Spatial Working Memory Deficits in Male Rats Following Neonatal Hypoxic Ischemic Brain Injury Can Be Attenuated by Task Modifications

Abstract

Hypoxia-ischemia (HI; reduction in blood/oxygen supply) is common in infants with serious birth complications, such as prolonged labor and cord prolapse, as well as in infants born prematurely (<37 weeks gestational age; GA). Most often, HI can lead to brain injury in the form of cortical and subcortical damage, as well as later cognitive/behavioral deficits. A common domain of impairment is working memory, which can be associated with heightened incidence of developmental disorders. To further characterize these clinical issues, the current investigation describes data from a rodent model of HI induced on postnatal (P)7, an age comparable to a term (GA 36–38) human. Specifically, we sought to assess working memory using an eight-arm radial water maze paradigm. Study 1 used a modified version of the paradigm, which requires a step-wise change in spatial memory via progressively more difficult tasks, as well as multiple daily trials for extra learning opportunity. Results were surprising and revealed a small HI deficit only for the final and most difficult condition, when a delay before test trial was introduced. Study 2 again used the modified radial arm maze, but presented the most difficult condition from the start, and only one daily test trial. Here, results were expected and revealed a robust and consistent HI deficit across all weeks. Combined results indicate that male HI rats can learn a difficult spatial working memory task if it is presented in a graded multi-trial format, but performance is poor and does not appear to remediate if the task is presented with high initial memory demand. Male HI rats in both studies displayed impulsive characteristics throughout testing evidenced as reduced choice latencies despite more errors. This aspect of behavioral results is consistent with impulsiveness as a core symptom of ADHD—a diagnosis common in children with HI insult. Overall findings suggest that task specific behavioral modifications are crucial to accommodating memory deficits in children suffering from cognitive impairments following neonatal HI.

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

“…An in-depth evaluation of analyses on sub-measures of maze performance as a function of Treatment is reported elsewhere ([43], Study 2). In brief, a 6 (Block) x 2 (Treatment) repeated measures ANOVA revealed a significant overall Treatment effect for average errors [F(1,21)=8.028, p<.05], with HI performing worse.…”

“…In brief, a 6 (Block) x 2 (Treatment) repeated measures ANOVA revealed a significant overall Treatment effect for average errors [F(1,21)=8.028, p<.05], with HI performing worse. An additional 6 (Block) x 2 (Treatment) repeated measures ANOVA assessing latency per choice also revealed a significant overall Treatment effect [F(1,21)=7.181, p<.05], indicating that HI animals took less time to make an arm choice compared to shams (see [43] for discussion), a possible reflection of impulsivity.…”

“…We recorded the number of errors for each trial, as well as latency per arm choice. A complete analysis of outcome data from this task is reported elsewhere [43]. Finally, one day a week, rats were tested on Control trials.…”

“…P7 HI male rats show deficits on a rapid auditory processing (RAP) task in both pre-pubertal and adult periods, indicating that deficits persist over time [39-42]. Similarly, deficits on spatial and working memory tasks have been reported in P7 HI rats on a Morris water maze, as well as a more difficult delayed-match-to-place radial maze (used to assess spatial learning and working memory, respectively; [29, 41-43]). The current study sought to explore and replicate well-studied deficits in spatial working memory and RAP in male rats subjected to HI injury on P7.…”

Models of hypoxia and ischemia-induced seizures

“…One feature noted in the clinical data regarding the long-term outcome of neonates suffering HI insult is that males tend to have a worse cognitive outcome than females. Gender-related differences in post-HI cognitive performance have been found in the rat model as well (Smith et al, 2014b).…”