Activity-Dependent Regulation of Basal Forebrain Cholinergic Neurons by Striatal Spiny Projection Neurons

Area of Science:

• Neuroscience
• Cellular and Molecular Neuroscience
• Systems Neuroscience

Background:

• Basal forebrain cholinergic neurons (BFCNs) are crucial for cognition, attention, and sleep-wake cycles.
• The specific neural circuits controlling BFCN activity remain incompletely understood.
• Striatal spiny projection neurons (SPNs) are known to project to the basal forebrain.

Purpose of the Study:

• To characterize the afferent connections controlling basal forebrain cholinergic neuron (BFCN) spiking.
• To investigate the functional roles of different spiny projection neuron (SPN) subtypes in regulating BFCNs.
• To elucidate the downstream mechanisms mediating SPN-evoked responses in BFCNs.

Main Methods:

• Monosynaptic rabies virus tracing to map SPN inputs to BFCNs.
• Optogenetic stimulation of D1R-SPN and D2R-SPN axons in ex vivo brain slices.
• Electrophysiological recordings to assess BFCN responses to SPN stimulation.
• Pharmacological manipulation to identify receptor involvement (NK1Rs, ASICs).

Main Results:

• Both D1 dopamine receptor-expressing SPNs (D1R-SPNs) and D2 dopamine receptor-expressing SPNs (D2R-SPNs) innervate BFCNs.
• Optogenetic activation of D1R-SPNs elicited stronger responses in BFCNs compared to D2R-SPNs.
• Transient D1R-SPN stimulation caused GABAergic inhibition, while sustained stimulation led to excitation via NK1Rs and ASICs.

Conclusions:

• A distributed population of D1R-SPNs significantly regulates BFCN activity.
• SPN-mediated regulation of BFCNs involves complex inhibitory and excitatory pathways.
• These findings highlight a novel role for SPNs in modulating arousal, cognition, and sleep.