Adult Neurogenesis and Executive Function

  • Hiroi, Noboru (PI)

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date1/18/134/30/20

Funding

  • NATIONAL INSTITUTE OF MENTAL HEALTH: $394,050.00
  • NATIONAL INSTITUTE OF MENTAL HEALTH: $208,728.00
  • NATIONAL INSTITUTE OF MENTAL HEALTH: $208,772.00
  • NATIONAL INSTITUTE OF MENTAL HEALTH: $1,951.00
  • NATIONAL INSTITUTE OF MENTAL HEALTH: $415,549.00
  • NATIONAL INSTITUTE OF MENTAL HEALTH: $417,500.00
  • NATIONAL INSTITUTE OF MENTAL HEALTH: $412,140.00

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