# Postnatal mechanisms of cognitive development in mice

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2022 · $607,523

## Abstract

Abstract
Cognitive deficits are major disabling impairments associated with neurodevelopmental disorders. Currently
available drugs have poor efficacy due to a limited understanding of the genetic and cellular mechanisms
underlying these deficits. Our project addresses this unmet need by exploring the mechanistic underpinnings of
cognitive deficits. Copy number variants (CNVs), such as a 1.5 Mb hemizygous deletion of 22q11.2, and variants
of single genes, such as heterozygous variants of Tbx1, a 22q11.2 gene, have been associated with a high risk
of cognitive deficits in humans and serve as promising mechanistic entry points. As many social, memory, and
cognitive deficits in individuals with these genetic variants manifest during childhood (i.e., a postnatal period after
birth and before full adulthood), our previous work focused on post-embryonic cellular events. We showed that
the heterozygosity of Tbx1 in early postnatal neural stem cells contribute to deficits in social interactions and that
altered postnatal myelination in the fimbria may represent a potential cellular substrate for impaired cognitive
speed. This proposed project will test the overarching hypothesis that alterations in postnatal myelination due to
dose alterations of genes implicated in neurodevelopmental disorders negatively impact cognitive speed. To
allow for the disambiguation of the relative roles of postnatal oligodendrogenesis and postnatal neurogenesis in
cognitive speed, we developed two conditional Tbx1 heterozygous mouse models: Ng2CreER;Tbx1flox/+ and
nesCreERT2;Tbx1flox/+ mice. To evaluate the relative roles played by Tbx1 and 22q11.2 CNV in cognitive speed,
we will include a mouse model of 22q11.2 hemizygous deletion. Aim 1 will evaluate the impacts on cognitive
speed of conditional heterozygous Tbx1 deletion from postnatal stem/progenitor cells of oligodendrocyte or
neuronal lineage in mice and determine the relative contributions to cognitive speed of Tbx1 deficiency
compared with global 22q11.2 hemizygosity. We will use rodent tasks for spatial memory, cognitive flexibility,
and working memory, as the speed of these cognitive dimensions are negatively impacted from childhood
among carriers of 22q11.2 hemizygosity. Aim 2 will identify regions with altered white matter integrity, assess
axonal myelination in affected brain regions, and evaluate the conductance speed of myelin-deficient pathways
using diffusion tensor imaging (DTI)-MRI, electron microscopy, and electrophysiological recordings, respectively,
in the three mouse models. Aim 3 will evaluate the in vivo functional roles of TBX1’s target genes in the
cognitive functions in mutant mice and establish the precise cellular processes associated with postnatal
oligodendrogenesis and myelin production in vivo and in vitro. The current proposal will reveal novel postnatal
cellular mechanisms associated with a distinct dimension of cognitive function, improving our understanding of
the cellular mechanisms con...

## Key facts

- **NIH application ID:** 10539977
- **Project number:** 2R01MH099660-10A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Noboru Hiroi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $607,523
- **Award type:** 2
- **Project period:** 2013-01-18 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10539977

## Citation

> US National Institutes of Health, RePORTER application 10539977, Postnatal mechanisms of cognitive development in mice (2R01MH099660-10A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10539977. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*