Sex Differences in Mechanisms and Outcome of Neonatal Hypoxia-Ischemia in Rodent Models: Implications for Sex-Specific Neuroprotection in Clinical Neonatal Practice

Clinical findings show that male infants with hypoxic-ischemic injury (HI) fare more poorly than matched females on cognitive outcomes. Rodent models of neonatal hypoxia-ischemia support this difference, with data showing that perinatal brain injury leads to long-term behavioral deficits primarily in male rodents and in female rodents treated with early androgens. Results support the idea that sex-specific gonadal hormones may modulate developmental response to injury and dovetail with overwhelming evidence of developmental androgen effects on typical brain morphology and behavior. However, mechanisms underlying sex differences in response to early brain injury may be more complicated. Specifically, activation of cell death pathways in response to HI may also differ by sex. In females, the preferential activation of the caspase-dependent apoptotic pathway may actually afford greater protection, potentially due to the actions of X-linked inhibitor of apoptosis (XIAP) within this pathway. This contrasts the pattern of preferential activation of the caspase-independent pathway in males. While an integrated model of sex-specific hormonal and genetic modulation of response to early injury remains to be fully elucidated, these findings suggest that infants might benefit from sex-specific neuroprotection following HI injury

Peripheral anomalies in USH2A cause central auditory anomalies in a mouse model of Usher syndrome and CAPD

Central auditory processing disorder (CAPD) is associated with difficulties hearing and processing acoustic information, as well as subsequent impacts on the development of higher-order cognitive processes (i.e., attention and language). Yet CAPD also lacks clear and consistent diagnostic criteria, with widespread clinical disagreement on this matter. As such, identification of biological markers for CAPD would be useful. A recent genome association study identified a potential CAPD risk gene, USH2A. In a homozygous state, this gene is associated with Usher syndrome type 2 (USH2), a recessive disorder resulting in bilateral, high-frequency hearing loss due to atypical cochlear hair cell development. However, children with heterozygous USH2A mutations have also been found to show unexpected low-frequency hearing loss and reduced early vocabulary, contradicting assumptions that the heterozygous (carrier) state is “phenotype free”. Parallel evidence has confirmed that heterozygous Ush2a mutations in a transgenic mouse model also cause low-frequency hearing loss (Perrino et al., 2020). Importantly, these auditory processing anomalies were still evident after covariance for hearing loss, suggesting a CAPD profile. Since usherin anomalies occur in the peripheral cochlea and not central auditory structures, these findings point to upstream developmental feedback effects of peripheral sensory loss on high-level processing characteristic of CAPD. In this study, we aimed to expand upon the mouse behavioral battery used in Perrino et al. (2020) by evaluating central auditory brain structures, including the superior olivary complex (SOC) and medial geniculate nucleus (MGN), in heterozygous and homozygous Ush2a mice. We found that heterozygous Ush2a mice had significantly larger SOC volumes while homozygous Ush2a had significantly smaller SOC volumes. Heterozygous mutations did not affect the MGN; however, homozygous Ush2a mutations resulted in a significant shift towards more smaller neurons. These findings suggest that alterations in cochlear development due to USH2A variation can secondarily impact the development of brain regions important for auditory processing ability

Age at developmental cortical injury differentially Alters corpus callosum volume in the rat

<p>Abstract</p> <p>Background</p> <p>Freezing lesions to developing rat cortex induced between postnatal day (P) one and three (P1 – 3) lead to malformations similar to human microgyria, and further correspond to reductions in brain weight and cortical volume. In contrast, comparable lesions on P5 do not produce microgyric malformations, nor the changes in brain weight seen with microgyria. However, injury occurring at all three ages does lead to rapid auditory processing deficits as measured in the juvenile period. Interestingly, these deficits persist into adulthood only in the P1 lesion case <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. Given prior evidence that early focal cortical lesions induce abnormalities in cortical morphology and connectivity <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B2">2</abbr><abbr bid="B3">3</abbr><abbr bid="B4">4</abbr></abbrgrp>, we hypothesized that the differential behavioral effects of focal cortical lesions on P1, P3 or P5 may be associated with underlying neuroanatomical changes that are sensitive to timing of injury. Clinical studies indicate that humans with perinatal brain injury often show regional reductions in corpus callosum size and abnormal symmetry, which frequently correspond to learning impairments <abbrgrp><abbr bid="B5">5</abbr><abbr bid="B6">6</abbr><abbr bid="B7">7</abbr></abbrgrp>. Therefore, in the current study the brains of P1, 3 or 5 lesion rats, previously evaluated for brain weight, and cortical volume changes and auditory processing impairments (P21-90), were further analyzed for changes in corpus callosum volume.</p> <p>Results</p> <p>Results showed a significant main effect of Treatment on corpus callosum volume [F (1,57) = 10.2, P < .01], with lesion subjects showing significantly smaller callosal volumes as compared to shams. An Age at Treatment × Treatment interaction [F(2,57) = 3.2, P < .05], indicated that corpus callosum size decreased as the age of injury decreased from P5 to P1. Simple effects analysis showed significant differences between P1 and P3 [F(1,28) = 8.7, P < .01], and P1 and P5 [F(1,28) = 15.1, P < .001], subjects. Rats with P1 injury resulting in microgyria had the greatest reduction in corpus callosum volume (22% reduction), followed by the P3 group (11% reduction), which showed a significant reduction in corpus callosum volume compared to shams [F(1,31) = 5.9, P < .05]. Finally, the P5 lesion group did not significantly differ from the sham subjects in callosal volume.</p> <p>Conclusion</p> <p>Decrements in corpus callosum volume in the P1 and 3 lesion groups are consistent with the reductions in brain weight and cortical volume previously reported for microgyric rats <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B8">8</abbr></abbrgrp>. Current results suggest that disruption to the cortical plate during early postnatal development may lead to more widely dispersed neurovolumetric anomalies and subsequent behavioral impairments <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>, compared with injury that occurs later in development. Further, these results suggest that in a human clinical setting decreased corpus callosum volume may represent an additional marker for long-term behavioral outcome.</p

Brain weight differences associated with induced focal microgyria

BACKGROUND: Disrupting neural migration with bilateral focal freezing necrosis on postnatal day 1 (P1) results in the formation of 4-layered microgyria. This developmental injury triggers a pervasive neural reorganization, which is evident at the electrophysiological, behavioral, and anatomical levels. In this experiment, we investigated changes in brain weight as an index of global disruption of neural systems caused by focal damage to the developing cortical plate. RESULTS: We found a dramatic reduction in overall brain weight in microgyric subjects. This reduction in brain weight among animals with microgyria is reflected in decreased total brain volume, with a disproportionate decrease in neocortical volume. This effect is so robust that it is seen across varied environments, at variable ages, and across the sexes. CONCLUSIONS: This finding supports previous work suggesting that substantial reorganization of the brain is triggered by the induction of bilateral freezing damage. These results have critical implications for the profound re-organizational effects of relatively small focal injuries early in development to distributed systems throughout the brain, and particularly in the cerebral cortex

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

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24&nbsp;months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500&nbsp;steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30&nbsp;minutes spent performing activities ≥500&nbsp;counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24&nbsp;months), both the number of steps per day (per 500&nbsp;steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500&nbsp;counts per minute (per 30&nbsp;minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score &gt;10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead