Brain circuits for positive and negative associations discovered

A paper, recently published in Nature, describes how researchers have discovered two neural circuits that encode positive and negative learned associations in mice. They showed that neurons from the basolateral amygdala (BLA) have projections to two nearby brain regions that produce opposite activities following fear and reward learning. These conflicting circuits cause either avoidance or reward-driven behaviour.

The facility to respond appropriately to positive or negative stimuli is critical to survival in most animals. Disruptions to this ability are thought to be responsible for a number of neurological conditions.

Dr Kay Tye, of the Massachusetts Institute of Technology (MIT), and corresponding author for the paper, 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."

Identifying positive from negative

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 fluorescent retrobead tracers to identify which neurons ended up in the different areas.

They then measured the strength of the neural connections 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 (as measured by AMPAR/NMDAR ratio relative to controls). 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 distal dendritic branching in CeM projectors than 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.

Paper Reference:

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