Proteomics-Based Identification of Retinal Protein Networks Impacted by Elevated Intraocular Pressure in the Hypertonic Saline Injection Model of Experimental Glaucoma.

Elevated intraocular pressure is considered a major cause of glaucomatous retinal neurodegeneration. To facilitate a better understanding of the underlying molecular processes and mechanisms, we report a study focusing on alterations of the retina proteome by induced ocular hypertension in a rat model of the disease. Glaucomatous processes were modeled through sclerosing the aqueous outflow routes of the eyes by hypertonic saline injections into an episcleral vein. Mass spectrometry-based quantitative retina proteomics using a label-free shotgun methodology identified over 200 proteins significantly affected by ocular hypertension. Various facets of glaucomatous pathophysiology were revealed through the organization of the findings into protein interaction networks and by pathway analyses. Concentrating on retinal neurodegeneration as a characteristic process of the disease, elevated intraocular pressure-induced alterations in the expression of selected proteins were verified by targeted proteomics based on nanoflow liquid chromatography coupled with nano-electrospray ionization tandem mass spectrometry using the parallel reaction monitoring method of data acquisition. Acquired raw data are shared through deposition to the ProteomeXchange Consortium (PXD042729), making a retina proteomics dataset on the selected animal model of glaucoma available for the first time.

Interleukin-15 modulates the response of cortical neurons to ischemia.

OBJECTIVE: Stroke is a major cause of death and disability in the United States. Current acute stroke therapy consists of clot-dissolving drugs, catheter-based interventions and physical rehabilitation. To date, there are no therapies that directly enhance neuronal survival after a stroke. Previous work from our lab demonstrated that Interleukin-15 (IL-15) peptide could rescue cardiomyocytes subjected to hypoxia. We sought to extend these findings to cortical neurons since IL-15 has been implicated to have an important role in neuronal homeostasis. METHODS: We have evaluated the effect of IL-15 peptide on primary cortical neurons derived from embryonic rats in vitro under conditions of anoxia and glucose deprivation, and in vivo following middle cerebral artery occlusion. RESULTS: IL-15 administration rescued neuronal cells subjected to anoxia coupled with glucose deprivation (AGD), as well as with reoxygenation. A hallmark of stroke is the ischemic microenvironment and associated oxidative stress, which results in DNA damage and ER stress, both of which contribute to neuronal cell damage and death. The expression of anoxia, ER stress, and DNA damage factors/markers was evaluated via western blot and correlated with the cellular survival effects of IL-15 in vitro. In addition, IL-15 effect of alleviating ER stress and increasing cell survival was also observed in vivo. INTERPRETATION: Our data indicate, for the first time, that administration of the pleiotropic factor IL-15 reduces neuronal cell death during AGD, which correlates with modulation of multiple cellular stress pathways.

Neuroprotective effects of Sonic hedgehog agonist SAG in a rat model of neonatal stroke.

BACKGROUND: Neonatal stroke affects 1 in 2800 live births and is a major cause of neurological injury. The Sonic hedgehog (Shh) signaling pathway is critical for central nervous system (CNS) development and has neuroprotective and reparative effects in different CNS injury models. Previous studies have demonstrated beneficial effects of small molecule Shh-Smoothened agonist (SAG) against neonatal cerebellar injury and it improves Down syndrome-related brain structural deficits in mice. Here we investigated SAG neuroprotection in rat models of neonatal ischemia-reperfusion (stroke) and adult focal white matter injury. METHODS: We used transient middle cerebral artery occlusion at P10 and ethidium bromide (EB) injection in adult rats to induce damage. Following surgery and SAG or vehicle treatment, we analyzed tissue loss, cell proliferation and fate, and behavioral outcome. RESULTS: We report that a single dose of SAG administered following neonatal stroke preserved brain volume, reduced gliosis, enhanced oligodendrocyte progenitor cell (OPC) and EC proliferation, and resulted in long-term cognitive improvement. Single-dose SAG also promoted proliferation of OPCs following focal demyelination in the adult rat. CONCLUSIONS: These findings indicate benefit of one-time SAG treatment post insult in reducing brain injury and improving behavioral outcome after experimental neonatal stroke. IMPACT: A one-time dose of small molecule Sonic hedgehog agonist protected against neonatal stroke and improved long-term behavioral outcomes in a rat model. This study extends the use of Sonic hedgehog in treating developing brain injury, previously shown in animal models of Down syndrome and cerebellar injury. Sonic hedgehog agonist is one of the most promising therapies in treating neonatal stroke thanks to its safety profile and low dosage.

