Allostatic Load and Biomarkers of Stress in the Preterm Infant: An Integrative Review.

BACKGROUND: Every year, an estimated 15 million babies are born preterm (<37 weeks' gestational age) globally. These preterm infants are exposed to repeated stressful and often painful procedures as part of routine life-saving care within the neonatal intensive care unit (NICU). Low thresholds for tactile and nociceptive input make it more difficult for neonates to discriminate between noxious and nonnoxious stimuli, which can result in continuous activation of stress responses in an attempt to achieve stability through adaptation, or allostasis. Rapidly reoccurring stressors can render stress-response systems over- or underactive, creating wear and tear, or allostatic load. A better understanding of biomarkers related to allostatic load might aid in early detection and prevention/alleviation of allostatic load in this population. PURPOSE: To identify stress biomarkers that have been studied in preterm infants at different time points in the NICU and as long-term outcome measures. METHOD/SEARCH STRATEGY: Systematic searches were conducted of PubMed, CINAHL, SCOPUS, and PsychInfo databases. FINDINGS/RESULTS: Twenty-one studies met inclusion criteria for this review. Several putative biomarkers were identified, including cortisol levels, epigenetic markers, brain microstructure, markers of oxidative stress, and the brain-gut-microbiome axis. CONCLUSION: The interaction of disease with therapeutic interventions may inadvertently increase infant allostatic load. In addition to human studies, future research should leverage newly available large data sets to conduct additional analyses.

A behavioral evaluation of sex differences in a mouse model of severe neuronal migration disorder.

Disruption of neuronal migration in humans is associated with a wide range of behavioral and cognitive outcomes including severe intellectual disability, language impairment, and social dysfunction. Furthermore, malformations of cortical development have been observed in a number of neurodevelopmental disorders (e.g. autism and dyslexia), where boys are much more commonly diagnosed than girls (estimates around 4 to 1). The use of rodent models provides an excellent means to examine how sex may modulate behavioral outcomes in the presence of comparable abnormal neuroanatomical presentations. Initially characterized by Rosen et al. 2012, the BXD29- Tlr4(lps-2J) /J mouse mutant exhibits a highly penetrant neuroanatomical phenotype that consists of bilateral midline subcortical nodular heterotopia with partial callosal agenesis. In the current study, we confirm our initial findings of a severe impairment in rapid auditory processing in affected male mice. We also report that BXD29- Tlr4(lps-2J) /J (mutant) female mice show no sparing of rapid auditory processing, and in fact show deficits similar to mutant males. Interestingly, female BXD29- Tlr4(lps-2J) /J mice do display superiority in Morris water maze performance as compared to wild type females, an affect not seen in mutant males. Finally, we report new evidence that BXD29- Tlr4(lps-2J) /J mice, in general, show evidence of hyper-social behaviors. In closing, the use of the BXD29- Tlr4(lps-2J) /J strain of mice - with its strong behavioral and neuroanatomical phenotype - may be highly useful in characterizing sex independent versus dependent mechanisms that interact with neural reorganization, as well as clinically relevant abnormal behavior resulting from aberrant neuronal migration.

Knockdown of the candidate dyslexia susceptibility gene homolog dyx1c1 in rodents: effects on auditory processing, visual attention, and cortical and thalamic anatomy.

The current study investigated the behavioral and neuroanatomical effects of embryonic knockdown of the candidate dyslexia susceptibility gene (CDSG) homolog Dyx1c1 through RNA interference (RNAi) in rats. Specifically, we examined long-term effects on visual attention abilities in male rats, in addition to assessing rapid and complex auditory processing abilities in male and, for the first time, female rats. Our results replicated prior evidence of complex acoustic processing deficits in Dyx1c1 male rats and revealed new evidence of comparable deficits in Dyx1c1 female rats. Moreover, we found new evidence that knocking down Dyx1c1 produced orthogonal impairments in visual attention in the male subgroup. Stereological analyses of male brains from prior RNAi studies revealed that, despite consistent visible evidence of disruptions of neuronal migration (i.e., heterotopia), knockdown of Dyx1c1 did not significantly alter the cortical volume, hippocampal volume, or midsagittal area of the corpus callosum (measured in a separate cohort of like-treated Dyx1c1 male rats). Dyx1c1 transfection did, however, lead to significant changes in medial geniculate nucleus (MGN) anatomy, with a significant shift to smaller MGN neurons in Dyx1c1-transfected animals. Combined results provide important information about the impact of Dyx1c1 on behavioral functions that parallel domains known to be affected in language-impaired populations as well as information about widespread changes to the brain following early disruption of this CDSG.

