# Neurodevelopmental defects of the thalamocortical pathway as a convergent feature of psychiatric disorders

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $756,868

## Abstract

PROJECT SUMMARY
Brain function emerges from the activity of hundreds of neuronal types embedded within a complex network of
neural circuits. Although the formation of neural circuits is guided by the emergent activity, many of the initial
‘wiring instructions’ are genetically encoded. Mutations in genes associated with neurodevelopmental
psychiatric disorders may disrupt the early stages of cell type and circuit development, leading to long-lasting
deficits in function. Our overarching goal is to identify the molecular and cellular mechanisms that govern
neuronal cell type specification and their early connectivity preferences. Disease associated mutations serve
as a discovery platform of molecular mechanisms that likely disrupt connectivity. In this project, we focus on
the development of the human thalamus and early stages of thalamocortical pathway formation. Given the
central role of the thalamocortical pathway in sensory, motor, and cognitive tasks, understanding its
development in the human brain would be fundamental to studies modeling the consequences of mutations
associated with multiple neuropsychiatric symptoms. Remarkable differences between mouse and human
development of the thalamocortical pathway pose a scientific challenge for studying the impact of genetic
variants on human thalamocortical pathway development, especially during its early formation. Innovations of
in vitro differentiation protocols for induced pluripotent stem cells have recently enabled studies of early
formation of the human thalamocortical pathway using organoids. As an exemplar, we propose to investigate
thalamocortical and corticothalamic axon outgrowth in organoids derived from patients with 22q11.2
microdeletion syndrome, which is associated with schizophrenia, autism, movement disorders, developmental
delays, and epilepsies. Neuroimaging studies in 22Q11 Deletion Syndrome (22Q11DS) patients have identified
differences in functional thalamocortical connectivity between patients and healthy control, establishing a
scientific premise for examining thalamocortical pathway development in cells with 22q11.2 microdeletion.
Investigations of neurodevelopmental defects using stem cell models will be complemented by a parallel effort
using a mouse model of human 22q11.2 microdeletion. We will identify molecular changes in cell fate
specification of thalamic neurons, and compare axonal outgrowth phenotypes in control and cells with the
22q11.2 microdeletion. Our preliminary data implicate FOXP2 transcription factor activity in mediating
thalamocortical pathway growth phenotypes in 22q11.2 DS thalamic neurons. The proposed project will
establish groundwork for studying the growing list of rare genetic mutations with high effect size discovered
through large scale studies of Autism, ADHD, and schizophrenia patients for their role in brain development,
focusing on the development of the thalamocortical pathway.

## Key facts

- **NIH application ID:** 10833190
- **Project number:** 5R01MH128364-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Tomasz Nowakowski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $756,868
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833190

## Citation

> US National Institutes of Health, RePORTER application 10833190, Neurodevelopmental defects of the thalamocortical pathway as a convergent feature of psychiatric disorders (5R01MH128364-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10833190. Licensed CC0.

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