Positive or Negative: How does the brain tell good from bad?
Researchers from the Massachusetts Institute of Technology (MIT) have identified two neural circuits emanating from the basolateral amygdala (BLA) that encode positive and negative learned associations in mice.
Neurons from this area have projections to two other nearby brain regions that show opposite activity following fear and reward learning. These conflicting circuits cause either avoidance or reward-driven behaviour.
Dr Kay Tye, principal investigator for the study, said: "Given that many mental health problems, including anxiety, addiction, and depression, may arise from perturbations in emotional processing, these findings could help to pave the way to a circuit-based approach to treating mental illness."
The BLA has projections to many brain regions including the Nucleus Accumbens (NAc), previously implicated in reward-related behaviours, and the Centromedial Amygdala (CeM), which has been linked to fear-conditioned behaviours. These neurons are intertwined within the BLA, so the researchers used special fluorescent tracers to track the neurons back to the BLA from the respective area.
They then measured the strength of the neural connections between the BLA and the corresponding regions after mice underwent fear or reward learning. The strength of the synaptic connections onto the neurons projecting towards the NAc decreased after fear learning and increased with reward learning. Conversely, the synaptic strength of the inputs onto the CeM projecting neurons increased after fear learning and decreased after reward learning.
These findings raised two major questions. First, is there a causal relationship between this activity and reward or fear-related behaviours? Second, how do NAc and CeM projections differ to enable them to achieve these opposing functions within the same brain region?
To prove a causal link between the projection-identified circuits and behaviour, the researchers used optogenetics. They found that optogenetic stimulation of the NAc projections led to enhanced positive reinforcement, while stimulation the CeM projections promoted negative reinforcement. Additionally, optogenetic inhibition of the CeM projections led to impaired fear learning and enhanced reward learning.
Finally, in order to identify how these distinct populations have opposing functions in fear and reward conditioning, the researchers looked for differences in electrophysiological, morphological and genetic features. They found there was a significant difference in action potential accommodation between the two populations. In addition, there was greater dendritic branching in CeM projectors compared with NAc projectors and a few differently expressed genes.
These differences in gene expression may underpin the mechanisms that lead to the opposing functions of BLA neurons projecting to the NAc and the CeM. A greater understanding of how the brain interpretes positive and negative inputs and translates these into behaviour could lead to potential therapeutic targets for mental conditions like depression, anxiety and depression.
Paper References:
Namburi P, Beyeler A, Yorozu S, Calhoon GG, Halbert SA, Wichmann R, Holden SS, Mertens KL, Anahtar M, Felix-Ortiz AC, Wickersham IR, Gray JM, Tye KM. (2015) A circuit mechanism for differentiating positive and negative associations Nature 520:675-678 doi: 10.1038/nature14366
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