Deficits in Auditory, Cognitive, and Motor Processing Following Reversible MCAO in Mice: Understanding the Human Stroke Phenotype

Stoke is characterized by a loss or alteration in neurological and/or bodily function resulting from a cerebral vascular accident (interruption of blood flow to the brain). Acute ischemic stroke is the third leading cause of death in the United States, and the leading cause of long-term functional disability in adults. Stroke-induced deficits may include various forms of aphasia (language loss), cognitive deficits (including attentional and memory impairments), and motor impairments. Through the use of animal models, researchers can experimentally induce “stroke-like” injuries comparable to those seen in clinical populations. Such models allow us to study and understand the neurophysiological, anatomical, and neurobehavioral consequences associated with ischemic insults to the brain. Middle cerebral artery occlusion (MCAO) can be induced in rodents, and is a widely used experimental technique to model focal ischemia in rodents. Various neurobehavioral tasks have been developed to assess the motor and cognitive dysfunctions associated with MCAO in rodents, and these studies have shown deficits related to impaired long-term sensorimotor function, as well as retention of spatial memory. The current study was designed to develop a more comprehensive neurobehavioral profile associated with experimental focal cerebral ischemia induced by transient MCAO in adult C57Bl/6 mice. Using a modified pre-pulse inhibition auditory discrimination paradigm, and other tasks thought to tap language-related processing, mice subjected to 60 minute MCAO or Sham injury were assessed. These tasks were selected based on evidence that rapid auditory processing (RAP) skills are associated with language processing indices in clinical populations, as well as infant research showing that early RAP scores are predictive of language development. Importantly, deficits in the encoding of temporal sound features have also been associated with deficits in speech perception in elderly listeners and aphasics. In addition, cognitive and sensorimotor ability was also evaluated using the Morris water maze, non-spatial water maze, and rotarod task. Combined behavioral results from post-MCAO mice provide evidence of a RAP deficit (suggesting “aphasia-like” deficits), and deficits in learning and memory, as well as sensorimotor function. Overall results support the ongoing use of MCAO mice as a valid model to study ischemic stroke in humans, and further suggest that language-related tasks can be used to model “aphasia-like” deficits in rodents

Developmental learning impairments in a rodent model of nodular heterotopia

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

Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities

Peer reviewe

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 x 10(-8)) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.Peer reviewe

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80%, depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures: word reading, nonword reading, spelling, phoneme awareness, and nonword repetition, in samples of 13,633 to 33,959 participants aged 5-26 years. We identified genome-wide significant association with word reading (rs11208009, p=1.098 x 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP-heritability, accounting for 13-26% of trait variability. Genomic structural equation modelling revealed a shared genetic factor explaining most variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis of multivariate GWAS results with neuroimaging traits identified association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain, and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide new avenues for deciphering the biological underpinnings of uniquely human traits

Mouse Models of Neuroanatomical, Behavioral, and Genetic Correlates of Language-related Impairments: an Investigation of Core Phenotypes.

The development of the brain is an immensely complicated process that is highly regulated by numerous genetic pathways. Disruption within any stage of this operation—from proliferation, to neuronal migration, to synaptogenesis—could ultimately lead to deleterious behavioral outcomes, ranging from severe intellectual disability and gross motor developmental delays to more subtle cognitive impairments such as language disability. It is therefore no surprise that neuroanatomical anomalies resulting from of altered cortical development are associated with a number of language related neurodevelopmental disorders such as specific language impairment (SLI), dyslexia, and autism spectrum disorders (ASD). Over the past decade, genetic association studies have identified numerous genetic variants that are more commonly observed in language and reading impaired populations. However, these studies cannot ascertain whether these genes are central to the etiology of the disorder (since association but not causatlity is repoterd). As another approach, rodent models have provided an invaluable tool to elucidate functional gene-brain-behavior relationships that are nearly impossible to examine clinically. Indeed, rodent models in the past have been successful in linking clinically relevant neuropathological changes associated with language disability to poor behavioral outcomes in the domains of auditory processing and cognitive performance on water maze tasks—behaviors that have been shown to be deficient in language and reading impaired populations. Given the pressing need to understand how genetics underlie the development of language dysfunction, the series of studies presented in this thesis was designed to examine and characterize neurobehavioral, neuroanatomic, and genetic profiles of language and reading related disorders in rodents, specifically using recombinant inbred and transgenic strains of mice. In these experiments, we defined relationships between: 1) key behavioral phenotypes associated with language dysfunction and social communication/interaction; 2) disruption of neuronal migration; 3) changes in subcortical anatomy along the central auditory pathway; and 4) sex differences across these factors. From these relationships, our goal was to identify how promising risk genes identified from clinical populations (e.g., DCDC2 (dyslexia) and CNTNAP2 (SLI and ASD)) as well as associated neuroanatomical anomalies of neuronal migration, may collectively mediate the constellation of language-related and cognitive dysfunctions observed in relevant clinical populations

Behavioral Implications of Knockout for the Dyslexia-Risk Gene Dcdc2 in Mice

Several genetic linkage and epidemiological studies have provided strong evidence that DCDC2 is a candidate gene for developmental dyslexia, a disorder that impairs a person’s reading ability despite adequate intelligence, education, and socio-economic status. Studies investigating embryonic intra-ventricular RNA interference (RNAi) of Dcdc2, a rat homolog of the DCDC2 gene in humans, indicate disruptions in neuronal migration in the rat cortex during development. Interestingly, these anatomical anomalies are consistent with post mortem histological analysis of human dyslexic patients. Other rodent models of cortical developmental disruption have shown impairment in rapid auditory processing and learning maze tasks in affected subjects. The current study investigates the rapid auditory processing abilities of mice heterozygous for Dcdc2 (one functioning Dcdc2 allele) and mice with a homozygous knockout of Dcdc2 (no functioning Dcdc2 allele). It is important to note that this genetic model for behavioral assessment is still in the pilot stage. However, preliminary results suggest that mice with a genetic mutation of Dcdc2 have impaired rapid auditory processing, as well as non-spatial maze learning and memory ability, as compared to wildtypes. By genetically knocking out Dcdc2 in mice, behavioral features associated with Dcdc2 can be characterized, along with other neurological abnormalities that may arise due to the loss of the functioning gene