# Mechanisms of Social Isolation-Induced Alterations in Prefrontal Cortex Myelin, Neural Circuits and Behavior

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $809,446

## Abstract

Abstract
There is increasing evidence that alterations in myelin contribute to cognitive and behavioral defects and that
this is partly mediated through myelin plasticity, but the cellular and molecular mechanisms by which this occurs
remain poorly understood. One example of the crucial role of myelin plasticity in mental health is the long-term
impact of juvenile social isolation (JSI). Children subjected to JSI suffer from dramatic long-term behavioral and
cognitive defects that persist after fostering and intervention. Imaging studies indicate that affected children have
defects in the myelination of neuronal circuits in the prefrontal cortex (PFC), a brain region implicated in memory,
executive function, social interactions, and psychiatric disorders. In prior studies, we found that like in children,
mice isolated during their juvenile period also present with long-term defects in social interactions and cognitive
function together with altered myelination of PFC neurons. In addition, we have demonstrated that JSI in mice
reduces the trophic factor Neuregulin 1 (NRG1) type III in the PFC and that mice with central hypomyelination
due to decreased signaling by NRG1 and its ErbB receptors (ErbBRs) have behavioral phenotypes like those
produced by JSI. Together, these data suggest that JSI influences PFC myelin plasticity through alterations in
NRG1/ErbB signaling, and that the resulting hypomyelination in turn impacts PFC function. However, critical
mechanistic aspects of how JSI alters PFC structure and function remain undefined. To fill these gaps in
knowledge and to determine if the effects of JSI can be prevented, ameliorated, or reversed by increasing type
III NRG1 levels, we propose the following aims. In Aim 1, we will determine the mechanisms by which JSI alters
PFC type III NRG1 expression, focusing on epigenetic regulation. Aim 2 will determine the cellular mechanisms
by which JSI and hypomyelination alter the function of PFC circuits using patch-clamp recordings combined with
laser scanning photo-stimulation (LSPS). In Aim 3, we will determine if the downregulation of NRG1 PFC
expression is sufficient to induce the JSI endophenotypes, and if restoration of type III NRG1 expression is
sufficient to attenuate, prevent, or rescue the impact of JSI on PFC myelination and function. For the latter aim,
we will use new genetically modified mice that allow for cell-specific inducible NRG1 KO or over-expression. The
proposed studies, which represent the continuation of a collaboration between labs with complementary
expertise, will provide new insights into the mechanisms of myelin plasticity and the interactions between
oligodendrocytes and neurons, the mechanisms by which JSI alters neuronal gene expression, the mechanisms
regulating the expression of NRG1, a gene involved in psychiatric disorders, and the mechanisms by which
myelin disruption alters neuronal function. Elucidation of these mechanisms has the potential to enable
intervention...

## Key facts

- **NIH application ID:** 10979782
- **Project number:** 1R01MH135425-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Gabriel Corfas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $809,446
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979782

## Citation

> US National Institutes of Health, RePORTER application 10979782, Mechanisms of Social Isolation-Induced Alterations in Prefrontal Cortex Myelin, Neural Circuits and Behavior (1R01MH135425-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10979782. Licensed CC0.

---

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