# Impact of immune cell-derived exosomes and miRNAs on brain function and behavior

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $346,433

## Abstract

ABSTRACT
Adaptive immune cells in the periphery (T and B cells) and innate immune cells in the brain (microglia) have
been implicated in the brain homeostasis in health and disease. Rodent studies using immunodeficient mice
have revealed that the loss of adaptive immune cells (T and B cells) led to impaired learning and memory,
anxiety-like behaviors, and impaired sociability. Nevertheless, it is not clear how adaptive immune cells
communicate with microglia and affect brain development and function. Our long-term goal is to understand
the molecular and cellular mechanisms underlying the communication between adaptive immune cells and
brain cells during brain development and in adulthood. Our preliminary studies revealed that Rag1-/- and [Rag2-
/-mice], lacking both T and B cells, exhibited impaired social behaviors. In Rag1-/- mice, increased c-Fos
expression and altered microglial phenotypes in the medial prefrontal cortex (mPFC) were observed. This is
consistent with previous reports that mPFC dysfunction is involved in social behaviors. [Notably, adoptive
transfer of wild-type (WT) splenocytes (containing T and B cells) rescued Rag1-/- social behavioral deficits.
Further, injection of WT serum exosomes rescued the same phenotype. The social behavioral deficits were
also observed in Rag2-/- mice despite the fact that Rag2 is normally absent in the WT brain. Together, these
findings suggest that T and B cells contribute to social behaviors via exosomes.] Indeed, we observed that
exosomes from the sera of Rag1-/- mice lacked the expression of T and B cell markers and multiple microRNAs
(miRNAs) presumably derived from T and B cells. The expression of predicted target gene(s) of these
miRNAs, such as Ski, was enhanced in the PFC of Rag1-/- mice. In contrast, WT serum exosomes decreased
Ski expression in microglia. Recent studies showed that microglia control neuronal synapses. Thus, our data
suggest that deficient adaptive immune cell-microglia communication via exosomes impairs social behaviors
by altering mPFC function. Hence, in this study, we will test our hypothesis that the lack of adaptive immune
cell-derived exosomes and their miRNAs results in impaired social behaviors via altered microglial control of
neuronal function in the medial PFC. We will first validate and extend our findings on serum exosomes and the
mPFC neurons in Rag1-/- mice, and determine the causal role for the lack of adaptive immune cells by
restoring them back into Rag1-/- mice with adoptive transfer technique (Aim 1). We will also examine the direct
impact of impaired exosome release and miRNA production in adaptive immune cells on microglia and
neurons in the mPFC and social behaviors by genetic approaches (Aim 2). [In addition, we will address the
contribution of pyramidal neurons and microglia in the mPFC to impaired social behaviors (Aim 3).] This study
will reveal novel mechanisms whereby adaptive immune cell-derived exosomes influence brain function and
behavior...

## Key facts

- **NIH application ID:** 9908179
- **Project number:** 5R01MH113645-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Shinichi Kano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $346,433
- **Award type:** 5
- **Project period:** 2018-03-16 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908179

## Citation

> US National Institutes of Health, RePORTER application 9908179, Impact of immune cell-derived exosomes and miRNAs on brain function and behavior (5R01MH113645-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9908179. Licensed CC0.

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