# Mechanisms of hypoxia-mediated memory impairment in an animal model of acute respiratory failure in preterm survivors

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $472,616

## Abstract

Summary
Due to advances in neonatal care, most preterm infants no longer develop cerebral palsy from hypoxic-ischemic
white matter injury (WMI). However, up to 50% develop gray matter associated cognitive and learning
disabilities by school age that persist throughout life. These developmental disabilities are commonly associated
with a systemic hypoxia (Hx) episode arising from lung immaturity, acute respiratory failure or other common
complications of prematurity. We have developed a preterm-equivalent mouse model which delivers a single
mild clinically relevant episode of Hx at P2. Our preliminary findings support that Hx impairs learning and memory
by disrupting hippocampal: (1) neuronal structural complexity; (2) gene expression; (3) synaptic plasticity/intrinsic
excitability; and (4) fear-conditioning responses in juvenile mice exposed to Hx. We hypothesize that neonatal
Hx is sufficient to persistently disrupt neuronal maturation without causing significant neuronal loss or white
matter injury (WMI). In aim 1, we will determine if Hx disrupts hippocampal maturation independent of acute or
delayed cerebral inflammation, neuronal degeneration or WMI. We will determine how Hx disrupts CA1 neuronal
dendritic arbor maturation and spine density using innovative super-resolution light microscopy integrated with
analysis of synaptic transmission, long-term potentiation (LTP) and intrinsic excitability. We will determine if these
changes occur independently of hippocampal neuronal or glial cell death. Since WMI is common in preterm
infants, we will determine if CA1 neuronal dysmaturation occurs independently of WMI. Aim 2 will build upon
preliminary data showing that Hx causes persistent gene transcriptional changes in mouse hippocampus at P16
and P30. The hippocampal response to Hx involved regulators of excitatory and inhibitory synaptic transmission,
synaptic plasticity and epigenetic regulators, all integral to learning and memory. To define novel molecular
mechanisms of hippocampal dysmaturation, we will take an unbiased approach using single nucleus RNAseq to
determine cell type-specific early and late gene expression changes arising from Hx at P2. In aim 3, we
hypothesize that disturbances in synaptic transmission at CA3-CA1 synapses disrupt hippocampus-dependent
memory mechanisms in young adult mice exposed to Hx as neonates at P2. We will determine the effects of Hx
on excitatory and inhibitory synaptic activity and on the subunit composition of glutamate receptors that regulate
learning and memory in neonates. We have identified that Hx disrupts the action of several key modulators of
excitatory synaptic activity. We will focus on the synaptic potassium channel SK2, which acts as a negative
feedback regulator to limit synaptic depolarization by NMDAR and AMPAR. To further define a mechanistic role
for glutamatergic synaptic activity in disrupted LTP, we will determine if an allosteric AMPA receptor agonist
(ampakine) delivered in vivo wil...

## Key facts

- **NIH application ID:** 10939062
- **Project number:** 1R01NS138147-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Stephen Arthur Back
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $472,616
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10939062

## Citation

> US National Institutes of Health, RePORTER application 10939062, Mechanisms of hypoxia-mediated memory impairment in an animal model of acute respiratory failure in preterm survivors (1R01NS138147-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10939062. Licensed CC0.

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