When faced with an unfamiliar threat, animals must make split-second decisions: should they flee to avoid potential harm or push forward in pursuit of a reward? This fundamental question is at the heart of a new study from the MCB lab of Naoshige Uchida , published in Nature Neuroscience (PDF), which uncovers how the mouse brain dynamically regulates avoidance behaviors by balancing competing neural signals. Their findings challenge long-held assumptions about dopamine, a neurotransmitter commonly associated with reward, showing that in certain brain regions, it plays a key role in promoting avoidance.
A Naturalistic Approach to Studying Threat Avoidance
“Our goal was to create a scenario that better reflects the complex choices animals make in the wild,” explains the last and corresponding author Mitsuko Watabe-Uchida, Research Fellow, Center for Brain Science. To do so, Iku Tsutsui-Kimura, a former postdoc who has now become an associate professor at Hokkaido University, developed a new behavioral paradigm using mice encountering a moving “monster” while seeking water in an open arena. The monster—a small object that moves back and forth while emitting a loud, unsettling roar—initially caused the mice to avoid the water source altogether. However, over time, the animals learned to tolerate the monster’s presence, striking a balance between caution and the need for hydration.
“The mice didn’t just suppress their fear entirely; instead, they learned to navigate between safety and necessity,” adds Watabe-Uchida. “It’s a nuanced, adaptive behavior.”
Even after the mice improved at acquiring water despite the monster’s presence, they remained cautious, quickly darting away after drinking. This indicated that the animals had not simply extinguished their fear but instead learned to override it when necessary. The researchers sought to uncover the neural mechanisms driving this behavior.
The Role of the Tail of the Striatum in Avoidance
To pinpoint how the brain governs these threat-coping decisions, the team focused on a specific region called the tail of the striatum (TS), which they had previously identified as critical for threat avoidance. The TS contains two main types of neurons: D1 neurons, which promote avoidance, and D2 neurons, which facilitate overcoming avoidance. The researchers found that early in training, D1 neurons were highly active, driving the mice to stay away from the monster. Over time, as the animals learned to tolerate the threat, D2 neuron activity increased, counterbalancing the influence of D1 neurons and allowing them to access the water despite their fear.
“This kind of dynamic balance is key,” says Watabe-Uchida. “Rather than simply being wired to avoid or not avoid, the brain appears to maintain a constant interplay between these competing signals, adjusting in real-time to changing circumstances.”
“We are intrigued by the finding indicating that the pathways involving D1 neurons and D2 neurons exert opposite influences on avoidance behavior at different phases of threat avoidance and overcoming,” adds Naoshige Uchida. “This provides a crucial insight into how this opponent circuit operates in a naturalistic behavior.”
Dopamine’s Surprising Role in Threat Processing
Dopamine is widely known for reinforcing rewarding behaviors, but its involvement in threat processing has been less clear. The researchers discovered that dopamine release in the TS surged when the monster moved, initially promoting avoidance. As the mice became more comfortable navigating the threat-reward conflict, dopamine levels gradually declined, facilitating the shift toward reward-seeking behavior.
By artificially increasing dopamine in the TS, the researchers found that avoidance behaviors became stronger, with heightened D1 neuron activity reinforcing the tendency to stay away. Conversely, suppressing dopamine activity, which is known to increase D2 neuron signaling, reduced avoidance and promoted reward acquisition.
“This was an unexpected finding,” says Watabe-Uchida. “Dopamine is typically associated with positive reinforcement, yet here we see it enhancing avoidance. It suggests that dopamine’s function is highly context-dependent, varying across different brain regions.”
The study’s insights have potential implications for understanding psychiatric conditions such as anxiety and post-traumatic stress disorder (PTSD), where avoidance behaviors can become maladaptive. It also raises important considerations for dopamine-based treatments, such as those used in Parkinson’s disease and schizophrenia. “We need to be mindful of the fact that dopamine influences multiple behavioral systems,” says Watabe-Uchida. “Altering its activity systemically could have unintended effects on threat processing and avoidance behaviors.”
A Multi-Level Competition in the Brain
The findings highlight two layers of competition within the brain. First, different populations of dopamine neurons appear to have opposing effects, with dopamine in the TS promoting avoidance while dopamine in other brain regions supports reward-seeking. Second, within the TS itself, the balance between D1 and D2 neurons determines whether an animal avoids or overcomes a threat.
“This intricate balancing act may be what allows animals to adapt flexibly to complex environments,” explains Watabe-Uchida. “Rather than a simple switch between fear and reward, the brain is constantly weighing competing priorities, adjusting its response as new information becomes available.”
Future research will explore how these competing systems are regulated and whether similar mechanisms exist in humans. By deepening our understanding of how the brain navigates threat-reward conflicts, scientists may uncover new strategies for treating disorders characterized by impaired avoidance or excessive fear.
