# Astrocytes and the pathology of nodes of Ranvier in depression

> **NIH NIH R21** · UNIVERSITY OF MISSISSIPPI MED CTR · 2020 · $193,750

## Abstract

Research in our laboratories and others has revealed disturbances at anatomic, cellular and molecular levels
in the central nervous system (CNS) in major depressive disorder (MDD). The alterations include structural and
molecular changes not only in neurons but also in astrocytes and oligodendrocytes, glial cells that critically
support neuronal function in gray and white matter (GM and WM). Similar glial cell pathology is observed in
animal models of depression-like behaviors caused by stress, a risk factor for depression. This proposal aims
to bridge a gap in our knowledge about the relevance of pathological disturbances of WM astrocytes in MDD
by studying the interaction of astrocytes processes at the nodes of Ranvier (NR) of myelinated axons and the
behavioral effects of disturbing such an interaction. Animal studies will be used to examine whether pathology
of the interaction between astrocytes and NRs is a potential mechanism underpinning WM-based connectivity
disturbances in depression. We and others have detected alterations in oligodendrocyte morphology and
expression of myelin components in the orbitofrontal cortex (OFC) and adjacent WM in depression and animal
models of stress. Importantly, interactions of astrocyte processes with axons around NRs are seminal to myelin
stability and signal propagation, and thus critical to the normal connectivity between the OFC and brain regions
involved in the pathophysiology of depression. However, despite the vital role of NRs in signal propagation, it is
unknown whether astrocyte processes abutting around and abutting NRs contribute to the physiopathology of
WM in depression, or to depression-like behaviors in animal models such as chronic unpredictable stress
(CUS). This project will test whether reduced astrocyte processes abutting NRs in the OFC WM and anterior
corpus callosum (CC), as well as diminished EAAT1, proteoglycans, and their axonal adhesion molecules at
NRs will increase the probability of depression-like behaviors. Likewise, we hypothesize that astrocyte and
axon NR components in the OFC WM from postmortem human brain will be significantly reduced in subjects
with MDD. The hypotheses will be tested with these aims: Specific aim 1: We will use morphometry and
immunohistochemistry to test the hypothesis that MDD in humans is associated with reduced extent of
astrocyte processes contacting NRs and lower levels of NR astrocyte-related ECMMs and partner axonal
proteins in the OFC WM, but not in the WM of the occipital cortex. Specific aim 2: We will test the hypothesis
that CUS decreases the extent of astrocyte processes, and the levels of ECMMs and their axonal partners at
NRs in OFC WM in rats. Specific aim 3: We will test the hypothesis that local suppression of astrocyte-related
ECMMs results in depression-like behaviors in rats. If astrocytes and axonal NRs components are involved in
the cellular and behavioral pathology of depression, future research in rodents will target the intr...

## Key facts

- **NIH application ID:** 9955344
- **Project number:** 5R21MH118675-02
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** JOSE JAVIER MIGUEL-HIDALGO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,750
- **Award type:** 5
- **Project period:** 2019-06-14 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955344

## Citation

> US National Institutes of Health, RePORTER application 9955344, Astrocytes and the pathology of nodes of Ranvier in depression (5R21MH118675-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9955344. Licensed CC0.

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