The effects of Kiaa0319 knockdown on cortical and subcortical anatomy in male rats.

Developmental dyslexia is a disorder characterized by a specific deficit in reading despite adequate overall intelligence and educational resources. The neurological substrate underlying these significant behavioral impairments is not known. Studies of post mortem brain tissue from male and female dyslexic individuals revealed focal disruptions of neuronal migration concentrated in the left hemisphere, along with aberrant symmetry of the right and left the planum temporale, and changes in cell size distribution within the medial geniculate nucleus of the thalamus (Galaburda et al., 1985; Humphreys et al., 1990). More recent neuroimaging studies have identified several changes in the brains of dyslexic individuals, including regional changes in gray matter, changes in white matter, and changes in patterns of functional activation. In a further effort to elucidate the etiology of dyslexia, epidemiological and genetic studies have identified several candidate dyslexia susceptibility genes. Some recent work has investigated associations between some of these genetic variants and structural changes in the brain. Variants of one candidate dyslexia susceptibility gene, KIAA0319, have been linked to morphological changes in the cerebellum and functional activational changes in the superior temporal sulcus (Jamadar et al., 2011; Pinel et al., 2012). Animal models have been used to create a knockdown of Kiaa0319 (the rodent homolog of the human gene) via in utero RNA interference in order to study the gene's effects on brain development and behavior. Studies using this animal model have demonstrated that knocking down the gene leads to focal disruptions of neuronal migration in the form of ectopias and heterotopias, similar to those observed in the brains of human dyslexics. However, further changes to the structure of the brain have not been studied following this genetic disruption. The current study sought to determine the effects of embryonic Kiaa0319 knockdown on volume of the cortex and hippocampus, as well as midsagittal area of the corpus callosum in male rats. Results demonstrate that Kiaa0319 knockdown did not change the volume of the cortex or hippocampus, but did result in a significant reduction in the midsagittal area of the corpus callosum. Taken in the context of previous reports of behavioral deficits following Kiaa0319 knockdown (Szalkowski et al., 2012), and reports that reductions of corpus callosum size are related to processing deficits in humans (Paul, 2011), these results suggest that Kiaa0319 has a specific involvement in neural systems important for temporal processing.

Deficits in auditory, cognitive, and motor processing following reversible middle cerebral artery occlusion in mice.

Middle cerebral artery occlusion(1) (MCAO) is a widely used experimental technique in rodents to model both the short-term pathological events and longer term neuroanatomical and functional damage associated with focal ischemia. Various neurobehavioral tasks have been developed to assess the motor and cognitive dysfunctions associated with MCAO in rodents, and these studies have revealed deficits related to long-term sensorimotor function, as well as retention of spatial memory. Assessment of auditory processing in a MCAO model has not been undertaken, despite findings suggesting an auditory processing deficit in humans with stroke induced-aphasia, a common post-stroke deficit. Using a modified pre-pulse inhibition paradigm, and other behavioral tasks thought to tap "language-related processing", adult male C57Bl/6 mice were subjected to 60 minute MCAO or Sham surgery and were behaviorally assessed from P58 to P124 (2 to 65 days post-surgery). Tasks were selected based on evidence that rapid auditory processing(2) (RAP) skills are associated with language processing indices in clinical populations. Cognitive and sensorimotor ability was evaluated using the Morris water maze, non-spatial water maze, and a post-injury rotarod task administered over multiple days (motor learning). Combined behavioral results from post-MCAO mice provide evidence of a RAP deficit as well as deficits in spatial, non-spatial, and motor learning. Overall results support a fuller characterization of behavioral deficits in auditory processing after MCAO.