Cue- versus reward-encoding basolateral amygdala projections to nucleus accumbens

Area of Science:

• Neuroscience
• Addiction Research
• Molecular Psychiatry

Background:

• Substance use disorders involve reinforcement by drugs (unconditioned stimulus, US) and drug-associated cues (conditioned stimulus, CS).
• The basolateral amygdala (BLA) plays a role in both US- and CS-mediated drug responses.
• Distinct neuronal populations within the BLA may differentially contribute to these processes.

Purpose of the Study:

• To investigate the distinct roles of two genetically defined BLA neuronal types (Rspo2- and Ppp1r1b-expressing) in mediating drug reinforcement and cue-induced drug seeking.
• To elucidate the circuit mechanisms underlying US- and CS-driven behaviors in the nucleus accumbens (NAc).

Main Methods:

• Utilized optogenetic stimulation and chemogenetics in mice.
• Investigated intracranial self-stimulation (ICSS) and cue-induced cocaine seeking.
• Examined projections from distinct BLA neuronal types to the NAc and their connections with dopamine receptor-expressing neurons.

Main Results:

• Both Rspo2 and Ppp1r1b BLA neurons project to the NAc and connect with dopamine D1 and D2 receptor neurons.
• Stimulation of either Rspo2 or Ppp1r1b terminals in the NAc supported ICSS.
• Only Ppp1r1b-expressing BLA neurons mediated cue-induced ICSS seeking.
• Modulating the Ppp1r1b-NAc pathway, but not Rspo2-NAc, altered cue-induced cocaine seeking after withdrawal.

Conclusions:

• The Ppp1r1b-expressing BLA subprojection to the NAc selectively encodes conditioned stimulus (CS)-mediated reward and drug reinforcement.
• While both BLA subprojections contribute to unconditioned stimulus (US)-mediated responses, Ppp1r1b neurons are critical for cue-driven drug seeking.
• These findings offer insights into differentiating and potentially manipulating drug- versus cue-induced behaviors in addiction.