Leptin Promotes Striatal Dopamine Release via Cholinergic Interneurons and Regionally Distinct Signaling Pathways.

Area of Science:

• Neuroscience
• Endocrinology
• Neuropharmacology

Background:

• Dopamine (DA) is crucial for motor control, reward, and motivated behaviors.
• Striatal DA signaling is influenced by hormones regulating feeding and energy balance, like leptin.
• Aberrant eating patterns are linked to changes in striatal DA signaling.

Purpose of the Study:

• To investigate the effect of leptin on dopamine release and uptake in the mouse striatum.
• To explore the role of cholinergic interneurons (ChIs) and nicotinic acetylcholine (ACh) receptors in leptin's action.
• To identify signaling pathways mediating leptin's effects in different striatal subregions.

Main Methods:

• Immunohistochemistry to detect leptin receptor (LepR) expression in the striatum.
• Fast-scan cyclic voltammetry (FSCV) to measure extracellular dopamine concentration ([DA]_o) and uptake.
• Electrophysiological recordings to assess ChI excitability and the impact of receptor antagonism or genetic deletion.

Main Results:

• Leptin increased extracellular DA concentration and DA uptake in the dorsal striatum (dStr), nucleus accumbens (NAc) core, and shell.
• Leptin enhanced ChI excitability; blocking nicotinic ACh receptors or lacking ACh synthesis abolished leptin's effect on DA release.
• Leptin's action required intracellular Ca²⁺, with distinct downstream pathways in dStr/NAc core versus NAc shell.

Conclusions:

• Leptin dynamically regulates DA release and uptake in motor and reward pathways via ChIs and nicotinic ACh receptors.
• This study provides the first evidence of leptin's direct action on striatal DA signaling.
• Understanding these mechanisms may offer novel therapeutic targets for pathological eating behaviors.