# Intraventricular hemorrhage affects production of cortical interneurons

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $365,313

## Abstract

Abstract
Premature infants with intraventricular hemorrhage (IVH) are at high risk of neurobehavioral disorders, including
inattention, hyperactivity, major depressive disorders, and seizures. These disorders can be attributed to the
defective development and function of cortical interneurons. However, the effect of IVH on the generation and
maturation of cortical interneuron is unknown, even though the window of interneuron neurogenesis overlaps
with the period when infants develop IVH (23-28 weeks of gestation). Interneurons are produced in the medial
and caudal ganglionic eminence (MGE and CGE). MGE gives rise to parvalbumin+ (PV) and somatostatin+
(SST) interneurons, whereas CGE produces calretinin+ and NRY+ interneurons. The production of interneurons
in the MGE is regulated by a number of transcription factors, including Nkx2.1, Dlx1/2, Lhx6/8, and Mash1,
which are primarily controlled by Sonic Hedgehog (Shh) signaling pathways. As the post-mitotic interneurons
migrate from MGE to the cortical layers, Sox6 plays critical roles in their specification and maturation into PV+
and SST+ interneurons. This production and maturation of interneurons would be affected by IVH, because it
initiates in the MGE/CGE and induces oxidative cell injury and death. Our preliminary studies in rabbits with
IVH show reduced neurogenesis in the MGE, deficit in PV+ and SST+ interneurons in the upper cortical layers,
and a decline in Shh and Sox6 levels relative to controls. To ameliorate neurogenesis in the MGE and restore
cortical interneuron deficit, our goal is to a) restore Shh > Nkx2.1 > Sox6 signaling and b) reduce oxidative
stress to minimize cell injury and death. Since Nrf2 transcription factor is a master redox switch to turn on
several antioxidant pathways, we will activate Nrf2 to minimize oxidative stress in our animal model of IVH.
Therefore we hypothesize: i) IVH disrupts interneuron neurogenesis and differentiation in the MGE and CGE
resulting in interneuron deficits in the cortical layers of preterm humans & rabbits, and ii) alleviating oxidative
stress (Nrf2 stimulation) or activating interneuron production (lenti-mDlx-Shh) and maturation (lenti-mDlx-Sox6)
will ameliorate PV and SST deficits and neurological function in rabbits with IVH. In Aim #1, we will determine
the effect of IVH on a) apoptosis, proliferation, and density of interneuron progenitors in the MGE (Nkx2.1+,
Dlx1/2+) and CGE (Dlx2+ & Coup-TFII+), b) the density of mature interneurons—PV, SST and others--in the
upper and lower cortical layers, and c) transcriptional changes in the MGE & CGE. Additionally, we will validate
rabbit data in humans by analyzing autopsy materials from preterm infants with and without IVH. In Aim #2 and
# 3, we will assess the effect of alleviating oxidative stress (Ad-Nrf2-GFP or sulforaphane) or activating
production of Shh (lenti-mDlx-Shh-GFP) and Sox6 (lenti-mDlx-Sox6-GFP) specifically in the interneuron
progenitors on a) the density of progenitors in...

## Key facts

- **NIH application ID:** 10355489
- **Project number:** 5R01NS110760-04
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** PRAVEEN BALLABH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $365,313
- **Award type:** 5
- **Project period:** 2019-03-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355489

## Citation

> US National Institutes of Health, RePORTER application 10355489, Intraventricular hemorrhage affects production of cortical interneurons (5R01NS110760-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10355489. Licensed CC0.

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