# From stress to anhedonia: examining inflammation and altered glutamate function as distinct or common etiological pathways

> **NIH NIH K01** · EMORY UNIVERSITY · 2023 · $180,068

## Abstract

Anhedonia is a common transdiagnostic symptom that frequently fails to respond to available psychosocial and
pharmacological treatments and has been linked to disability and suicidal risk. Development of new treatments
for anhedonia has been hindered by its substantial heterogeneity. To address this problem, the NIMH
Research Domain Criteria (RDoC) approach has emphasized the need to identify circuit-specific sub-domains
of functional impairment. One potential pathway to anhedonic symptoms is through neurobiological changes
associated with prolonged exposure to stress (“stress-induced anhedonia”), characterized neurally by reduced
activation in reward-related regions such as the medial prefrontal cortex (mPFC) and ventral striatum, and
behaviorally by a failure to pursue rewards and reduced ability to anticipate positive or rewarding outcomes
(i.e. pessimistic biases). While the specific mechanisms by which elevated stress may lead to anhedonia are
not fully understood, two candidate mechanisms are elevated inflammatory cytokines and altered
glutamatergic functioning. Stressors are known to increase glutamate, particularly in mPFC, leading to
numerous negative effects including excito-toxicity, shrinkage of dendrites, and reduction of spine synapse
density. Stressors have also been shown to activate immune responses, elevating proinflammatory cytokine
tumor necrosis factor (TNF) alpha, interleukin-6 (IL-6), and IL-1b. Critically, a growing body of work has
suggested that elevated inflammation and altered glutamate functioning may be linked. The goal of the current
proposal is therefore to explore the independent and additive contributions of inflammation and glutamatergic
functioning to the experience of pessimistic expectations in stress-induced anhedonia. We propose to employ
plasma analysis of peripheral inflammatory markers and MRS glutamate in 40 healthy control participants
without anhedonia and 60 participants with anhedonia stratified by level of peripheral inflammation. In Aim 1
we will analyze associations between perceived stress, inflammation, and an ecological momentary
assessment (EMA) measure of pessimistic expectations. In Aim 2, we will use an acute stress manipulation
and MR spectroscopy to examine changes in mPFC glutamate in response to acute stress, examining
associations between perceived stress, glutamatergic response to stress, and pessimistic expectations.
Finally, in Aim 3 we will examine whether glutamatergic response to stress is related to individual differences in
inflammation and will test a serial mediation model of inflammation and glutamate response to stress on
pessimistic expectations. This work will provide insight into the neurobiological mechanisms that underlie
stress-induced anhedonia and the results will be used to inform future work using targeted treatments.

## Key facts

- **NIH application ID:** 10595532
- **Project number:** 5K01MH126308-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Jessica Cooper Robinson
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $180,068
- **Award type:** 5
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10595532

## Citation

> US National Institutes of Health, RePORTER application 10595532, From stress to anhedonia: examining inflammation and altered glutamate function as distinct or common etiological pathways (5K01MH126308-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10595532. Licensed CC0.

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