Reward and Punishment Take Similar Paths in the Mouse Brain

Summary: Researchers found specific neurons in the striosome that help mice learn to avoid negative experiences.

Source: Cold Spring Harbor Laboratory

Cold Spring Harbor Laboratory (CSHL) scientists have discovered neurons in the mouse brain that help an animal learn to avoid negative experiences. The cells reside in a part of the brain involved in regulating the motivations that influence behavior.

Previously, this part of the brain, known as the striosome, was thought to be dedicated to supporting our ability to learn from positive reinforcement and seek out rewards. The discovery that some neurons in this same structure contribute to negative-reinforcement learning reveals the striosome to be a complex motivation-processing hub. Understanding its function is critical, says Bo Li, the CSHL professor who led the study, because motivation processing is impaired in people with certain mental illnesses.

“We know those neurons are important for normal motivation–the motivation to pursue a reward or the motivation to avoid punishment,” Li says. “So we have hopes that the striosome neurons could be critical for either, or both depression and addiction.” Li and his colleagues reported their findings in the journal Cell.

The striosome is situated within a region of the brain called the dorsal striatum. Its cells are defined by the chemicals they produce rather than anatomical boundaries, which has made it difficult to study their function. Li and his team were able to do so because they identified a gene, Tshz1, that is used by some of the neurons there. Using Tshz1 as a genetic tag, the researchers traced the neurons within the striosome. That allowed them to manipulate the cells and monitor their activity in mice.

Their experiments, done in collaboration with other CSHL scientists as well as researchers at Stanford University and the Howard Hughes Medical Institute’s Janelia Research Campus, revealed that mice need Tshz1-expressing cells in the striosome to learn to associate certain places or sounds with an unpleasant experience. Surprisingly, those cells played no role in the animals’ reward learning, a function that falls to other neurons within the striosome. Li says:

This shows the striatum
The motivation center (green) of the mouse brain passes through a pathway called the dorsal striatum. On the bottom are three views of the mouse brain. Image is credited to Allen Brain Atlas, Mouse Brain Connectivity Atlas, Dorsal Striatum.

“So it seems like the striosome is not as simple as we initially believed. There’s actually two kinds of neurons in the striosome that allow the animal to do both–reward pursuing and also punishment avoidance. Those different things are both critical for us to survive with. You can imagine if you are not sensitive to punishment, you’re going to get into trouble if you run into danger and if you are not sensitive to reward, of course, you can also have a difficulty in survival, because you are not going forward for the food, for example.”

Ultimately, Li says, understanding how neurons in the striosome interact with other motivation-processing parts of the brain to guide behavior will allow researchers to home in on cells or circuits that contribute to mental illnesses. That, he hopes, will lead to better treatments.

About this neuroscience research article

Cold Spring Harbor Laboratory
Sara Roncero-Menendez – Cold Spring Harbor Laboratory
Image Source:
The image is credited to Allen Brain Atlas, Mouse Brain Connectivity Atlas, Dorsal Striatum.

Original Research: Closed access
“A Genetically Defined Compartmentalized Striatal Direct Pathway for Negative Reinforcement” by Bo Li et al. Cell.


A Genetically Defined Compartmentalized Striatal Direct Pathway for Negative Reinforcement

• Tshz1 labels a population of striatal direct pathway medium spiny neurons (dMSNs)
• Tshz1-expressing ( Tshz1 +) dMSNs are localized in the striosome
• Tshz1 + striosomal dMSNs represent punishment and drive negative reinforcement
• Pdyn labels another population of striosomal dMSNs mediating positive reinforcement

The striosome compartment within the dorsal striatum has been implicated in reinforcement learning and regulation of motivation, but how striosomal neurons contribute to these functions remains elusive. Here, we show that a genetically identified striosomal population, which expresses the Teashirt family zinc finger 1 ( Tshz1) and belongs to the direct pathway, drives negative reinforcement and is essential for aversive learning in mice. Contrasting a “conventional” striosomal direct pathway, the Tshz1 neurons cause aversion, movement suppression, and negative reinforcement once activated, and they receive a distinct set of synaptic inputs. These neurons are predominantly excited by punishment rather than reward and represent the anticipation of punishment or the motivation for avoidance. Furthermore, inhibiting these neurons impairs punishment-based learning without affecting reward learning or movement. These results establish a major role of striosomal neurons in behaviors reinforced by punishment and moreover uncover functions of the direct pathway unaccounted for in classic models.

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