# Central Motivation of Depression; An Expanded Kynurenine Theory

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2020 · $455,937

## Abstract

Project Summary
Encephalitis attributed to viral infection is often refractory to established drugs. Enteroviruses (Picornaviridae)
are a common cause of encephalitis with neurological sequelae; as are Arborviruses (West Nile and Zika that
are emerging infectious pathogens spreading across the United States). Viral encephalitis impairs neurological
function that may lead to acute seizures (ictogenesis), neurodegeneration and persistent comorbid conditions
including cognitive impairment, depression and anxiety. Therefore, finding new and novel therapeutics is
important for public health. Only recently was a suitable animal model developed to investigate how viral
encephalitis causes this neuropathogenic sequelae. When infected with Theiler's murine encephalomyelitis virus
(TMEV, a Picornavirus), C57BL/6 mice survive the infection, but develop acute seizures followed by persistent
comorbid conditions including cognitive impairment and anxiety. Activation of the innate immune system is
strongly implicated in development of these symptoms. Although modifications are frequently investigated as a
means to limit damage to the brain, this immune response is designed and indeed critical to fight the infection.
Effective therapies are needed to prevent neurological sequelae without compromising immune function. We
have uncovered two proteins that appear to meet these criteria. The indoleamine 2,3-dixogenases (Ido's: Ido1
and Ido2) encode inflammation-dependent rate-limiting enzymes that initiate metabolism of tryptophan to
kynurenine. Kynurenine is then metabolized in a cell-specific manner to generate either neurotoxic/seizure-
inducing or neuroprotective/anti-seizure metabolites. By genetic modification of the Ido's, we have generated
mice with diminished or enhanced neurological sequelae following viral encephalitis. We propose to identify the
source of Ido responsible for these sequelae. To achieve this goal, we will conduct a series of rigorous
multidisciplinary (ex vivo, genetic and pharmaceutical) experiments with the TMEV model of encephalitis. This
mouse model recapitulates clinical observations including neurodegeneration, formation of a glial scar and the
development of spontaneous seizures. Specific Aim 1 will characterize in detail the ability of viral infection to
modulate Ido activity within cells implicated in the progression of encephalitis. Specific Aim 2 will define which
cell's Ido activity is mediating ictogenesis and neurodegeneration. Specific Aim will characterize Ido-dependent
persistent behaviors. And Specific Aim 4 will initiate translational research to examine the ability of Ido-inhibitors
to attenuate neurological sequelae associated with encephalitis. Our data support a paradigm shifting hypothesis
where changes in Ido activity has the potential to prevent viral-induced neurological sequelae without affecting
the immune system's ability to fight infection. Data generated from the proposed experiments should have broad
implica...

## Key facts

- **NIH application ID:** 9979974
- **Project number:** 5R01NS106688-06
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Robert H. McCusker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $455,937
- **Award type:** 5
- **Project period:** 2014-08-06 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979974

## Citation

> US National Institutes of Health, RePORTER application 9979974, Central Motivation of Depression; An Expanded Kynurenine Theory (5R01NS106688-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979974. Licensed CC0.

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