Deficits in Acoustic Startle Reactivity and Auditory Temporal Processing after Traumatic Brain Injury.

Traumatic brain injury (TBI) exacts significant neurological and financial costs on patients and their families. In adult patients with moderate-to-severe TBI, central auditory impairments have been reported. These auditory impairments may interfere with language receptivity, as observed in children with developmental brain injury.

Effects of Juvenile or Adolescent Working Memory Experience and Inter-Alpha Inhibitor Protein Treatment after Neonatal Hypoxia-Ischemia.

Hypoxic-Ischemic (HI) brain injury in the neonate contributes to life-long cognitive impairment. Early diagnosis and therapeutic interventions are critical but limited. We previously reported in a rat model of HI two interventional approaches that improve cognitive and sensory function: administration of Inter-alpha Inhibitor Proteins (IAIPs) and early experience in an eight-arm radial water maze (RWM) task.

Proteoglycan 4 Reduces Neuroinflammation and Protects the Blood-Brain Barrier after Traumatic Brain Injury.

Neuroinflammation and dysfunction of the blood-brain barrier (BBB) are two prominent mechanisms of secondary injury in neurotrauma. It has been suggested that Toll-like receptors (TLRs) play important roles in initiating and propagating neuroinflammation resulting from traumatic brain injury (TBI), but potential beneficial effects of targeting these receptors in TBI have not been broadly studied. Here, we investigated the effect of targeting TLRs with proteoglycan 4 (PRG4) on post-traumatic neuroinflammation and BBB function.

Anti-Cytokine Therapy to Attenuate Ischemic-Reperfusion Associated Brain Injury in the Perinatal Period.

Perinatal brain injury is a major cause of morbidity and long-standing disability in newborns. Hypothermia is the only therapy approved to attenuate brain injury in the newborn. However, this treatment is unfortunately only partially neuroprotective and can only be used to treat hypoxic-ischemic encephalopathy in full term infants.

TrkB-enhancer facilitates functional recovery after traumatic brain injury.

Brain-derived neurotrophic factor (BDNF), a key player in regulating synaptic strength and learning, is dysregulated following traumatic brain injury (TBI), suggesting that stimulation of BDNF signaling pathways may facilitate functional recovery. This study investigates whether CN2097, a peptidomimetic ligand which targets the synaptic scaffold protein, postsynaptic density protein 95, to enhance downstream signaling of tropomyosin-related kinase B, a receptor for BDNF, can improve neurological function after TBI. Moderate to severe TBI elicits neuroinflammation and c-Jun-N-terminal kinase (JNK) activation, which is associated with memory deficits.

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

Hypoxic-ischemic (HI) brain injury is recognized as a significant problem in the perinatal period, contributing to life-long language-learning and other cognitive impairments. Central auditory processing deficits are common in infants with hypoxic-ischemic encephalopathy and have been shown to predict language learning deficits in other at risk infant populations. Inter-alpha inhibitor proteins (IAIPs) are a family of structurally related plasma proteins that modulate the systemic inflammatory response to infection and have been shown to attenuate cell death and improve learning outcomes after neonatal brain injury in rats.

Effects of age, experience and inter-alpha inhibitor proteins on working memory and neuronal plasticity after neonatal hypoxia-ischemia.

Neonatal cerebral hypoxia-ischemia (HI) commonly results in cognitive and sensory impairments. Early behavioral experience has been suggested to improve cognitive and sensory outcomes in children and animal models with perinatal neuropathology. In parallel, we previously showed that treatment with immunomodulator Inter-alpha Inhibitor Proteins (IAIPs) improves cellular and behavioral outcomes in neonatal HI injured rats.

Neutralizing anti-interleukin-1β antibodies modulate fetal blood-brain barrier function after ischemia.

We have previously shown that increases in blood-brain barrier permeability represent an important component of ischemia-reperfusion related brain injury in the fetus. Pro-inflammatory cytokines could contribute to these abnormalities in blood-brain barrier function. We have generated pharmacological quantities of mouse anti-ovine interleukin-1β monoclonal antibody and shown that this antibody has very high sensitivity and specificity for interleukin-1β protein.

Effects of inter-alpha inhibitor proteins on neonatal brain injury: Age, task and treatment dependent neurobehavioral outcomes.

Hypoxic-ischemic (HI) brain injury is frequently associated with premature and/or full term birth related complications. HI injury often results in learning and processing deficits that reflect widespread damage to an extensive range of cortical and sub-cortical brain structures. Further, inflammation has been implicated in the long-term progression and severity of HI injury.

Ontogeny of inter-alpha inhibitor proteins in ovine brain and somatic tissues.

Inter-alpha inhibitor proteins (IAIPs) found in relatively high concentrations in human plasma are important in inflammation. IAIPs attenuate brain damage in young and adult subjects, decrease during sepsis and necrotizing enterocolitis in premature infants, and attenuate sepsis-related inflammation in newborn rats. Although a few studies have reported adult organ-specific IAIP expression, information is not available on age-dependent IAIP expression.

Use of an eight-arm radial water maze to assess working and reference memory following neonatal brain injury.

Working and reference memory are commonly assessed using the land based radial arm maze. However, this paradigm requires pretraining, food deprivation, and may introduce scent cue confounds. The eight-arm radial water maze is designed to evaluate reference and working memory performance simultaneously by requiring subjects to use extra-maze cues to locate escape platforms and remedies the limitations observed in land based radial arm maze designs.

Early neural disruption and auditory processing outcomes in rodent models: implications for developmental language disability.

