Developmental learning impairments in a rodent model of nodular heterotopia

Abstract

Developmental malformations of neocortex—including microgyria, ectopias, and periventricular nodular heterotopia (PNH)—have been associated with language learning impairments in humans. Studies also show that developmental language impairments are frequently associated with deficits in processing rapid acoustic stimuli, and rodent models have linked cortical developmental disruption (microgyria, ectopia) with rapid auditory processing deficits. We sought to extend this neurodevelopmental model to evaluate the effects of embryonic (E) day 15 exposure to the anti-mitotic teratogen methylazoxymethanol acetate (MAM) on auditory processing and maze learning in rats. Extensive cortical anomalies were confirmed in MAM-treated rats post mortem. These included evidence of laminar disruption, PNH, and hippocampal dysplasia. Juvenile auditory testing (P21–42) revealed comparable silent gap detection performance for MAM-treated and control subjects, indicating normal hearing and basic auditory temporal processing in MAM subjects. Juvenile testing on a more complex two-tone oddball task, however, revealed a significant impairment in MAM-treated as compared to control subjects. Post hoc analysis also revealed a significant effect of PNH severity for MAM subjects, with more severe disruption associated with greater processing impairments. In adulthood (P60–100), only MAM subjects with the most severe PNH condition showed deficits in oddball two-tone processing as compared to controls. However, when presented with a more complex and novel FM sweep detection task, all MAM subjects showed significant processing deficits as compared to controls. Moreover, post hoc analysis revealed a significant effect of PNH severity on FM sweep processing. Water Maze testing results also showed a significant impairment for spatial but not non-spatial learning in MAM rats as compared to controls. Results lend further support to the notions that: (1) generalized cortical developmental disruption (stemming from injury, genetic or teratogenic insults) leads to auditory processing deficits, which in turn have been suggested to play a causal role in language impairment; (2) severity of cortical disruption is related to the severity of processing impairments; (3) juvenile auditory processing deficits appear to ameliorate with maturation, but can still be elicited in adulthood using increasingly complex acoustic stimuli; and (4) malformations induced with MAM are also associated with generalized spatial learning deficits. These cumulative findings contribute to our understanding of the behavioral consequences of cortical developmental pathology, which may in turn elucidate mechanisms contributing to developmental language learning impairment in humans.

Immuno-modulator inter-alpha inhibitor proteins ameliorate complex auditory processing deficits in rats with neonatal hypoxic-ischemic brain injury

“…Thus, as previously reported, improved behavioral performance in HI injured animals is likely to interact with, the age of assessment, treatment dose, injury and test timing and the cognitive/sensory domain that is examined (Threlkeld, McClure et al 2006, Threlkeld, Hill et al 2012, Threlkeld, Gaudet et al 2014, Gaudet, Lim et al 2016). It is important to emphasize that these interacting factors have been reported in many other rodent models of neurodevelopmental disorders including those with neocortical microgiria, heterotopia and knockdown of candidate genes specific to human learning impairments (Threlkeld, McClure et al 2007, Threlkeld, Hill et al 2009, Threlkeld, Hill et al 2009). These complexities are further supported by the present results showing profound differences in tone-order discrimination for adult rats that were treated with IAIPs as neonates at the time of Hypoxia-ischemia exposure, as compared to untreated subjects.…”

“…We have previously shown that as the demand of a specific task increases, the deficits become more apparent in juvenile and adult rodents exposed to neonatal HI brain injury relative to sham subjects, irrespective of the quantity of HI injury (Threlkeld, Hill et al 2009, Gaudet, Lim et al 2016). Therefore, given the above considerations, the present study sought to determine the efficacy of IAIPs to improve auditory processing using a modified acoustic startle paradigm with increasing levels of cue complexity (i.e., task demand; simple normal single tone detection, gap detection in white noise and complex oddball tone-pair discrimination) in adult rats exposed to neonatal HI.…”

Inhibition of X-Linked Inhibitor of Apoptosis with Embelin Differentially Affects Male versus Female Behavioral Outcome following Neonatal Hypoxia-Ischemia in Rats

“…Deficits in RAP have been suggested to be predictive of such language impairments in these and other populations [14,15,16,17,18]. Tests of RAP have been successfully developed for use in animal models, and such tasks reveal deficits in rodents with induced brain injuries including HI [22,23,24,25,26,37,38], microgyria and/or ectopia [27,28,29,30,31,32,33,34,35], and prenatal teratogenic exposure [36]. However, these models have never shown comparable deficits in female rodents with early injury [30,31,37,38], consistent with clinical data indicating poorer prognosis for male infants suffering HI as compared to matched females.…”

“…In fact, indices of rapid auditory processing (RAP) are consistently impaired in populations with language disability, possibly reflecting anomalies in underlying neural ‘machinery’ critical to language development and processing [[15], [19], [20]; for a review, see [21]]. Importantly, RAP can be measured in animal models, and is consistently impaired in male rodents with induced neonatal brain injuries including perinatal HI [22,23,24,25,26], microgyria and ectopia (small perinatally occurring cortical malformations) [27,28,29,30,31,32,33,34,35], and prenatal teratogenic exposure [36]. Interestingly, female rodents fail to show significant behavioral RAP deficits associated with any comparable perinatal brain injury, including HI [30,31,37,38].…”

A Behavioral Evaluation of Sex Differences in a Mouse Model of Severe Neuronal Migration Disorder

“…For example, rodent studies have examined disruption of normal cortical development through injury (focal freeze lesion; [14]–[17]), embryonic exposure to teratogens [18], and/or genetic factors (either intrinsic or genetically manipulated; [19]–[21]). Results show that differing types of neuropathology can lead to different types of anomalous behavioral outcomes.…”