# Adult Neurogenesis and Executive Function

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $385,000

## Abstract

Cognitive deficits are major disabling impairments associated with autism and schizophrenia. Because the
underlying genetic and cellular mechanisms of such deficits are still poorly understood, mechanism-based
therapeutic options do not exist, limiting the effective integration of patients into society. Previous clinical work
has shown that executive functions such as working memory and cognitive flexibility start to lag behind from
adolescence to adulthood in individuals with autism and schizophrenia. However, the precise genetic,
anatomical and cellular substrates through which this occurs are still poorly understood. We have identified
two genes encoded in copy number variants (CNVs) at human chromosome 22q11.2, a high-risk factor for
autism and schizophrenia, for which dose alterations impair the developmental maturation of working memory.
Our published work shows that mice developmentally expand working memory capacity from adolescence to
adulthood and that constitutively elevated activity of catechol-O-methyl-transferase (COMT) impairs the
working memory of mice during adulthood, but not adolescence. During the previous funding period, we have
further found that over-expression of COMT and the transcription factor TBX1, another 22q11.2 gene, in adult
neural progenitor cells of the hippocampus recapitulates this age-dependent deficit in working memory
capacity. The objective of the proposed project is to test our overarching hypothesis that dose alterations of
CNV-encoded genes impair the developmental maturation of executive function through defective adult
neurogenesis in the hippocampus. To test this hypothesis, we developed experimental tools to regulate CNV-
encoded genes in adult neural progenitor cells in the hippocampus at specific developmental time points.
Moreover, we have established a screening system to identify other autism- and schizophrenia-associated
CNV genes whose dose alterations affect adult neurogenesis and executive function. Our experimental
readouts include executive function and adult neurogenesis. Upon completion of the proposed studies, these
technically innovative experiments will, for the first time, establish a common cellular mechanism through which
altered doses of autism- and schizophrenia-associated genes impair the developmental maturation of
executive function. Identification of the developmental time window, neuroanatomical region(s), and cellular
subtypes necessary for maturation of executive function will have a major impact on our understanding of the
developmental mechanisms of executive function and its derailed trajectories. This proposal could lead to a
better understanding of the neurobiological substrates for an important dimensional aspect of developmental
neuropsychiatric disorders.

## Key facts

- **NIH application ID:** 9982429
- **Project number:** 5R01MH099660-09
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Noboru Hiroi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2013-01-18 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982429

## Citation

> US National Institutes of Health, RePORTER application 9982429, Adult Neurogenesis and Executive Function (5R01MH099660-09). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9982429. Licensed CC0.

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