Neuroscientists identify brain pathway that prioritizes safety over other needs

A new study published in Nature Neuroscience has identified a brain circuit in mice that overrides basic needs like hunger or social contact in favor of seeking safety. Researchers found that a connection between the lateral hypothalamus and the brainstem initiates movement toward shelter in threatening contexts, even when mice are motivated by food or social interaction.

Animals, including humans, are constantly balancing competing needs—such as hunger, social connection, and safety. While the brain must continually assess environmental cues to prioritize which need to address, little was known about the specific deep brain circuits that govern this prioritization. This study set out to uncover whether certain neural pathways could drive safety-seeking behavior even when other needs are pressing.

“We are interested in how the brain controls behaviors through movement and wanted to explore how lateral hypothalamic circuits communicate with brainstem circuits that initiate locomotion,” said study author Ole Kiehn, a professor of neuroscience at the University of Copenhagen and Karolinska Institutet.

The research team focused on the lateral hypothalamus, a region long associated with drives like feeding, and the pedunculopontine nucleus in the brainstem, which plays a key role in initiating movement. Prior studies suggested that electrical or chemical stimulation of the lateral hypothalamus could induce movement in animals, but the precise neurons involved and their role in context-specific behaviors remained unclear.

To explore this, the researchers conducted a series of experiments using genetically modified mice that allowed them to precisely identify and manipulate specific populations of neurons. They focused on excitatory neurons in the lateral hypothalamus that send projections to the pedunculopontine nucleus. Using optogenetics—a method that uses light to control neuron activity—they stimulated these neurons and observed the behavioral outcomes.

When these lateral hypothalamic neurons were activated, the mice rapidly initiated movement. The direction of this movement depended on the context. In situations where the animals faced a potential threat, such as an aversive sound or air puff, they moved toward shelter—even if they were hungry or engaged in social exploration. This behavior was specific to stimulation of this circuit; control stimulations using different wavelengths of light or non-targeted viral injections did not produce the same response.

In behavioral tests, the team showed that activation of this circuit reliably caused mice to abandon food or social interactions and seek shelter. For example, in a test where food and shelter were placed in opposite corners of an arena, hungry mice that had been fasting for over 16 hours chose to retreat to the shelter when the circuit was activated. The same was true when the competing option was the opportunity to investigate another mouse of the opposite sex.

Additional experiments confirmed that this safety-seeking behavior was not a byproduct of general discomfort or motor activation. When the researchers broadly stimulated movement-related neurons elsewhere in the brainstem, the mice became active but did not consistently head for shelter. This suggested that the observed behavior was not just general locomotion but a directed, purposeful action prioritizing safety.

“We initially we thought that lateral hypothalamic to pedunculopontine nucleus circuits would be involved in food seeking, which involves approach to food rather than running to safety away from food,” Kiehn told PsyPost. “It was a surprise to discover the innate and generalized nature of the safety circuits.”

To further test the circuit’s role, the researchers used chemogenetics to artificially increase or decrease the activity of these neurons over longer periods. When they increased activity, mice spontaneously returned to the shelter more often, even in the absence of explicit threats. When they suppressed activity, the animals were slower to respond to threats and less likely to seek shelter. These changes occurred without affecting overall movement levels, indicating that the circuit plays a specific role in driving safety-related behavior.

Neural recordings supported these findings. Using fiber photometry, the researchers tracked real-time activity in the circuit as mice encountered cues linked to potential threats. Activity in the lateral hypothalamus–pedunculopontine circuit rose just before the animals initiated movement toward safety. The increase in neural activity preceded the actual motion, indicating that this pathway likely initiates the decision to retreat.

The researchers also examined whether this circuit had connections to other areas of the brain involved in emotion and motivation. They found that many of the same neurons projected to regions like the ventral tegmental area, the locus coeruleus, and the periaqueductal gray—areas linked to reward, arousal, and defensive behavior. However, only the projection to the pedunculopontine nucleus appeared to directly initiate shelter-seeking locomotion.

To rule out the influence of these other regions, the team selectively inhibited neurons in the ventral tegmental area during activation of the hypothalamus–brainstem pathway. The safety-seeking behavior remained unchanged. This suggests that while other regions may be coactivated, the primary driver of the shelter-seeking response was the connection between the lateral hypothalamus and the pedunculopontine nucleus.

Interestingly, the study also addressed the question of whether the response was related to traditional escape behaviors. Unlike rapid fleeing responses triggered by immediate threats such as predators, the behavior observed here resembled a slower, more deliberate retreat to shelter. This suggests that the circuit may help the animal weigh current needs against potential risks and choose a course of action that favors long-term survival.

The study also ruled out the involvement of a well-known group of hypothalamic neurons called orexin neurons, which are implicated in arousal and feeding. Although these neurons share some characteristics with the population studied here, they were found to be anatomically and functionally distinct.

One of the most intriguing aspects of the study is the possibility that this circuit can be shaped by experience. The researchers observed that external cues, such as sounds previously paired with air puffs, could activate the circuit even in the absence of a physical threat. This suggests that the pathway could play a role in learned avoidance or anxiety-related behaviors.

“Basically, what we have discovered is an evolutionary survival mechanism in the mouse’s brain,” Kiehn explained. “It connects part of the hypothalamus (the lateral hypothalamus) to and area of the brainstem – the pedunculopontine nucleus- that plays a key role in initiating movement. When active, the network sets aside other needs such as food seeking and social contact and makes the mouse run for cover.”

While the findings come from studies in mice, the researchers noted that both the lateral hypothalamus and the pedunculopontine nucleus are found in all vertebrates, including humans. This raises the possibility that similar mechanisms may underlie how other animals—and potentially people—prioritize safety in complex environments.

But the researchers also noted that mice are prey animals with highly developed threat avoidance behaviors, so it is unclear whether the same prioritization system exists in animals that face fewer natural predators. “Even though a lot of species, humans included, are not prey as such, it is possible that similar circuits are vital to the universal balancing of needs fulfilment and avoiding danger,” Kiehn said. “Because the circuit we have discovered can also be affected by external signals that may serve as learning cues, it is possible that the circuit is affected by stressful situations that may eventually lead to increased anxiety.”

Future research will need to determine how this circuit interacts with higher-level decision-making processes and how it may be modulated in different internal states, such as hunger, fatigue, or stress. It is also possible that dysfunction in this circuit could contribute to disorders where threat perception is altered, such as anxiety or post-traumatic stress.

The study, “A hypothalamus–brainstem circuit governs the prioritization of safety over essential needs,” was authored by Nathalie Krauth, Lara K. Sach, Giacomo Sitzia, Christoffer Clemmensen, and Ole Kiehn.