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. 2015;37(4-5):440-52.
doi: 10.1159/000375487. Epub 2015 Mar 17.

Dissociation in the Effects of Induced Neonatal Hypoxia-Ischemia on Rapid Auditory Processing and Spatial Working Memory in Male Rats

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Dissociation in the Effects of Induced Neonatal Hypoxia-Ischemia on Rapid Auditory Processing and Spatial Working Memory in Male Rats

Amanda L Smith et al. Dev Neurosci. 2015.

Abstract

Infants born prematurely are at risk for cardiovascular events causing hypoxia-ischemia (HI; reduced blood and oxygen to the brain). HI in turn can cause neuropathology, though patterns of damage are sometimes diffuse and often highly variable (with clinical heterogeneity further magnified by rapid development). As a result, though HI injury is associated with long-term behavioral and cognitive impairments in general, pathology indices for specific infants can provide only limited insight into individual prognosis. The current paper addresses this important clinical issue using a rat model that simulates unilateral HI in a late preterm infant coupled with long-term behavioral evaluation in two processing domains - auditory discrimination and spatial learning/memory. We examined the following: (1) whether deficits on one task would predict deficits on the other (suggesting that subjects with more severe injury perform worse across all cognitive domains) or (2) whether domain-specific outcomes among HI-injured subjects would be uncorrelated (suggesting differential damage to orthogonal neural systems). All animals (sham and HI) received initial auditory testing and were assigned to additional auditory testing (group A) or spatial maze testing (group B). This allowed within-task (group A) and between-task (group B) correlation. Anatomic measures of cortical, hippocampal and ventricular volume (indexing HI damage) were also obtained and correlated against behavioral measures. Results showed that auditory discrimination in the juvenile period was not correlated with spatial working memory in adulthood (group B) in either sham or HI rats. Conversely, early auditory processing performance for group A HI animals significantly predicted auditory deficits in adulthood (p = 0.05; no correlation in shams). Anatomic data also revealed significant relationships between the volumes of different brain areas within both HI and shams, but anatomic measures did not correlate with any behavioral measure in the HI group (though we saw a hippocampal/spatial correlation in shams, in the expected direction). Overall, current data provide an impetus to enhance tools for characterizing individual HI-related pathology in neonates, which could provide more accurate individual prognoses within specific cognitive/behavioral domains and thus improved patient-specific early interventions.

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Figures

Figure 1
Figure 1
A. A 5 (Day) x 9 (Gap) x 2 (Treatment; HI and Sham) repeated measures ANOVA revealed a significant overall Treatment effect with HI animals performing worse on a Silent Gap 0-100 task (p<.05). B. A 5 (Day) x 9 (Gap) x 2 (Treatment; HI and Sham) repeated measures ANOVA revealed a significant overall Treatment effect with HI animals performing worse on a Silent Gap 0-10 task (p <.05)
Figure 2
Figure 2
A. A 9 (Gap) x 2 (Treatment; HI and Sham) repeated measures ANOVA revealed a significant overall Treatment effect with HI animals performing worse on a Silent Gap 0-100 task during adulthood (p<.05). B. A 5 (Day) x 9 (Gap) x 2 (Treatment; HI and Sham) repeated measures ANOVA revealed a significant overall Treatment effect with HI animals performing worse on a Silent Gap 0-10 task during adulthood (p<.05).
Figure 3
Figure 3
A bi-variate correlation (Pearson's r) for sham animals revealed significant positive correlations between performance on short and long duration silent gaps (p<.05). Significant positive correlations were also seen between the 1st and 2nd half of maze testing in regards to errors made (p<.05). Latency per choice analyses showed a trend to be significantly positively correlated during the 1st and 2nd half of maze testing (p=.065). Significant negative correlations were also seen between latency per choice analyses on 1st half of maze testing and errors during the 2nd half of maze testing (p=.075), as well as latency per choice analyses on 2nd half of maze testing and errors during the 2nd half of testing (p<.05). Percent hippocampal damage was positively correlated with errors on both the 1st (p<.05) and 2nd (p<.05) half of the maze. Percent ventricular damage correlated negatively with errors in only the 1st half of the maze (p<.05).
Figure 4
Figure 4
A bi-variate correlation (Pearson's r) for HI animals revealed a trend for a significant correlations between performance on short and long duration silent gaps (p<.07). Cortical and hippocampal damage was positively correlated (p<.05), whereas cortical and ventricular damage was significantly negatively correlated (p<.05). Hippocampal damage and ventricular damage were also significantly negatively correlated (p<.05). All other comparisons were not significant.
Figure 5
Figure 5
An overall 2 (Hemisphere) x 2 (Treatment) repeated measures ANOVA revealed a significant Treatment effect where HI animals had significantly smaller overall cortical volume as compared to Shams (p<.05). We also found significant Hemisphere [*p<.05] and Hemisphere x Treatment (p<.005) effects, indicating that HI animals had smaller right cortical volumes than shams.
Figure 6
Figure 6
A 2 (Hemisphere) x 2 (Treatment) repeated measures ANOVA revealed a significant overall Treatment effect (p<.05), as well as significant Hemisphere (*p<.005) and Hemisphere x Treatment effect (p<.005).
Figure 7
Figure 7
A 2 (Hemisphere) x 2 (Treatment) repeated measures ANOVA revealed a significant Hemisphere x Treatment effect (p<.005) where HI animals had significantly larger right ventricular volumes as compared to shams.
Figure 8
Figure 8
Representative photomicrographs of Nissl stained coronal sections representing a typical sham brain (A), mild HI damage (B), moderate HI damage (C), and severe HI damage (D).

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