Neurotensin orchestrates valence assignment in the amygdala.

The ability to associate temporally segregated information and assign positive or negative valence to environmental cues is paramount for survival. Studies have shown that different projections from the basolateral amygdala (BLA) are potentiated following reward or punishment learning1-7. However, we do not yet understand how valence-specific information is routed to the BLA neurons with the appropriate downstream projections, nor do we understand how to reconcile the sub-second timescales of synaptic plasticity8-11 with the longer timescales separating the predictive cues from their outcomes. Here we demonstrate that neurotensin (NT)-expressing neurons in the paraventricular nucleus of the thalamus (PVT) projecting to the BLA (PVT-BLA:NT) mediate valence assignment by exerting NT concentration-dependent modulation in BLA during associative learning. We found that optogenetic activation of the PVT-BLA:NT projection promotes reward learning, whereas PVT-BLA projection-specific knockout of the NT gene (Nts) augments punishment learning. Using genetically encoded calcium and NT sensors, we further revealed that both calcium dynamics within the PVT-BLA:NT projection and NT concentrations in the BLA are enhanced after reward learning and reduced after punishment learning. Finally, we showed that CRISPR-mediated knockout of the Nts gene in the PVT-BLA pathway blunts BLA neural dynamics and attenuates the preference for active behavioural strategies to reward and punishment predictive cues. In sum, we have identified NT as a neuropeptide that signals valence in the BLA, and showed that NT is a critical neuromodulator that orchestrates positive and negative valence assignment in amygdala neurons by extending valence-specific plasticity to behaviourally relevant timescales.

Social isolation recruits amygdala-cortical circuitry to escalate alcohol drinking.

How do social factors impact the brain and contribute to increased alcohol drinking? We found that social rank predicts alcohol drinking, where subordinates drink more than dominants. Furthermore, social isolation escalates alcohol drinking, particularly impacting subordinates who display a greater increase in alcohol drinking compared to dominants. Using cellular resolution calcium imaging, we show that the basolateral amygdala-medial prefrontal cortex (BLA-mPFC) circuit predicts alcohol drinking in a rank-dependent manner, unlike non-specific BLA activity. The BLA-mPFC circuit becomes hyperexcitable during social isolation, detecting social isolation states. Mimicking the observed increases in BLA-mPFC activity using optogenetics was sufficient to increase alcohol drinking, suggesting the BLA-mPFC circuit may be a neural substrate for the negative impact of social isolation. To test the hypothesis that the BLA-mPFC circuit conveys a signal induced by social isolation to motivate alcohol consumption, we first determined if this circuit detects social information. Leveraging optogenetics in combination with calcium imaging and computer vision pose tracking, we found that BLA-mPFC circuitry governs social behavior and neural representation of social contact. We further show that BLA-mPFC stimulation mimics social isolation-induced mPFC encoding of sucrose and alcohol, and inhibition of the BLA-mPFC circuit decreases alcohol drinking following social isolation. Collectively, these data suggest the amygdala-cortical circuit mirrors a neural encoding state similar to social isolation and underlies social isolation-associated alcohol drinking.