Most researchers in the field of neural plasticity are familiar with the "Kennard Principle," which purports a positive relationship between age at brain injury and severity of subsequent deficits (plateauing in adulthood). As an example, a child with left hemispherectomy can recover seemingly normal language, while an adult with focal injury to sub-regions of left temporal and/or frontal cortex can suffer dramatic and permanent language loss. Here we present data regarding the impact of early brain injury in rat models as a function of type and timing, measuring long-term behavioral outcomes via auditory discrimination tasks varying in temporal demand.

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.

Effects of test experience and neocortical microgyria on spatial and non-spatial learning in rats.

Neocortical neuronal migration anomalies such as microgyria and heterotopia have been associated with developmental language learning impairments in humans, and rapid auditory processing deficits in rodent models. Similar processing impairments have been suggested to play a causal role in human language impairment. Recent data from our group has shown spatial working memory deficits associated with neocortical microgyria in rats.

Ontogeny and the effects of in utero brain ischemia on interleukin-1β and interleukin-6 protein expression in ovine cerebral cortex and white matter.

Interleukin (IL)-1β and IL-6 have been implicated in brain development, injury progression, and fetal/maternal immune interactions. We examined IL-1β and IL-6 protein expression in cerebral cortex (CC) and white matter (WM) from non-ischemic ovine fetuses at 87-90, 122-127, and 135-137 days of gestation, pregnant ewes at 87-90 and 135-137 days of gestation, and fetuses exposed to 48 or 72h of reperfusion after ischemia. Protein expression was determined by Western immunoblot.

Ovine proinflammatory cytokines cross the murine blood-brain barrier by a common saturable transport mechanism.

Objectives: The cytokines interleukin (IL)-1beta and IL-6 are modulators of the neuroimmune axis and have been implicated in neuronal cell death cascades after ischemia or infection. Previous work has shown that some cross-species conservation exists between human and rodent blood-brain barrier (BBB) transport systems. To further assess cross-species conservation of cytokine transport across the BBB, the current studies investigated permeability and inhibition of ovine IL-1beta and IL-6 in the mouse.

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.

Early acoustic discrimination experience ameliorates auditory processing deficits in male rats with cortical developmental disruption.

Auditory temporal processing deficits have been suggested to play a causal role in language learning impairments, and evidence of cortical developmental anomalies (microgyria (MG), ectopia) has been reported for language-impaired populations. Rodent models have linked these features, by showing deficits in auditory temporal discrimination for rats with neuronal migration anomalies (MG, ectopia). Since evidence from human studies suggests that training with both speech and non-speech acoustic stimuli may improve language performance in developmentally language-disabled populations, we were interested in whether/how maturation and early experience might influence auditory processing deficits seen in male rats with induced focal cortical MG.

Detection of silent gaps in white noise following cortical deactivation in rats.

Rodent studies using cortical removal techniques, ranging from transient deactivation to surgical ablation of cortex, reveal the importance of auditory cortical integrity in detecting short silent gaps in white noise (2-15 ms). Processing limits for longer gaps under decorticate conditions in rats remain unknown. Determining the temporal threshold for subcortical resolution of gaps in noise could, however, shed light on both normal hierarchical processing of acoustic temporal stimuli, as well as the etiology of processing anomalies following developmental cortical disruption.

Use of a modified prepulse inhibition paradigm to assess complex auditory discrimination in rodents.

Prepulse inhibition (PPI; also termed startle reduction or reflex modification, see Ref. [H.S.

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

Background: 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.

Developmental disruptions and behavioral impairments in rats following in utero RNAi of Dyx1c1.

Developmental malformations of cortex have been shown to co-occur with language, learning, and other cognitive deficits in humans. Rodent models have repeatedly shown that animals with such developmental malformations have deficits related to auditory processing and learning. More specifically, freeze-lesion induced microgyria as well as molecular layer ectopias have been found to impair rapid auditory processing ability in rats and mice.

Disruption of neuronal migration by RNAi of Dyx1c1 results in neocortical and hippocampal malformations.

The brains of individuals with developmental dyslexia have neocortical neuronal migration abnormalities including molecular layer heterotopias, laminar dysplasias, and periventricular nodular heterotopias (PNH). RNA interference (RNAi) of Dyx1c1, a candidate dyslexia susceptibility gene, disrupts neuronal migration in developing embryonic neocortex. Using in utero electroporation, we cotransfected cells in the rat neocortical ventricular zone (VZ) at E14/15 with short hairpin RNA vectors targeting Dyx1c1 along with either plasmids encoding enhanced green fluorescent protein or plasmids encoding monomeric red fluorescent protein only.

Auditory processing and learning/memory following erythropoietin administration in neonatally hypoxic-ischemic injured rats.

Background: Hypoxia-ischemia (HI) is a common injury arising from prematurity/complications at birth and is associated with later language, auditory, and learning impairments.

Objective: To investigate the efficacy of two doses (300 or 1000 U/kg) of Erythropoietin (Epo) in protecting against neuropathological and behavioral impairments associated with HI injury in rats.

Methods: HI injury (right carotid artery cauterization and 120 min of 8% O(2)) was induced on postnatal day 7 (P7) and Epo or saline was administered i.

Developmental timeframes for induction of microgyria and rapid auditory processing deficits in the rat.

Induction of a focal freeze lesion to the skullcap of a 1-day-old rat pup leads to the formation of microgyria similar to those identified postmortem in human dyslexics. Rats with microgyria exhibit rapid auditory processing deficits similar to those seen in language-impaired (LI) children, and infants at risk for LI and these effects are particularly marked in juvenile as compared to adult subjects. In the current study, a startle response paradigm was used to investigate gap detection in juvenile and adult rats that received bilateral freezing lesions or sham surgery on postnatal day (P) 1, 3 or 5.