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Updated: Aug 5, 2026
07:26
Assessment of Stress Effects on Cognitive Flexibility using an Operant Strategy Shifting Paradigm
Published on: May 4, 2020
A cortical insula-orbitofrontal circuit drives stress-induced dopamine system dysfunction
Olivia J Yang1,2, Hannah B Reiley3,4,5, Angela M Boley3,4
1Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas at San Antonio, San Antonio, TX, 78229, USA. yango@livemail.uthscsa.edu.
Molecular Psychiatry
|July 30, 2026
Summary
Stress significantly impacts psychiatric disorders by disrupting the dopamine system. This study identifies a novel insula-orbitofrontal circuit that regulates dopamine neuron activity, offering new therapeutic targets for stress-related conditions.
Area of Science:
- Neuroscience
- Psychiatry
- Dopamine System Research
Background:
- Stress is a major risk factor for psychiatric disorders like PTSD and depression.
- Psychosis involves aberrant salience processing linked to elevated dopamine transmission.
- Stress increases dopamine release and alters behavior, but upstream circuits remain unclear.
Purpose of the Study:
- To identify the upstream circuits through which stress influences dopamine neuron activity.
- To investigate the role of the insular cortex (IC) in stress-induced dopamine dysregulation.
- To characterize a novel insula-orbitofrontal circuit (IC-OFC) and its regulation of the ventral tegmental area (VTA).
Main Methods:
- In vivo extracellular electrophysiology in rats.
- Selective chemogenetic activation of the IC-OFC circuit.
- Inactivation of the IC-OFC-VTA pathway to assess behavioral and neurophysiological effects.
Main Results:
- Activation of the insular cortex (IC) selectively increases ventral tegmental area (VTA) dopamine neuron activity.
- Chemogenetic activation of the IC-OFC circuit replicated this effect.
- Inactivation of the IC-OFC-VTA pathway reversed stress-induced dopamine elevations and normalized behaviors.
Conclusions:
- A previously unrecognized insula-orbitofrontal circuit (IC-OFC) powerfully regulates VTA dopamine neuron activity.
- This IC-OFC-VTA circuit mediates stress-induced pathological dopamine system activation.
- The findings reveal a novel circuit target for intervention in stress-related psychiatric disorders.
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