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The Orbitofrontal Cortex to Striatal Cholinergic Interneuron Circuit Controls Cognitive Flexibility Shaping
Jiaxin Li1, Yao Zhou1, Fangyuan Yin1
1Institute for Stem Cell and Neural Regeneration and Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China.
Biological Psychiatry
|October 13, 2024
Summary
Enhancing orbitofrontal cortex (OFC) to dorsomedial striatum (DMS) circuit flexibility, particularly via cholinergic interneurons (CINs), can restore cognitive flexibility and reduce alcohol-seeking behavior.
Area of Science:
- Neuroscience
- Behavioral Science
Background:
- The orbitofrontal cortex (OFC) to dorsomedial striatum (DMS) circuit is vital for cognitive flexibility.
- The precise role of OFC projections to specific DMS neuron types in cognitive flexibility and substance use remains unclear.
Purpose of the Study:
- To investigate how OFC projections to DMS neurons modulate cognitive flexibility.
- To explore the OFC-DMS circuit's role in alcohol-seeking behavior and potential therapeutic strategies.
Main Methods:
- Mice underwent alcohol self-administration and cognitive flexibility tests (place discrimination).
- Electrophysiology and in vivo optogenetics were employed to study neural circuit function in alcohol-seeking behavior.
Main Results:
- OFC afferents functionally influence striatal cholinergic interneurons (CINs), impacting cognitive flexibility.
- Chronic alcohol consumption impaired cognitive flexibility and OFC-DMS circuit function.
- Restoring OFC-DMS circuit plasticity via long-term potentiation ameliorated cognitive deficits.
- CINs mediate the circuit's impact on flexibility, preferentially affecting D2 receptor-expressing MSNs.
- Activating the OFC-CIN-D2 receptor-expressing MSN circuit reduced alcohol-seeking behavior.
Conclusions:
- Modulating OFC-CIN circuit function offers a potential therapeutic avenue for alcohol use disorders.
- Targeting cognitive flexibility within this circuit may help treat uncontrolled alcohol-seeking behavior.
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