Subregion-specific input organization of prefrontal-projecting basal forebrain cholinergic neurons and weakened striatal–NBM inhibitory transmission in 5xFAD mice
Year: 2026
Type: article
Abstract: Basal forebrain cholinergic neurons regulate cortical activity and cognition and are vulnerable in Alzheimer’s 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. Highlights Whole-brain rabies tracing reveals input organization of mPFC-projecting BF cholinergic neurons. NBM and HDB cholinergic neurons projecting to mPFC show distinct monosynaptic input profiles. Striatal D1-MSNs are a major input source to mPFC-projecting NBM cholinergic neurons. Striatal–NBM inhibitory transmission is functionally impaired in 5xFAD mice.
Source: Neurobiology of Disease
Institutions: Texas A&M Health Science Center, Texas A&M University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,180
OpenAlex ID: W7164928028