# Developmental origins of mental illness: evolution and reversibility

> **NIH NIH P50** · HARVARD UNIVERSITY · 2021 · $1,983,261

## Abstract

Overall abstract
Most mental illnesses emerge during vulnerable windows of brain development to impact cognitive function in
humans. While hundreds of genes and/or environmental factors have been linked to mental illnesses, even
neighboring point mutations on a single gene (eg. Shank3) can lead to `early' disorders such as autism or `late'
schizophrenia. This poses a double challenge to understanding their etiology and potential treatment – how to
track the trajectory of circuit derailment and the relevance of such studies in animals like mice whose cognitive
skills may be less well-characterized. Our proposed Conte Center renewal will tackle these problems directly
by uniting four pioneering neurobiologists focused on the formation and refinement of neuronal circuits in two
stages of development, fetal and pre-adolescent critical periods. Our central hypothesis is that whatever the
predisposing environmental factors or genetic bases, the proximate cause of aberrant behavior in cognitive
disorders will be found in distinct patterns of altered neuronal connectivity. First, to examine how excitatory-
inhibitory balance is established in fetal life, Arlotta combines cutting edge stem cell, genomic, imaging and
physiological recording technology for the longitudinal study of human brain organoids carrying specific gene
mutation. Second, key conceptual insights from Hensch in the first phase of our Center identified the pivotal
role of parvalbumin (PV+) cells in determining postnatal critical period timing. Because of their high metabolic
activity, PV+ cells are vulnerable to oxidative stress in mental illness, as are the gamma oscillations which they
generate (in association with cognition). Manipulations altering PV+ cell maturational profiles powerfully shift
plastic windows in sensory cortex, indicating that malleability of critical periods themselves may contribute to
cognitive disorders as well. Third, Hensch and Feng confirmed an impairment of multisensory integration in the
insular cortex of mice carrying autism risk mutations in Shank3 and Mecp2. Notably, these lie on opposite ends
of PV+ circuit hypo- or hyper-maturation. Here, we will take advantage of reversible and conditional genetic
mutations in these genes to map critical periods for other higher functions of relevance: attention, cognitive
flexibility, and social preference– all established in the Hensch lab. Moreover, for direct comparison to his mice,
Feng will produce marmosets carrying Cre recombinase in PV+ cells or Shank3 deletion using CRISPR
technology. His unique infrastructure will enable manipulation and analysis of the same circuits in this primate
with better evolved frontal cortex and behaviors. Fourth, we capitalize on a sophisticated platform for complete
3D electron microscopic circuit reconstruction established by Lichtman during the first phase of our Center to
compare and contrast the emergence of `connectopathies' from human organoids to mice and marmosets.
Ultima...

## Key facts

- **NIH application ID:** 10145779
- **Project number:** 5P50MH094271-09
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Takao K Hensch
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,983,261
- **Award type:** 5
- **Project period:** 2011-09-05 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145779

## Citation

> US National Institutes of Health, RePORTER application 10145779, Developmental origins of mental illness: evolution and reversibility (5P50MH094271-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145779. Licensed CC0.

---

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