# The Impact of Stress-induced KCC2 Downregulation on Mesolimbic Dopamine Signaling and Reward Processing

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2023 · $386,920

## Abstract

Environmental stress is a major risk factor for neuropsychiatric disorders, but the fundamental
mechanisms underlying this vulnerability remains unknown. A growing evidence indicates that stress-related
psychopathology arises in part from the dysregulation of brain mesolimbic reward circuitry, which is primarily
comprised of the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Our data in rodents indicate
that stress dysregulates reward processing via decreased function of anion transporter KCC2 located in VTA
GABA neurons. This form of stress-induced neuroadaptation in GABAergic signaling has not been fully
characterized, and we plan to investigate its impact on dopamine signaling and reward processing in rats. Given
that VTA GABA neurons provide a major inhibitory input to the mesolimbic dopamine neurons, we will measure
the impact of these neurons and stress-induced KCC2 downregulation on dopamine signaling. These studies
will account for functionally distinct tonic and phasic modes of dopamine neuron activity, which can be
differentially regulated by VTA GABA neurons. Heterogeneous populations of dopamine neurons participate in
anatomically separate circuits that mediate different aspects of reward processing. To test if stress-induced
KCC2 hypofunction dysregulates dopamine signaling in a circuit-specific manner, we will measure GABAergic
transmission onto specific dopamine projections to the core, medial, and lateral shell of the NAc. Ultimately, we
will examine the role of stress-induced KCC2 downregulation and VTA GABA neurons in different aspects of
reward processing. Rats will be exposed to acute stress and we will measure reward learning and incentive
motivation while manipulating KCC2 in VTA GABA neurons. Behavioral tasks will be accompanied by multi-unit
electrophysiology and optogenetics to further explore the contribution of different VTA neuron types to distinct
reward processes. Taken together, these studies will comprehensively examine the impact of stress on reward
processing and hold the potential to improve our understanding of GABAergic regulation of complex dopamine
signaling.

## Key facts

- **NIH application ID:** 10544517
- **Project number:** 5R01MH125996-02
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Alexey Ostroumov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $386,920
- **Award type:** 5
- **Project period:** 2022-01-01 → 2026-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10544517

## Citation

> US National Institutes of Health, RePORTER application 10544517, The Impact of Stress-induced KCC2 Downregulation on Mesolimbic Dopamine Signaling and Reward Processing (5R01MH125996-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10544517. Licensed CC0.

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