How Experiencing a Negative Event Alters Responses to Others
Post by Shahin Khodaei
The takeaway
Previous negative experiences affect how mice respond to other mice in a similar state. This behavior is mediated by the corticotropin-releasing factor (CRF) system in a region of the brain called the medial prefrontal cortex.
What's the science?
As humans, we recognize the signs that another person has experienced a stressful event and respond to them, for example showing consoling or prosocial behaviors. Similar to humans, the previous experiences of a mouse can affect how it responds to another stressed mouse. These different responses may be regulated by the corticotropin-releasing factor (CRF) system in the brain, specifically in a region called the medial prefrontal cortex which is important in emotion and socialization. This week in Nature Neuroscience, Martese and colleagues investigated 1) the ways in which mice with different experiences react to a stressed mouse, and 2) the role of the CRF system in these responses.
How did they do it?
The authors used mice as either observers or demonstrators. Observer mice were placed in a box and presented with two demonstrator mice – one that was given a stressful experience right before the test (either being restrained for 15 minutes, or getting a shock to their feet), and one that was unstressed. The authors looked at how the observer interacted with the demonstrators. In some experiments, the observer was subjected to a stressful “negative self-experience” (NSE) one day before the test. The authors compared how much the observer interacted with each of the demonstrators.
To study whether CRF neurons in the medial prefrontal cortex played a role in the behavior of the observers, the authors used genetic techniques to add certain genes to these brain cells. These genes either 1) decreased the level of CRF, 2) caused the cells to emit light when they were activated, which could then be measured using a microscope, or 3) allowed the authors to decrease the activity of the cells using optogenetics.
What did they find?
When a naïve observer was placed in front of one naïve and one restraint-stressed demonstrator, the observer spent more time sniffing and interacting with the stressed demonstrator. In contrast, if observer mice had experienced a NSE of restraint, they spent less time with the restraint-stressed demonstrator (and sometimes completely avoided them). This change in response was experience-specific. If the type of stressful experience did not match between the observer and demonstrator (i.e., one was footshock-stressed and the other was restraint-stressed), the observer with NSE behaved just like a naïve observer, and spent more time with the stressed demonstrator. This suggests mice were responding uniquely to other mice experiencing similar negative events. For male mice, the behavior of the observer with NSE depended on the social status of the mouse: dominant mice avoided the stressed demonstrator, and non-dominant mice showed no preference between the stressed and naïve demonstrator. For female mice, the behavior of the observer with NSE depended on the phase of the estrus cycle (the mouse equivalent of the menstrual cycle).
The authors focused on the CRF system in the medial prefrontal cortex. They showed that reducing the level of CRF in these neurons made observers with NSE behave more similarly to naïve observers. The authors then assessed how the activity of these neurons changed in observers. They found that in naïve observers, the activity of CRF neurons increased when they were near the un-stressed demonstrator. In contrast, for observers with NSE, the activity of these neurons increased near the stressed demonstrator. If they reduced this CRF neural activity using optogenetics, naïve observers started to avoid stressed demonstrators (i.e., behave more like NSE observers) and NSE observers preferred stressed demonstrators (i.e., behave more like naïve observers). These results show that the CRF system is involved in how previous experiences influence the way mice approach stressed animals.
What's the impact?
This study sheds light on the mechanisms involved in how previous experiences influence behavioral responses to stress in others. Importantly, this research reveals a neurobiological mechanism involving the CRF system for how interactions with others may differ, based on previous negative experiences.