[ß-Glu2]TRH Is a Functional Antagonist of Thyrotropin-Releasing Hormone (TRH) in the Rodent Brain.

Selective antagonists of thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2), in order to enable a better understanding of this peptide's central functions, have not been identified. Using pGlu-Glu-Pro-NH2 ([Glu2]TRH) as a lead peptide and with modification at its central residue, our studies focused on some of its analogues synthesized as potential functional antagonists of TRH in the rodent brain. Among the peptides studied, the novel isomeric analogue [ß-Glu2]TRH was found to suppress the analeptic and antidepressant-like pharmacological activities of TRH without eliciting intrinsic effects in these paradigms. [ß-Glu2]TRH also completely reversed TRH's stimulation of acetylcholine turnover in the rat hippocampus without a cholinergic activity of its own, which was demonstrated through in vivo microdialysis experiments. Altogether, [ß-Glu2]TRH emerged as the first selective functional antagonist of TRH's prominent cholinergic actions, by which this endogenous peptide elicits a vast array of central effects.

Proteomics Complementation of the Rat Uterotrophic Assay for Estrogenic Endocrine Disruptors: A Roadmap of Advancing High Resolution Mass Spectrometry-Based Shotgun Survey to Targeted Biomarker Quantifications.

The widely used rat uterotrophic assay to assess known and potential estrogenic compounds only considers uterine weight gain as endpoint measurement. To complement this method with an advanced technology that reveals molecular targets, we analyzed changes in protein expression using label-free quantitative proteomics by nanoflow liquid chromatography coupled with high-resolution mass spectrometry and tandem mass spectrometry from uterine protein extracts of ovariectomized rats after daily 17ß-estradiol exposure for five days in comparison with those of vehicle-treated control animals. Our discovery-driven study revealed 165 uterine proteins significantly regulated by estrogen treatment and mapped by pathway analyses. Estrogen-regulated proteins represented cell death, survival and development, cellular growth and proliferation, and protein synthesis as top molecular and cellular functions, and a network found with the presence of nuclear estrogen receptor(s) as a prominent molecular node confirmed the relevance of our findings to hormone-associated events. An exploratory application of targeted proteomics to bisphenol A as a well-known example of an estrogenic endocrine disruptor is also presented. Overall, the results of this study have demonstrated the power of combining untargeted and targeted quantitative proteomic strategies to identify and verify candidate molecular markers for the evaluation of endocrine-disrupting chemicals to complement a conventional bioassay.

Administration of Interleukin-15 Peptide Improves Cardiac Function in a Mouse Model of Myocardial Infarction.

Interleukin-15 is a pleotropic factor, capable of modulating metabolism, survival, proliferation, and differentiation in many different cell types. The rationale behind this study relates to previous work demonstrating that IL-15 is a major factor present in stem cell extracts, which protects cardiomyocytes subjected to hypoxic stress in vitro. The objective of this current study was to assess whether administration of IL-15 peptide will also show protective effects in vivo. The data indicate that administration of IL-15 reduces cell death, increases vascularity, decreases scar size, and significantly improves left ventricular ejection fraction in a mouse model of myocardial infarction.

Spatial patterns of health vulnerability to heatwaves in Vietnam.

The increasing frequency and intensity of heat events have weighty impacts on public health in Vietnam, but their effects vary across regions. In this study, we have applied a vulnerability assessment framework (VAF) to systematically assess the spatial pattern of health vulnerability to heatwaves in Vietnam. The VAF was computed as the function of three dimensions: exposure, sensitivity, and adaptive capacity, with the indicators for each dimension derived from the relevant literature, consultation with experts, and available data. An analytic hierarchy process (AHP) was used to determine the weight of indicators. Each province in Vietnam's vulnerability to the health impacts of heatwaves was evaluated by applying the vulnerability index, computed using 13 indicators (sensitivity index, 9; adaptive capacity index, 3; and exposure index, 1). As a result of this analysis, this study has identified heatwave vulnerability 'hotspots', primarily in the Southeast, Central Highlands, and South Central Coast of Vietnam. However, these hotspots are not necessarily the same as the area most vulnerable to climate change, because some areas that are more sensitive to heatwaves may have a higher capacity to adapt to them due to a host of factors including their population characteristics (e.g. rates of the elderly or children), socio-economic and geographical conditions, and the availability of air-conditioners. This kind of information, provided by the vulnerability index framework, allows policymakers to determine how to more efficiently allocate resources and devise appropriate interventions to minimise the impact of heatwaves with strategies tailored to each region of Vietnam.

