Subregion-Specific Input Organization of Prefrontal-Projecting Basal Forebrain Cholinergic Neurons and Weakened Striatum-to-NBM Inhibitory Transmission in 5xFAD mice

Basal forebrain cholinergic neurons regulate cortical activity and cognition and are vulnerable in Alzheimers disease (AD). However, the upstream circuits controlling projection-defined basal forebrain cholinergic populations remain incompletely understood. Here, we used projection-specific rabies-mediated monosynaptic tracing to map whole-brain inputs to medial prefrontal cortex (mPFC)-projecting cholinergic neurons in the nucleus basalis of Meynert (NBM) and horizontal limb of the diagonal band of Broca (HDB). mPFC-projecting NBM and HDB cholinergic neurons received broad but distinct input patterns. NBM cholinergic neurons received prominent striatal input, including input from D1-expressing medium spiny neurons, whereas HDB cholinergic neurons showed proportionally weaker striatal input and broader non-striatal contributions. Optogenetic electrophysiology confirmed that striatal inputs formed monosynaptic GABAergic inhibitory synapses onto NBM cholinergic neurons. This inhibitory transmission was weakened in 5xFAD mice, indicating impairment of a striatal-NBM inhibitory circuit in an AD mouse model. Together, these findings reveal subregion-specific input organization of mPFC-projecting basal forebrain cholinergic neurons and identify a vulnerable striatal-NBM circuit in AD. HighlightsO_LIWhole-brain rabies tracing reveals input organization of mPFC-projecting BF cholinergic neurons. C_LIO_LINBM and HDB cholinergic neurons projecting to mPFC show distinct monosynaptic input profiles. C_LIO_LIStriatal D1-MSNs are a major input source to mPFC-projecting NBM cholinergic neurons. C_LIO_LIStriatal-NBM inhibitory transmission is functionally impaired in 5xFAD mice. C_LI