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

ABSTRACT: 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. Here, we expanded these studies to examine the combined effects of IAIPs and multiple weeks of RWM assessment beginning with juvenile or adolescent rats to evaluate optimal age windows for behavioral interventions. Subjects were divided into treatment groups; HI with vehicle, sham surgery with vehicle, and HI with IAIPs, and received either juvenile (P31 initiation) or adolescent (P52 initiation) RWM testing, followed by adult retesting. Error rates on the RWM decreased across weeks for all conditions. Whereas, HI injury impaired global performance as compared to shams. IAIP-treated HI subjects tested as juveniles made fewer errors as compared to their untreated HI counterparts. The juvenile group made significantly fewer errors on moderate demand trials and showed improved retention as compared to the adolescent group during the first week of adult retesting. Together, results support and extend our previous findings that combining behavioral and anti-inflammatory interventions in the presence of HI improves subsequent learning performance. Results further indicate sensitive periods for behavioral interventions to improve cognitive outcomes. Specifically, early life cognitive experience can improve long-term learning performance even in the presence of HI injury. Results from this study provide insight into typical brain development and the impact of developmentally targeted therapeutics and task-specific experience on subsequent cognitive processing.

SUBMITTER: Bradford A

PROVIDER: S-EPMC7765798 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Bradford Aaron A Hernandez Miranda M Kearney Elaine E Theriault Luke L Lim Yow-Pin YP Stonestreet Barbara S BS Threlkeld Steven W SW

Brain sciences 20201217 12

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. Here, we expanded these studies to examine the combined effects of IAIPs and multiple we ...[more]

PMID: 33348631

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Project description:Hippocampal injury following neonatal hypoxia-ischemia (HI) leads to memory impairments despite therapeutic hypothermia (TH). In the hippocampus, the expression of calbindin-1 (Calb1), a Ca2+-buffering protein, increases during postnatal development and decreases with aging and neurodegenerative disorders. Since persistent Ca2+ dysregulation after HI may lead to ongoing injury, persistent changes in hippocampal expression of Calb1 may contribute to memory impairments after neonatal HI. We hypothesized that, despite TH, neonatal HI persistently decreases Calb1 expression in the hippocampus, a change associated with memory deficits in the mouse. We induced cerebral HI in C57BL6 mice at postnatal day 10 (P10) with right carotid ligation and 45 min of hypoxia (FiO2 = 0.08), followed by normothermia (36°C, NT) or TH (31°C) for 4 h with anesthesia-shams as controls. Nissl staining and glial fibrillary acidic protein (GFAP) immunohistochemistry (IHC) were used to grade brain injury and astrogliosis at P11, P18, and P40 prior to the assessment of Calb1 expression by IHC. The subset of mice followed to P40 also performed a memory behavior task (Y-maze) at P22-P26. Nonparametric statistics stratified by sex were applied. In both anterior and posterior coronal brain sections, hippocampal Calb1 expression doubled between P11 and P40 due to an increase in the cornus ammonis (CA) field (Kruskal-Wallis [KW] p < 0.001) and not the dentate gyrus (DG). Neonatal HI produced delayed (P18) and late (P40) deficits in the expression of Calb1 exclusively in the CA field (KW p = 0.02) in posterior brain sections. TH did not attenuate Calb1 deficits after HI. Thirty days after HI injury (at P40), GFAP scores in the hippocampus (p < 0.001, r = -0.47) and CA field (p < 0.001, r = -0.39) of posterior brain sections inversely correlated with their respective Calb1 expression. Both sexes demonstrated deficits in Y-maze testing, including approximately 40% lower spontaneous alterations performance and twice as much total impairment compared to sham mice (KW p < 0.001), but it was only in females that these deficits correlated with the Calb1 expression in the hippocampal CA field (p < 0.05) of the posterior sections. Hippocampal atrophy after neonatal HI also correlated with worse deficits in Y-maze testing, but it did not predict Calb1 deficits. Neonatal HI produces a long-lasting Calb1 deficit in the hippocampal CA field during development, which is not mitigated by TH. Late Calb1 deficit after HI may be the result of persistent astrogliosis and can lead to memory impairment, particularly in female mice.

Project description:Alpha band (8-12 Hz) phase dynamics in the visual cortex are thought to reflect fluctuations in cortical excitability that influences perceptual processing. As such, visual stimuli are better detected when their onset is concurrent with specific phases of the alpha cycle. However, it is unclear whether alpha phase differentially influences cognitive performance at specific times relative to stimulus onset (i.e., is the influence of phase maximal before, at, or after stimulus onset?). To address this, participants performed a delayed-recognition, working memory (WM) task for visual motion direction during two separate visits. The first visit utilized functional magnetic resonance (fMRI) imaging to identify neural regions associated with task performance. Replicating previous studies, fMRI data showed engagement of visual cortical area V5, as well as a prefrontal cortical region, the inferior frontal junction (IFJ). During the second visit, transcranial magnetic stimulation (TMS) was applied separately to both the right IFJ and right V5 (with the vertex as a control region) while electroencephalography (EEG) was simultaneously recorded. During each trial, a single pulse of TMS (spTMS) was applied at one of six time points (-200, -100, -50, 0, 80, 160 ms) relative to the encoded stimulus onset. Results demonstrated a relationship between the phase of the posterior alpha signal prior to stimulus encoding and subsequent response times to the memory probe two seconds later. Specifically, spTMS to V5, and not the IFJ or vertex, yielded faster response times, indicating improved WM performance, when delivered during the peak, compared to the trough, of the alpha cycle, but only when spTMS was applied 100 ms prior to stimulus onset. These faster responses to the probe correlated with decreased early event related potential (ERP) amplitudes (i.e., P1) to the probe stimuli. Moreover, participants that were least affected by spTMS exhibited greater functional connectivity between V5 and fronto-parietal regions. These results suggest that posterior alpha phase indexes a critical time period for motion processing in the context of WM encoding goals, which occurs in anticipation of stimulus onset.

Dataset Information

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

Publications

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

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