Sonic Hedgehog Agonist Protects Against Complex Neonatal Cerebellar Injury.

The cerebellum undergoes rapid growth during the third trimester and is vulnerable to injury and deficient growth in infants born prematurely. Factors associated with preterm cerebellar hypoplasia include chronic lung disease and postnatal glucocorticoid administration. We modeled chronic hypoxemia and glucocorticoid administration in neonatal mice to study whole cerebellar and cell type-specific effects of dual exposure. Chronic neonatal hypoxia resulted in permanent cerebellar hypoplasia. This was compounded by administration of prednisolone as shown by greater volume loss and Purkinje cell death. In the setting of hypoxia and prednisolone, administration of a small molecule Smoothened-Hedgehog agonist (SAG) preserved cerebellar volume and protected against Purkinje cell death. Such protective effects were observed even when SAG was given as a one-time dose after dual insult. To model complex injury and determine cell type-specific roles for the hypoxia inducible factor (HIF) pathway, we performed conditional knockout of von Hippel Lindau (VHL) to hyperactivate HIF1α in cerebellar granule neuron precursors (CGNP) or Purkinje cells. Surprisingly, HIF activation in either cell type resulted in no cerebellar deficit. However, in mice administered prednisolone, HIF overactivation in CGNPs resulted in significant cerebellar hypoplasia, whereas HIF overactivation in Purkinje cells caused cell death. Together, these findings indicate that HIF primes both cell types for injury via glucocorticoids, and that hypoxia/HIF + postnatal glucocorticoid administration act on distinct cellular pathways to cause cerebellar injury. They further suggest that SAG is neuroprotective in the setting of complex neonatal cerebellar injury.

Targeting Alpha Toxin To Mitigate Its Lethal Toxicity in Ferret and Rabbit Models of Staphylococcus aureus Necrotizing Pneumonia.

The role broad-spectrum antibiotics play in the spread of antimicrobial resistance, coupled with their effect on the healthy microbiome, has led to advances in pathogen-specific approaches for the prevention or treatment of serious bacterial infections. One approach in clinical testing is passive immunization with a monoclonal antibody (MAb) targeting alpha toxin for the prevention or treatment of Staphylococcus aureus pneumonia. Passive immunization with the human anti-alpha toxin MAb, MEDI4893*, has been shown to improve disease outcome in murine S. aureus pneumonia models. The species specificity of some S. aureus toxins necessitates testing anti-S. aureus therapeutics in alternate species. We developed a necrotizing pneumonia model in ferrets and utilized an existing rabbit pneumonia model to characterize MEDI4893* protective activity in species other than mice. MEDI4893* prophylaxis reduced disease severity in ferret and rabbit pneumonia models against both community-associated methicillin-resistant S. aureus (MRSA) and hospital-associated MRSA strains. In addition, adjunctive treatment of MEDI4893* with either vancomycin or linezolid provided enhanced protection in rabbits relative to the antibiotics alone. These results confirm that MEDI4893 is a promising candidate for immunotherapy against S. aureus pneumonia.

Arhgap36-dependent activation of Gli transcription factors.

Hedgehog (Hh) pathway activation and Gli-dependent transcription play critical roles in embryonic patterning, tissue homeostasis, and tumorigenesis. By conducting a genome-scale cDNA overexpression screen, we have identified the Rho GAP family member Arhgap36 as a positive regulator of the Hh pathway in vitro and in vivo. Arhgap36 acts in a Smoothened (Smo)-independent manner to inhibit Gli repressor formation and to promote the activation of full-length Gli proteins. Arhgap36 concurrently induces the accumulation of Gli proteins in the primary cilium, and its ability to induce Gli-dependent transcription requires kinesin family member 3a and intraflagellar transport protein 88, proteins that are essential for ciliogenesis. Arhgap36 also functionally and biochemically interacts with Suppressor of Fused. Transcriptional profiling further reveals that Arhgap36 is overexpressed in murine medulloblastomas that acquire resistance to chemical Smo inhibitors and that ARHGAP36 isoforms capable of Gli activation are up-regulated in a subset of human medulloblastomas. Our findings reveal a new mechanism of Gli transcription factor activation and implicate ARHGAP36 dysregulation in the onset and/or progression of GLI-dependent cancers.

