Entries from the anterior cingulate to the nucleus accumbens control the social transfer of pain and analgesia

Social transmission of pain and relief

In rats, both pain and fear can be transferred by short social contact from an animal to a spectator. Neurons in a region of the brain called the anterior cingulate cortex in the spectating animal mediate these transfers. However, the specific projections of the anterior cingulate involved in such empathy-related behaviors are unknown. Smith et al. found that projections from the anterior cingulate cortex to the nucleus accumbens are necessary for the social transfer of pain in mice (see Klein and Gogolla’s Perspective). Fear, however, was mediated by projections from the anterior cingulate cortex to the basolateral amygdala. Interestingly, in animals in pain, analgesia can also be transferred socially.

Science, this problem p. 153; see also p. 122

Structured Summary

INTRODUCTION

Empathy, the adoption of the other’s sensory and emotional state, plays a critical role in social interactions. Although, historically, empathy has often been considered an affective-cognitive process experienced only by humans, it is now recognized that many species, including rodents, have evolutionarily conserved behavioral antecedents of empathy, such as observational fear. Therefore, it is possible to begin to define the neural mechanisms that mediate the behavioral manifestations of empathy in species that are ideal for the application of modern circuit neuroscience tools.

JUSTIFICATION

In humans and rodents, the anterior cingulate cortex (ACC) appears to encode information about other people’s affective status. However, little is known about which targets downstream from the ACC contribute to empathy-related behaviors. To address this topic, we optimized a protocol for the social transfer of pain behavior in mice and compared the ACC-dependent neural circuits responsible for this behavior with the ACC neural circuits necessary for the social transfer of two related behavioral states: analgesia and fear. These behaviors exhibit a key component of empathy, the adoption of another person’s sensory and affective state.

RESULTS

A social interaction of 1 hour between an observer mouse and a cage companion with inflammatory pain led to mechanical hyperalgesia in the observer mouse, which lasted 4 hours, but not 24 hours. This social transfer of pain was also evident after the thermal test and led to affective changes that were detected by a co-specific. The social interaction led to the activation of neurons in the ACC and several downstream targets, including nucleus accumbens (NAc), which was revealed by tracking the monosynaptic rabies virus to be directly connected to the ACC. The bidirectional manipulation of activity at the ACC-to-NAc inputs influenced the acquisition of socially transferred pain, but not the expression of the mechanical sensitivity used to assess pain thresholds. A behavioral protocol revealed the rapid social transfer of analgesia, which also required activity at the inputs of ACC-to-NAc. In contrast, ACC entry activity for NAc was not necessary for the social transfer of fear, which instead required activity in ACC projections into the basolateral amygdala (BLA).

CONCLUSION

We established that rats quickly adopt the sensory-affective state of a social partner, regardless of the value of the information (that is, pain, fear or pain relief). We found that ACC generates specific and appropriate empathetic behavioral responses through distinct downstream targets. Specifically, the input activity from ACC to NAc is necessary for the social transfer of pain and analgesia, but not the social transfer of fear, which instead requires input activity from ACC to BLA. Elucidating specific circuit mechanisms that mediate various forms of empathy in experimentally accessible animal models is necessary to generate hypotheses that can be evaluated in humans using non-invasive assays. A more sophisticated understanding of brain mechanisms of empathy preserved evolutionarily will also accelerate the development of new therapies for empathy-related deficits associated with a wide range of neuropsychiatric disorders.

Different ACC neural circuits mediate the social transfer of states of pain and fear.

The pain induced by Freund’s complete adjuvant (CFA) is transferred from cage mates to spectators after a social interaction of 1 hour. Passers-by also experience pain relief after interacting with cage mates who are experiencing pain and analgesia with morphine. The social transfer of pain and analgesia requires ACC-to-NAc projections, while the social transfer of fear requires ACC projections to the BLA. The data represent the mean ± SEM; the dashed line indicates the average baseline limit for all groups; **P <0.01 and ****P <0.0001.

Abstract

Empathy is an essential component of social communication that involves experiencing the sensory and emotional states of others. We observed that a brief social interaction with a mouse in pain or analgesia with morphine resulted in the transfer of these experiences to his social partner. Optogenetic manipulations demonstrated that the anterior cingulate cortex (ACC) and its projections to the nucleus accumbens (NAc) were selectively involved in the social transfer of pain and analgesia. In contrast, the ACC → NAc circuit was not necessary for the social transfer of fear, which instead relied on ACC projections into the basolateral amygdala. These findings reveal that ACC, an area of the brain strongly implicated in human empathic responses, mediates different forms of empathy in mice, influencing different targets downstream.

Source