Studies by Cold Spring Harbor Laboratory researchers led by neuroscientist Bo Li, PhD, have uncovered how neurons called somatostatin-expressing (Sst+) central amygdala (CeA) neurons within the amygdala structure of the brain help us learn about threats and rewards. The researchers also demonstrated how these neurons relate to dopamine (DA) neurons, and suggest that their discoveries could lead to future treatments for anxiety or drug addiction. Li and colleagues described their in vivo studies in Nature, in a paper titled “Plastic and stimulus-specific coding of salient events in the central amygdala.”

Deep within the brain’s temporal lobes, two small almond-shaped cell masses, called the amygdala, assist with a variety of brain activities. The structure helps us learn and remember. It triggers our fight-or-flight response, and even promotes the release of the feel-good chemical called dopamine. Scientists have learned all this by studying the amygdala over time. But we still haven’t reached a full understanding of how these processes work. “The central amygdala is implicated in a range of mental processes including attention, motivation, memory formation and extinction, and in behaviors driven by either aversive or appetitive stimuli,” the authors wrote. However, they pointed out, “A fundamental question, which remains unresolved, is how the CeA processes various salient stimuli and contributes to the divergent behavioral responses to these stimuli.”

Sst+ CeA neurons, which express the neural peptide somatostatin, are the largest genetically identified neuronal population in the CeA, the team explained. These neurons send long distance projections to a number of targets, and “play critical roles” in learning both aversive and appetitive behaviors, which reflect many of the divergent functions of the CeA. However, the team noted, “How these neurons and their projections take part in divergent behavioral responses is also unclear.”

To test how Sst+ CeA neurons help us to learn, Li and his colleagues trained mice to associate specific sounds with particular rewards or punishments, and imaged the animals’ brains during their experiments. Previously, scientists had assumed that the amygdala couldn’t distinguish between good and bad stimuli. Li’s team found that not only did the neurons respond differently to rewards versus punishments, but they responded differently to particular types of rewards. “… we show that somatostatin-expressing (Sst+) CeA neurons, which mediate much of CeA functions, generate experience-dependent and stimulus-specific evaluative signals essential for learning,” they wrote. For example, if mice received water, their neurons fired differently than if they received food or sugar water.  “The population responses of these neurons in mice encode the identities of a wide range of salient stimuli, with the responses of separate subpopulations selectively representing the stimuli that have contrasting valences, sensory modalities, or physical properties (e.g., shock and water reward).” Li stated, “This is entirely new to us. These neurons really care about the nature of each individual stimulus. It’s almost like a sensory area.”

The team also saw that the mice’s brains fired more Sst+ CeA neurons more strongly after training. This suggested the neurons are important for learning. “These signals scale with stimulus intensity, undergo pronounced amplification and transformation during learning, and are required for both reward and aversive learning,” the team continued. When the neuroscientists then inhibited Sst+ CeA neurons in some of the mice. They found that these animals could not learn to associate sounds with rewards or punishments.

With the neurons inhibited, the team made another key finding. Normal dopamine neuron responses were also suppressed. While previous research had linked the CeA to dopamine neurons, it was unclear exactly how they were connected. “Our results also identify a unique role of SstCeA→DA neurons in reward learning, which is probably mediated by their specific regulation of DA neurons,” the investigators stated.

“We found those neurons are required for normal function for dopamine neurons, and therefore are important for reward learning,” Li says. “That is direct evidence of how CeA neurons regulate the function of dopamine neurons.”

The team concluded “Our results help explain the diverse roles of the CeA, especially its role in reward learning, and also provide in vivo evidence for the long-standing hypothesis that the CeA regulates midbrain DA neurons.”

Next, Li plans to examine the relationship between Sst+CeA neurons and addiction. This could one day lead to better treatments for opioid or methamphetamine addicts, he suggested. “Our study provides a basis for developing more specific ways to regulate these neurons in different disease conditions.”

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