape maze” (Galaburda et al. 1215). Such differences in performance at times occur with reference to gene variants that have led to the noted malformations (Galaburda et al. 1215). An example of such discrepancy has been noted with respect to Lashley III Maze, where BXSB/MpJ ectopic mice are able to perform well whereas the NZB/BINJ mice fail to learn the maze (Galaburda et al. 1215). Such differences could be attributed to the location of the malformation. Whereas BXSB/MpJ mice have ectopias in the frontal cortex, the NZB/BINJ have such ectopias located in parietal cortex (Galaburda et al. 1215). Conversely, “in two tests of working memory, one involving an inverted Lashley III maze, the other a delayed-match-to-sample task, ectopic BXSB/MpJ mice performed poorly.” (Galaburda et al. 1215). However in “a reference memory spatial water maze” the BXSB/MpJ mice performed exemplarily (Galaburda et al. 1215). Such discrepancies have been explained on the pathology of the frontal cortex, a part of the brain that forms part of the working memory circuit (Galaburda et al. 1215). However, these impairments have been noted to occur whether the anomalies are induced in experimental procedures or develop spontaneously without the contribution of experimental interventions (Galaburda et al. 1215).
One study that has provided a link between impaired neuronal migration elicited by curtailed gene expression and neurobehavioral disorders was in respect to deficits in spatial working memory. In this study by Szalkowski et al., the effect Dyx1c1-targeted RNAi “on the working memory performance in Sprague-Dawley rats” (244). The working memory performance in the study was evaluated via a match-to-place radial water maze which involves a brief single evaluation memory (for a period of approximately four to 10 seconds) and then moving on to a new goal each day (Szalkowski et al. 244). Histological assessments identified impaired neuronal migration and laminar disruption in the rats treated to impede the expression of DYX1C1 (Szalkowski et al. 244). Such abnormalities were correlated with a “subtle but significant and persistent impairment in working memory” when compared with the control group (Szalkowski et al. 244). Through these observations, the potential role of Dyx1c1 in facilitating neuronal migration and subsequent implication in working memory impairment in subjects with curtailed expression of the gene was reinforced. Go to conclusion