Abstract

Motivation: Task-based fMRI studies highlighted the dorsolateral prefrontal cortex (dlPFC) involvement during working memory (WM) processes. However, BOLD fMRI indirectly estimates neural activity and lacks neuroreceptor specificity. Goal(s): We investigated inhibitory and excitatory receptor density influence on functional connectivity (FC) during varying WM loads. Approach: Using N-back fMRI tasks and Receptor-Enriched Analysis of Functional Connectivity by Targets (REACT), we assessed GABA-A and mGluR5 connectivity effects. Results: We found decreased GABA-A- and increased mGluR5-enriched FC with increasing WM load in networks involving the dlPFC, in line with fMRI and single-voxel MRS studies. Therefore, REACT is a promising tool bridging whole-brain molecular organization and FC. Impact: Our molecular-enriched fMRI analysis revealed how varying working memory load modulates functional connectivity related to the underlying neurotransmitters. This provides crucial information for a better understanding of the neural mechanisms underlying brain disorders like Alzheimer’s disease and Schizophrenia.