Associative learning, the process by which an organism forms a link between a cue or behavior and an intrinsically valenced stimulus, is a critical feature of adaptive behavior and survival. Learning to run upon hearing a roar associated with a predator allows one to avoid getting maimed or eaten; learning to rush to the kitchen when you smell freshly baked cookies enables you to snag a warm, tasty treat. As demonstrated by these two examples, associations can occur with both negatively valenced and positively valenced stimuli, with the former often invoking withdrawal and avoidance behaviors and the latter enforcing active approaching behaviors. Because associative memory acts as such a cornerstone in shaping flexible and appropriate behaviors, when this process goes awry, various negative consequences can ensue: depression, substance abuse, and anxiety disorder are only a few of such maladies tied to disturbances in circuitry underlying associative and motivational functionality. Consequently, studying this subject is of paramount therapeutic, as well as intellectual, interest.

Dr. Kay Tye’s Lab at the Massachusetts Institute of Technology aims to understand these very processes, employing a variety of methods from optogenetics and electrophysiological recordings to pharmacological and imaging techniques. A recent paper published by Dr. Tye and colleagues provides significant insight into the routing of positive and negative information from the amygdala during memory retrieval, suggesting that specific cell populations in the basolateral amygdala (BLA) encode different types of emotional valence depending upon the region to which they project. While the BLA as a whole is crucial in forming both positively and negatively valenced associations, subpopulations within the BLA demonstrate distinct activity patterns to rewarding versus aversive conditioned stimuli.

The main targets of the BLA investigated in Beyeler et al.’s (2016) study included the nucleus accumbens (NAc), central amygdala (CeA), and ventral hippocampus (vHPC). While the NAc is generally involved in positive reinforcement, the CeA is linked to learning that mediates aversive behaviors, and the vHPC presumably promotes anxiogenic actions. To examine the neural codes of BLA neurons targeting the NAc, CeA, and vHPC, Beyeler et al. (2016) utilized a dual-virus approach entailing optogenetic-mediated phototagging and in vivo electrophysiological recordings in mice trained to associate a particular tone with sucrose (a rewarding outcome) delivery and another tone with quinine delivery (an aversive outcome). After the mice learned the associations between each stimulus and its respective outcome—assessed as showing anticipatory licking selectively after hearing the sucrose-predictive tone for 70% of the trials—Beyeler et al. (2016) performed acute recordings in the BLA.

Half of the neurons recorded in the BLA were found to respond to sucrose and/or quinine, with 28% of neurons demonstrating selective responses to the tone associated with sucrose and a mere 9% altering firing selectively to the tone associated with quinine. In addition, 13% of BLA neurons responded to both tones similarly, and less than 1% responded to both tones in qualitatively different manners.



Nevertheless, the most notable finding relates to the analysis of the subpopulations in the BLA that responded to both or to either of these auditory cues. Specifically, the subpopulation of BLA neurons that projected to the NAc exhibited a starkly different response profile than that of the BLA-CeA neurons. Zero BLA-NAc neurons were found to be excited by the tone associated with quinine, but nearly all (77%) were excited by the tone tied to sucrose; Any BLA-NAc neurons that reacted to the quinine-associated tone demonstrated inhibition by the conditioned stimulus. In contrast, all BLA-CeA projectors recorded were excited by the tone paired with quinine.

Classifying BLA projector populations using “valence bias”—considering excitation and inhibition as qualitatively different—reinforced the differential activity of the three subpopulations examined. Approximately half of the BLA population encoding valence showed a positive bias—increasing firing for the sucrose-associated tone and/or decreasing activity to the quinine-associated tone—while the other half appeared to encode negative valence—increasing firing to the quinine cue and decreasing firing to the sucrose cue. Within the BLA, a greater percentage of BLA-NAc projectors were observed to be encode positive valence (80%, compared to 31% in the BLA-CeA); whereas more BLA-CeA cells encoded negative valence (69%). Interestingly, the BLA-vHPC subpopulation responded evenly to both tones, with 43% encoding positive valence.


These findings clearly suggest that BLA-NAc neurons preferentially encode cues associated with rewarding outcomes, consistent with the known role of the NAc in positive reinforcement; and that BLA-CeA neurons preferentially encode cues linked to aversive outcomes, also consistent with its acknowledged role in assigning negative valence to stimuli. The observation of BLA-vHPC responses evenly distributed between positive and negative valence is somewhat surprising due to its supposed role in anxiogenic behavior and requires further investigation.

If you find this experiment intriguing and would like to learn more about the nuances of and mechanisms underlying neural systems supporting associative learning, motivation,  and emotional processing, attend Dr. Kay Tye’s talk this Tuesday, February 21, at 4:00 pm at the Center for Neural Circuits and Behavior.


Gina D’Andrea-Penna is a first-year neurosciences Ph.D. student whose interests largely reside in the domain of cognitive neuroscience, particularly in investigating perceptual awareness, attention, and working memory.



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