Critical Role of Alpha-Toxin and Protective Effects of Its Neutralization by a Human Antibody in Acute Bacterial Skin and Skin Structure Infections.

Methicillin-resistant Staphylococcus aureus (MRSA) causes large-scale epidemics of acute bacterial skin and skin structure infections (ABSSSI) within communities across the United States. Animal models that reproduce ABSSSI as they occur in humans are urgently needed to test new therapeutic strategies. Alpha-toxin plays a critical role in a variety of staphylococcal infection models in mice, but its role in the pathogenesis of ABSSSI remains to be elucidated in rabbits, which are similar to humans in their susceptibility to S. aureus superantigens and certain bicomponent pore-forming leukocidins. We report here a new rabbit model of ABSSSI and show that those infected with a mutant deficient in expression of alpha-toxin (Δhla) developed a small dermonecrotic lesion, whereas those infected with isogenic USA300 MRSA wild-type or complemented Δhla strains developed ABSSSI that mimic the severe infections that occur in humans, including the large central dermonecrotic core surrounded by erythema, induration, and marked subcutaneous hemorrhage. More importantly, immunoprophylaxis with MEDI4893*, an anti-alpha-toxin human monoclonal antibody, significantly reduced the severity of disease caused by a USA300 wild-type strain to that caused by the Δhla mutant, indicating that this toxin could be completely neutralized during infection. Thus, this study illustrates a potential high standard for the development of new immunotherapeutic agents in which a toxin-neutralizing antibody provides protection to the same degree achieved with a toxin gene knockout. When MEDI4893* was administered as adjunctive therapy with a subtherapeutic dose of linezolid, the combination was significantly more efficacious than either agent alone in reducing the severity of ABSSSI.

Technique for office-based, ultrasonography-guided percutaneous biopsy of renal cortical neoplasms using a novel transducer for facilitated ultrasound targeting.

OBJECTIVES: To help clarify which small renal cortical neoplasms (RCNs) require surgery by using office-based, ultrasonography-guided percutaneous renal biopsy. PATIENTS AND METHODS: Biopsies were performed using facilitated ultrasound targeting (FUT) technology, which incorporates a needle guide and onscreen beam-steered technology to permit highly precise needle deployment. Patient and tumour characteristics, procedure time, complications and biopsy efficacy were documented. Wong-Baker pain levels were obtained before, during and 1 h after the procedure. RESULTS: Seven patients underwent biopsy, six for RCNs and one for medical renal disease. The mean (range) patient age was 68.5 (54-79) years, and the mean (range) tumour diameter was 2.55 (2.0-2.9) cm. Mean pain levels before, during and 1 h after the procedure were 0, 1.6 and 0.5, respectively. There were no intra- or post-procedural complications. Biopsy results were diagnostic in five of the six RCN cases and in the single case of medical renal disease. CONCLUSIONS: Our preliminary experience shows that office-based percutaneous renal biopsy using a novel transducer for FUT is safe and effective. An international multicentre study is planned to confirm these preliminary results.

Anti-alpha-toxin monoclonal antibody and antibiotic combination therapy improves disease outcome and accelerates healing in a Staphylococcus aureus dermonecrosis model.

Alpha-toxin (AT) is a major virulence determinant in Staphylococcus aureus skin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), prevents S. aureus disease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893*, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893* postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893* resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment of S. aureus skin and soft tissue infections.

Oligodendrocyte regeneration after neonatal hypoxia requires FoxO1-mediated p27Kip1 expression.

