An endocannabinoid-regulated basolateral amygdala-nucleus accumbens circuit modulates sociability

Area of Science:

• Neuroscience
• Autism Spectrum Disorders Research
• Molecular Psychiatry

Background:

• Social interaction (SI) deficits are a core symptom of autism spectrum disorders (ASDs), with limited treatment options.
• Understanding the brain circuits and neuromodulatory systems governing sociability is crucial for developing effective ASD therapies.

Purpose of the Study:

• To investigate the role of the basolateral amygdala-nucleus accumbens (BLA-NAc) glutamatergic circuit in regulating social behavior.
• To explore the potential of modulating 2-arachidonoylglycerol (2-AG) endocannabinoid signaling as a therapeutic strategy for social deficits in ASD models.

Main Methods:

• In vivo optogenetics to activate or inhibit the BLA-NAc circuit in mice.
• Pharmacological manipulation using JZL184 (a monoacylglycerol lipase inhibitor) to augment 2-AG signaling.
• Assessment of social interaction in wild-type (WT) and Shank3B-/- mice (an ASD model).
• Ex vivo electrophysiological recordings to analyze neurotransmission in the nucleus accumbens (NAc).

Main Results:

• Activation of the BLA-NAc circuit decreased SI and increased social avoidance in mice.
• Augmentation of 2-AG signaling via JZL184 counteracted the SI deficits induced by BLA-NAc stimulation.
• Inhibition of the BLA-NAc circuit enhanced SI in Shank3B-/- mice but not WT mice.
• Systemic or NAc-targeted JZL184 administration normalized SI deficits in Shank3B-/- mice by correcting aberrant neurotransmission.

Conclusions:

• The BLA-NAc glutamatergic circuit plays a significant role in regulating social interaction.
• 2-AG endocannabinoid signaling modulates BLA-NAc activity and can ameliorate social deficits.
• Targeting 2-AG augmentation offers a potential therapeutic avenue for social impairments in ASDs by normalizing excitatory and inhibitory neurotransmission in the NAc.