New research on the brain mechanisms regulating animals’ decision to seek food in a threatening environment, from the lab of Fabricio Do Monte, DVM, PhD, assistant professor of neurobiology and anatomy, has been published in Nature Communications.

First author for the paper titled “A hypothalamic-thalamostriatal circuit that controls approach-avoidance conflict in rats,” is Douglas Engelke, PhD, postdoctoral fellow, while graduate student Xu Zhang, is the second author.

“In nature, animals are constantly exposed to conflicting situations that involve both rewarding and risking components, challenging them to make decisions to maximize survival rate,” the authors wrote. “These processes are well-conserved across species, and maladaptive behaviors during these conflicting situations in humans may explain the high prevalence of comorbidity between anxiety disorders and eating disorders.”

The Do Monte Lab focused on the paraventricular nucleus of the thalamus (PVT), a brain region important to regulate many biological responses including stress, fear, anxiety, and food seeking behaviors.  They believed that PVT neurons “integrate food-associated cues with predator-related threat signals to guide the most appropriate behavioral strategy.”

To test their hypothesis, the authors created a model in which rats previously trained to press a lever for food during the presentation of audiovisual cues had to overcome their fear of a predator odor in order to approach the source of food. This model takes advantage of the innate fear responses that rats exhibit when exposed to predator odors (e.g., cat saliva). By exposing the rats to food-paired cues and the predator odor stimulus in combination, the group sought to create a conflict between food-seeking and anti-predator defensive responses, which resembles the motivational conflict observed in a natural environment.

“We found that when faced with both food cues and cat odor during the conflict test, rats displayed a repertoire of defensive behaviors including freezing, avoidance, and head-out (risk-assessment) responses,” Zhang said. “Additionally, the rats showed a strong suppression of food-seeking responses characterized by three distinct behavioral changes: a reduction in time spent exploring the food area, an attenuation in the rate of lever presses, and an increase in the latency to press after the onset of the food cue.”

Through their experiments, the researchers observed that rats exposed to the predator odor showed increased activity in brain regions that are known to be involved in anti-predator defenses. In addition, they found increased neuronal activity in the anterior part of the PVT (aPVT), an area important to control food-seeking behaviors, suggesting a potential role for the aPVT in regulating the behavioral shift between searching for food and avoiding potential harm imposed by the predator.

Using electrophysiological tools, the group recorded the activity of individual aPVT neurons while the rats were performing the conflict test. “When we examined changes in the firing rates of aPVT neurons, we observed that the majority of the cells that were either excited or inhibited by the food cues before the conflict, stopped responding to the food cues during the conflict, suggesting that aPVT neurons integrate food- and predator-related information,” Engelke said.

The Do Monte team also identified a sub-population of aPVT neurons that express corticotrophin-releasing factor (CRF), an important neuropeptide that is released during stressful situations and has been implicated in food-seeking regulation. Therefore, they hypothesized that aPVT neurons expressing CRF (aPVTCRF) could be involved during the food vs. predator odor conflict.

Indeed, when the authors used a chemogenetic technique to inactivate specifically the aPVTCRF neurons during conflict, the rats showed reduced defensive responses and restored food-seeking behavior. Using a genetic/laser technique called optogenetics, the authors also demonstrated that activation of a pathway that connects the aPVTCRF neurons to the nucleus accumbens – a brain region important for motivation – was sufficient to mimic the suppression in food seeking and the avoidance responses induced by predator odor.

The authors went further to demonstrate that aPVTCRF neurons receive direct connections from the ventromedial hypothalamus, a key structure regulating innate fear responses. Interestingly, inactivating ventromedial hypothalamus neurons that are connected with the aPVT reduced rats’ defensive responses to the predator odor exclusively during the conflict test, indicating that this pathway transmits predator-threat signals to aPVT neurons during situations of conflict.

“Besides odor information from the ventromedial hypothalamus, the PVT region receives auditory and visual information coming from cortical areas, suggesting that PVT neurons can also integrate other types of sensorial stimuli associated with potential threats”, the authors said.

Do Monte said he believes that this study can advance the understanding of the neural mechanisms that govern the opposing drives of approaching rewards and avoiding threats, which can help to elucidate response selection and adaptive behaviors in humans.

This work was supported by a National Institutes of Health (NIH) grant R00-MH105549, an NIH grant R01-MH120136, a Brain & Behavior Research Foundation grant (NARSAD Young Investigator), and a Rising STARs Award from UT System to Do Monte.