Diffuse white matter injury (DWMI) caused by hypoxia is associated with permanent neurodevelopmental disabilities in preterm infants. The cellular and molecular mechanisms producing DWMI are poorly defined. Using a mouse model of neonatal hypoxia, we demonstrate a biphasic effect on oligodendrocyte development, resulting in hypomyelination. Oligodendrocyte death and oligodendrocyte progenitor cell (OPC) proliferation during the week after hypoxia were followed by delayed oligodendrocyte differentiation and abnormal myelination, as demonstrated by electron microscopy. Cdk2 activation was essential for the regenerative OPC response after hypoxia and was accompanied by reduced FoxO1-dependent p27(Kip1) expression. p27(Kip1) was also reduced in OPCs in human infant white matter lesions after hypoxia. The negative effects of hypoxia on oligodendrogenesis and myelination were more pronounced in p27(Kip1)-null mice; conversely, overexpression of FoxO1 or p27(Kip1) in OPCs after hypoxia promoted oligodendrogenesis. Our studies demonstrate for the first time that neonatal hypoxia affects the Foxo1/p27(Kip1) pathway during white matter development. We also show that molecular manipulation of this pathway enhances oligodendrocyte regeneration during a critical developmental time window after DWMI. Thus, FoxO1 and p27(Kip1) may serve as promising target molecules for promoting timely oligodendrogenesis in neonatal DWMI.

17ß-estradiol eye drops protect the retinal ganglion cell layer and preserve visual function in an in vivo model of glaucoma.

Neuroprotection in glaucoma as a curative strategy complementary to current therapies to lower intraocular pressure (IOP) is highly desirable. This study was designed to investigate neuroprotection by 17ß-estradiol (E2) to prevent retinal ganglion cell (RGC) death in a glaucoma model of surgically elevated IOP in rats. We found that daily treatment with E2-containing eye drops resulted in significant E2 concentration in the retina with concomitant profound neuroprotective therapeutic benefits, even in the presence of continually elevated IOP. The number of apoptotic cells in the RGC layer was significantly decreased in the E2-treated group, when compared to the vehicle-treated controls. Deterioration in visual acuity in these animals was also markedly prevented. Using mass spectrometry-based proteomics, beneficial changes in the expression of several proteins implicated in the maintenance of retinal health were also found in the retina of E2-treated animals. On the other hand, systemic side effects could not be avoided with the eye drops, as confirmed by the measured high circulating estrogen levels and through the assessment of the uterus representing a typical hormone-sensitive peripheral organ. Collectively, the demonstrated significant neuroprotective effect of topical E2 in the selected animal model of glaucoma provides a clear rationale for further studies aiming at targeting E2 into the eye while avoiding systemic E2 exposure to diminish undesirable off-target side effects.

Separation of dansylated 17ß-estradiol, 17α-estradiol, and estrone on a single HPLC column for simultaneous quantitation by LC-MS/MS.

We show here that baseline separation of dansylated estrone, 17ß-estradiol, and 17α-estradiol can be done, contrary to previous reports, within a short run time on a single RP-LC analytical column packed with particles bonded with phenyl-hexyl stationary phase. The chromatographic method coupled with isotope dilution tandem MS offers a simple assay enabling the simultaneous analysis of these analytes. The method employs (13)C-labeled estrogens as internal standards to eliminate potential matrix effects arising from the use of deuterated estrogens. The assay also offers adequate accuracy and sensitivity to be useful for biological samples. The practical applicability of the validated method is demonstrated by the quantitative analyses of in vivo samples obtained from rats treated with Premarin®.

Effect of estradiol replacement on hippocampal concentrations of estrogens in aged rhesus macaques maintained on an obesogenic diet.

Replacement involving estrogens has proven efficacy at treating a wide range of disorders that develop with menopause or after surgical removal of the ovaries. Here, we tested whether an estradiol (E2) replacement paradigm that recapitulates physiological E2 levels in the circulation also recapitulates physiological E2 levels within the hippocampus. E2 was delivered continuously to old ovariectomized (OVX) rhesus macaques, maintained on a high-fat, high-sugar Western-style diet (WSD) for ∼30 months, via subcutaneous implants; this resulted in physiological concentrations of both estrone (E1) and E2 in the circulation (determined by LC-MS/MS). Surprisingly, however, hippocampal concentrations of E2 were markedly (P < 0.01) higher than in ovary-intact animals maintained on a regular chow diet. The data suggest that E2 replacement paradigms that appear to recapitulate physiological E2 concentrations in the circulation may produce hyper-physiological E2 levels within some brain areas, especially when individuals are maintained on a WSD.

The protective effect of green space on heat-related respiratory hospitalization among children under 5 years of age in Hanoi, Vietnam.

