Essential role of VGLUT2-negative claustro-prefrontal projections in working memory

In Press
Current Biology

Tan JY, Chong HR, Ho MZH, Xuan O, Ramesh P, Graf M, Augustine GJ, and Kamigaki T.

The claustrum (CLA) is a key integrative hub with extensive bidirectional connectivity to higher-order regions, particularly the medial prefrontal cortex (mPFC). Such connectivity supports diverse cognitive functions, including attention, sensory integration, salience detection, and memory. A recent review highlights the growing evidence that the CLA contributes to cognitive control, including working memory (WM), by coordinating activity across distributed cortical networks. Consistent with this, recent work implicates the CLA in WM, although the specific CLA-to-mPFC pathways mediating this function remain unclear. The CLA comprises heterogeneous neuronal subpopulations with divergent molecular, anatomical, physiological, and projection profiles. VGLUT2-positive neurons constitute a major population providing excitatory input to the mPFC. However, non-specific CLA activation paradoxically produces net mPFC inhibition via local interneuron recruitment. This suggests that VGLUT2-negative neurons—the remaining projection type—form distinct pathways that contribute to inhibitory effects28, and exert unique cognitive influences. We identified the previously uncharacterized population of VGLUT2-negative neurons within the CLA that project to the mPFC in mice. These neurons are enriched ventral to the parvalbumin-dense CLA core and preferentially innervate mPFC layer 6, unlike the broader laminar projections of VGLUT2-positive neurons. Fiber photometric calcium measurements revealed that these neurons were selectively active during maintenance of a spatial WM and less active during error trials. Optogenetic silencing of these neurons during WM maintenance, but not encoding, severely impaired performance. Silencing during decision-making modestly improved performance, suggesting that disengagement of this pathway facilitates optimal processing. These findings reveal a claustro-prefrontal circuit crucial for WM maintenance and phase-dependent behavioral modulation.

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