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Essential role of VGLUT2-negative claustro-prefrontal projections in working memory
Jia Yun Tan1, Huee Ru Chong1, Malcolm Zheng Hao Ho2
1Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore.
Current Biology : CB
|May 22, 2026
Summary
Researchers identified a novel VGLUT2-negative claustrum (CLA) to medial prefrontal cortex (mPFC) pathway crucial for working memory (WM). This circuit
Area of Science:
- Neuroscience
- Cognitive Neuroscience
- Systems Neuroscience
Background:
- The claustrum (CLA) is an integrative brain region with extensive connections to higher-order cortical areas, including the medial prefrontal cortex (mPFC).
- CLA connectivity supports cognitive functions like attention, sensory integration, salience detection, and memory.
- Emerging evidence suggests the CLA's role in cognitive control, particularly working memory (WM), through coordinating cortical networks, though specific pathways remain unclear.
Purpose of the Study:
- To identify and characterize novel CLA-to-mPFC pathways involved in cognitive functions, specifically working memory.
- To elucidate the role of distinct neuronal subpopulations within the CLA, particularly VGLUT2-negative neurons, in modulating mPFC activity and behavior.
- To investigate the functional contribution of these identified pathways to working memory maintenance and decision-making.
Main Methods:
- Identification of VGLUT2-negative CLA neurons projecting to the mPFC in mice.
- Characterization of their anatomical projections, specifically targeting mPFC layer 6.
- In vivo fiber photometry to measure neuronal activity during spatial WM tasks.
- Optogenetic manipulation (silencing) of these neurons during different phases of the WM task and decision-making.
Main Results:
- A previously uncharacterized population of VGLUT2-negative CLA neurons projecting to mPFC layer 6 was identified.
- These neurons exhibited selective activity during WM maintenance and reduced activity during error trials.
- Optogenetic silencing impaired WM maintenance but improved decision-making, indicating a phase-dependent role.
Conclusions:
- A novel claustro-prefrontal circuit involving VGLUT2-negative CLA neurons is critical for working memory maintenance.
- This pathway's activity is dynamically modulated during WM performance, influencing both maintenance and decision-making.
- Disengagement of this circuit may facilitate optimal cognitive processing, highlighting its role in flexible cognitive control.
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