Infants born very prematurely (<28 weeks gestation) have immature lungs and often require supplemental oxygen. However, long‐term hyperoxia exposure can arrest lung development leading to bronchopulmonary dysplasia (BPD), which increases acute and long‐term respiratory morbidity and mortality. The neural mechanisms controlling breathing are highly plastic during development. Whether the ventilatory control system adapts to pulmonary disease associated with hyperoxia exposure in infancy remains unclear. Here, we tested the hypothesis that there would be age‐dependent adaptations in the control of breathing in an established rat model of hyperoxia‐induced BPD. Hyperoxia exposure (FIO2: 0.9 from 0–10 days of life) led to a BPD‐like lung phenotype, including sustained reductions in alveolar surface area and counts, and modest increases in airway resistance. Hyperoxia exposure also led to chronic increases in room air and acute hypoxic minute ventilation (VE) and age‐dependent changes in breath‐to‐breath tidal volume and breathing frequency variability. Hyperoxia‐exposed rats had normal hypoxic ventilatory responses, oxygen saturation (SpO2) in room air, but greater reductions in SpO2 during acute hypoxia (12% O2) indicating reduced hypoxic sensitivity and/or hypoventilation due to diseased lungs. However, VE was increased indicating an increase in respiratory drive. Perinatal hyperoxia led to greater glial fibrillary acidic protein expression and an increase in neuron counts within 6 of 8 and 1 of 8 key brainstem regions controlling breathing, respectively, suggesting astrocytic expansion. In conclusion, perinatal hyperoxia in rats induced a BPD‐like phenotype and age‐dependent adaptations in VE that may be mediated through changes to the neural architecture of the ventilatory control system. Our results suggest chronically altered ventilatory control in BPD. Support or Funding Information Children's Research Hospital of Wisconsin Research Institute, NIH R01 HL 122358, & Parker B. Francis Foundation This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Coiled-coil forms of Homer1, including Homer1b and c (Homer1b/c) have been shown to play a role in hippocampal learning and memory and synaptic plasticity. We have previously found that overexpression of hippocampal Homer1c is sufficient to rescue learning and memory ability in aged learning impaired rats and in Homer1 knockout (KO) mice, and to rescue group I metabotropic glutamate receptor (mGluR1/5) mediated long-term potentiation in KO mice. Here, to determine if Homer1b/c is necessary for successful learning and memory we have utilized a rAAV5 vector expressing a Homer1b/c-targeting short hairpin RNA to knock down the expression of hippocampal Homer1b/c in adult 4–6-month old male Sprague Dawley rats. We have found that reduced hippocampal Homer1b/c expression elicits significant learning deficits in contextual fear conditioning, but not in the Morris water maze or novel object recognition tasks. Furthermore, we demonstrate that reduced hippocampal Homer1b/c is sufficient to completely block mGluR1/5 mediated long-term depression in the Schaffer collateral pathway. These results support a significant role for Homer1b/c in learning and synaptic plasticity; however, the exact role of each of these two protein isoforms in learning and memory remains elusive.

Infants born prematurely have immature lungs, and the neural mechanisms that control breathing are still developing. Premature infants often require supplemental oxygen therapy (hyperoxia) which acutely improves oxygen saturation but consequently leads to bronchopulmonary dysplasia (BPD; chronic lung disease in infants). Whether hyperoxia‐induced BPD also exacerbates the control of breathing is unknown. Thus, the major objective of this study was to elucidate the short and long‐term effects of hyperoxia‐induced BPD on the control of breathing. Sprague Dawley rat pups were exposed to room air (21% O2/Bal. N2) or hyperoxia (90% O2/Bal. N2) from postnatal day 0–10 (P0–10) and ventilation measured during room air (20 min) and hypoxic (10 min; 12% O2/Bal. N2) conditions at P10, 12, 14, 17, 21, 43, and 60 using plethysmography to test the hypothesis that hyperoxia‐induced BPD would decrease breathing stability and impair development of key brainstem respiratory nuclei. By P20, hyperoxic treated pups had significantly (p<0.05) reduced inspiratory (33%) and expiratory flow rates (24%) compared to control (normoxic‐reared) pups, consistent with BPD and pulmonary histologic data from prior publications. Minute ventilation in hyperoxia‐treated pups was significantly decreased (−20% of control) at P10 but increased thereafter while breathing room air (+50% of control; P12–14), and increased ~25% under hypoxic conditions (P12–14, 60, p<0.05). These changes were initially driven by significant increases in breathing frequency (P12–17; +20–46%) and later by increased tidal volume (P43–60; 50%). Room air and hypoxia breathing frequency variability was significantly lower by 20–35% from P10–21 and elevated by 70% at P60, respectively. Moreover, the cumulative histograms of breathing frequencies binned every 10 breaths/min were significantly different in room air and hypoxia conditions across all ages in hyperoxic pups compared to control pups. Preliminary analyses indicated tidal volume variability across room air and hypoxia is also significantly elevated acutely (P10) by 100% and chronically (P60) by 250% in hyperoxic pups compared to control pups. Additional preliminary data indicate increased expression of an astrocytic marker (GFAP) throughout brainstem respiratory nuclei in P60 rats perinatally treated with hyperoxia, consistent with astrogliosis. These data demonstrate significant and lasting anatomical and physiological changes to the brainstem and the neural control of breathing in a rat model of BPD, suggesting additional potential pathologies in human BPD patients.Support or Funding InformationChildren's Hospital of Wisconsin Research InstituteThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Infants born very prematurely (<28 weeks gestation) have immature lungs and often require supplemental oxygen. However, long‐term hyperoxia exposure can arrest lung development leading to bronchopulmonary dysplasia (BPD), which increases acute and long‐term respiratory morbidity and mortality. The neural mechanisms controlling breathing are highly plastic during development. Whether the ventilatory control system adapts to pulmonary disease associated with hyperoxia exposure in infancy remains unclear. Here, we tested the hypothesis that there would be age‐dependent adaptations in the control of breathing in an established rat model of hyperoxia‐induced BPD. Hyperoxia exposure (FIO2: 0.9 from 0–10 days of life) led to a BPD‐like lung phenotype, including sustained reductions in alveolar surface area and counts, and modest increases in airway resistance. Hyperoxia exposure also led to chronic increases in room air and acute hypoxic minute ventilation (VE) and age‐dependent changes in breath‐to‐breath tidal volume and breathing frequency variability. Hyperoxia‐exposed rats had normal hypoxic ventilatory responses, oxygen saturation (SpO2) in room air, but greater reductions in SpO2 during acute hypoxia (12% O2) indicating reduced hypoxic sensitivity and/or hypoventilation due to diseased lungs. However, VE was increased indicating an increase in respiratory drive. Perinatal hyperoxia led to greater glial fibrillary acidic protein expression and an increase in neuron counts within 6 of 8 and 1 of 8 key brainstem regions controlling breathing, respectively, suggesting astrocytic expansion. In conclusion, perinatal hyperoxia in rats induced a BPD‐like phenotype and age‐dependent adaptations in VE that may be mediated through changes to the neural architecture of the ventilatory control system. Our results suggest chronically altered ventilatory control in BPD.Support or Funding InformationChildren's Research Hospital of Wisconsin Research Institute, NIH R01 HL 122358, & Parker B. Francis FoundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.