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

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.

Effects of Sex and Mild Intrainsult Hypothermia on Neuropathology and Neural Reorganization following Neonatal Hypoxic Ischemic Brain Injury in Rats

“…Though the P7 HI rat was classically thought to model term infants with HIE, it is now thought to more accurately model insults seen in the late-preterm infant (GW 34–36; this new interpretation is reflected in updates to the website translatingtime.net, in which the Finlay group has calculated age comparisons between species (see [ 30 ])). Corresponding results confirm both neuropathologies and behavioral deficits typical of late-preterm HI insult in a P7 HI rat model [ 31 , 32 ]. Interestingly, in a recent study we have shown that mild temperature reduction during an HI insult led to “task-specific” benefits on a battery of behavioral tasks that generally favored females [ 33 ].…”

Sex Differences in Behavioral Outcomes Following Temperature Modulation During Induced Neonatal Hypoxic Ischemic Injury in Rats

“…Our lab and others have used the well-established Rice-Vannucci rat model of HI, where HI injury is experimentally induced on postnatal day (P) 7—roughly equating to injury in the late-preterm infant (34–36 gestational weeks (GW); [ 46 , 47 , 48 , 49 , 50 ]). Using this model, our lab has demonstrated behavioral deficits in male P7 HI rats, as assessed by tests of auditory processing, motor ability, spatial/non-spatial learning, working memory, and visual attention [ 25 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. Our findings and those of others nicely parallel what is seen in the clinical population, thereby validating the use of the P7 HI model to study the consequences of neonatal HI.…”

Therapeutic Interventions in Rat Models of Preterm Hypoxic Ischemic Injury: Effects of Hypothermia, Caffeine, and the Influence of Sex

“…Other authors argue that P7 corresponds to 36 GW, which is still earlier than previously thought, with P10 being roughly equivalent to a term infant [ 89 ]. P7 HI male rats exhibit reliable deficits in rapid auditory processing as juveniles and adults, and deficits are persistent and stable within subjects [ 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 ]. This follows other rodent models of language-related disabilities [ 106 , 107 , 108 , 109 , 110 , 111 , 112 ], and supports the idea that rapid acoustic processing deficits in animal models can serve as a biomarker of neural disruptions linked to language impairments [ 61 , 63 , 64 , 65 , 66 , 67 , 68 ].…”

“…Most pediatric associations agree that it should not be used in preterm infants, outside of a research setting, due to potential deleterious outcomes [ 20 ]. However, premature infants might benefit from an abbreviated and milder temperature reduction as shown below in work by Smith [ 103 , 104 ].…”

“…However, they did successfully use a more modest form of temperature reduction in P7 HI rats, specifically a 1.5 °C temperature reduction for 2 h ( Figure 1 ). This intervention—in contrast to the 4 °C/5 h regimen described above—was effective in mitigating some long-term behavioral deficits in both male and female rats with P7 HI injury and offered some protection from gross brain injury ( Figure 1 ) [ 103 , 105 ]. Using a repeated measures ANOVA, cooled HI female and male rats showed improved performance compared to normothermic HI rats on a silent gap rapid auditory processing task (Females: p < 0.05, Males: p < 0.05) [ 104 ].…”