Combined effects of global warming and rapid urbanization replace green spaces with urban facilities. Children in urban areas are at a higher risk of heat-related adverse health effects. Our study aimed to examine the protective effect of urban green space on heat-related respiratory hospitalization among children under 5 years of age in Hanoi, the capital city of Vietnam. We estimated district-specific meteorological conditions from 2010 to 2014 by using a dynamic downscaling approach with a fine-resolution numerical climate model. The green space in each district was calculated using satellite data. The attributable fraction of heat-related respiratory hospitalization was estimated using a two-stage model, including a distributed lag non-linear model (DLNM) coupled with multivariate meta-analysis. The association between heat-related respiratory hospitalization and green spaces at the district level was explored using a linear regression model. The central districts were more crowded and hotter, with less green spaces than the outer districts. At temperatures > 34 °C (extreme heat threshold), the hospitalizations in the central districts increased significantly; however, in the outer districts, the hospitalization rate was insignificant. On average, extreme heat attributed 0.33% to citywide hospitalization, 0.35% in the center, and 0.32% in the outer region. Every 1% increase in the green space fraction will reduce heat-related respiratory hospitalization risk by 3.8%. Heat significantly increased the risk of respiratory hospitalization among children under 5 years in Hanoi, Vietnam. These findings are valuable for authorities to consider strategies to protect children's health against the effects of heat, including increasing green space.

Isolated Congenital Mitral Regurgitation Repair in Children: Long-term Outcomes of Artificial Rings.

BACKGROUND: Because isolated congenital mitral regurgitation (ICMR) is rare, the role of artificial rings in annuloplasty for ICMR is still debated. In this study we compared long-term results of annuloplasty with and without rings for ICMR. METHODS: We performed a retrospective review of all patients ≤ 18 years old undergoing repair for ICMR from 1993 to 2019 at our hospital. Techniques of annuloplasty depended on individual lesions of the mitral valve (MV). One hundred twelve cases were divided into 3 groups: group A (43 cases) with ≥26-mm ring, group B (35 cases) with <26-mm ring, and group C (34 cases) with a band. Study endpoints were overall survival and MV reoperation. RESULTS: Patients in group A were older than the others (median age 11 compared with 5 and 4 years, respectively). The MV lesions were complicated, but annular dilatation existed in 91% of cases. Three patients died, and there were 25 reoperations during a median follow-up period of 11 years. Groups B and C had higher rates of reoperation than group A (hazard ratios, 5.35 [95% confidence interval, 1.71-17.75] and 3.61 [95% confidence interval, 1.03-12.60], respectively). Most reoperations in group B (13/14 cases) were due to stenosis, whereas 6 of 7 reoperations in group C were due to recurrent regurgitation. CONCLUSION: MV reconstruction for ICMR in children had good long-term survival. Annuloplasty with ≥26-mm ring had the lowest risk of reoperation. In cases of young children bands are more favored than <26-mm rings, but they carry a risk of recurrent regurgitation.

Neonatal cerebral hypoxia-ischemia impairs plasticity in rat visual cortex.

Ocular dominance plasticity (ODP) following monocular deprivation (MD) is a model of activity-dependent neural plasticity that is restricted to an early critical period regulated by maturation of inhibition. Unique developmental plasticity mechanisms may improve outcomes following early brain injury. Our objective was to determine the effects of neonatal cerebral hypoxia-ischemia (HI) on ODP. The rationale extends from observations that neonatal HI results in death of subplate neurons, a transient population known to influence development of inhibition. In rodents subjected to neonatal HI and controls, maps of visual response were derived from optical imaging during the critical period for ODP and changes in the balance of eye-specific response following MD were measured. In controls, MD results in a shift of the ocular dominance index (ODI) from a baseline of 0.15 to -0.10 (p < 0.001). Neonatal HI with moderate cortical injury impairs this shift, ODI = 0.14 (p < 0.01). Plasticity was intact in animals with mild injury and in those exposed to hypoxia alone. Neonatal HI resulted in decreased parvalbumin expression in hemispheres receiving HI compared with hypoxia alone: 23.4 versus 35.0 cells/high-power field (p = 0.01), with no change in other markers of inhibitory or excitatory neurons. Despite abnormal inhibitory neuron phenotype, spontaneous activity of single units and development of orientation selective responses were intact following neonatal HI, while overall visual responses were reduced. Our data suggest that specific plasticity mechanisms are impaired following early brain injury and that the impairment is associated with altered inhibitory neuronal development and cortical activation.