# Project 2

> **NIH NIH P50** · HARVARD UNIVERSITY · 2022 · $485,725

## Abstract

ABSTRACT (Lichtman)
It is likely that abnormalities in the number or pattern of synaptic connections (“connectopathies”) underlie
neurodevelopmental and psychiatric disorders such as autism spectrum disorder and schizophrenia. But
finding pathological structural motifs in brain circuitry may require sufficient resolution to analyze each synapse
and identify the networks linking thousands of pre- and postsynaptic neurons together. Such high resolution
volumetric structural analysis can be achieved with serial section electron microscopy, however this process
has been extremely slow and labor intensive preventing the comparison of samples and analysis of volumes
containing multiple neurons. To solve these problems we have devised a largely automated computer and
technology intensive pipeline to overcome the principal obstacles that have to date prevented discovering
structural abnormalities in brain circuits. We propose to use this suite of automated microscopy and analysis
tools to reconstruct circuits in insular or prefrontal cerebral cortex from mouse, marmoset and human (cerebral
organoids and actual cerebral cortex). The aims are designed to provide synaptic and circuit level information
about the effects of molecular perturbations being studied by other members of our Conte team. Each of these
perturbations is associated with human neuropsychiatric and neurodevelopmental disorders. In all, 10
experimental brain tissues and their controls will be analyzed. We will take a structural inventory for a full
thickness of cerebral cortex determining among other things: the number and types of neurons; the number
and types of synapses; the synaptic vesicle numbers per synapse, mitochondrial numbers and densities per
synapse; and sizes of active zones, dendritic spine number, density and size. In addition we will itemize the
glial cell types, their prevalence, and look for differences is glial cell structure. All of these approaches have
been used previously by us. Finally we will reconstruct circuits using a seed cell approach that we have also
previously developed. It is our hope that providing this kind of detailed synaptic and connectional information
for many abnormal and control tissue will help focus research on the sites of physical abnormality in diseases
that to date have little in the way structural underpinnings.

## Key facts

- **NIH application ID:** 10386841
- **Project number:** 5P50MH094271-10
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Jeff W Lichtman
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $485,725
- **Award type:** 5
- **Project period:** 2011-09-05 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386841

## Citation

> US National Institutes of Health, RePORTER application 10386841, Project 2 (5P50MH094271-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10386841. Licensed CC0.

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