Research Article

Anterior cingulate inputs to nucleus accumbens control the social transfer of pain and analgesia

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Science  08 Jan 2021:
Vol. 371, Issue 6525, pp. 153-159
DOI: 10.1126/science.abe3040

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Social transmission of pain and relief

In mice, both pain and fear can be transferred by short social contact from one animal to a bystander. Neurons in a brain region called the anterior cingulate cortex in the bystander animal mediate these transfers. However, the specific anterior cingulate projections 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 the Perspective by Klein and Gogolla). Fear, however, was mediated by projections from the anterior cingulate cortex to the basolateral amygdala. Interestingly, in animals with pain, analgesia can also be transferred socially.

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

Structured Abstract


Empathy, the adoption of another’s sensory and emotional state, plays a critical role in social interactions. Although, historically, empathy was often considered to be an affective-cognitive process experienced solely by humans, it is now appreciated that many species, including rodents, display evolutionarily conserved behavioral antecedents of empathy such as observational fear. It is therefore possible to begin to define the neural mechanisms that mediate behavioral manifestations of empathy in species that are optimal for application of modern circuit neuroscience tools.


In both humans and rodents, the anterior cingulate cortex (ACC) appears to encode information about the affective state of others. However, little is known about which downstream targets of 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 circuitry responsible for this behavior with the ACC neural circuitry required for the social transfer of two related behavioral states: analgesia and fear. These behaviors exhibit a key component of empathy, the adoption of another’s sensory and affective state.


A 1-hour social interaction between a bystander mouse and a cagemate experiencing inflammatory pain led to mechanical hyperalgesia in the bystander mouse, which lasted 4 hours but not 24 hours. This social transfer of pain was also evident after thermal testing and led to affective changes that were detected by a conspecific. The social interaction led to activation of neurons in the ACC and several downstream targets, including the nucleus accumbens (NAc), which was revealed by monosynaptic rabies virus tracing to be directly connected to the ACC. Bidirectional manipulation of activity in ACC-to-NAc inputs influenced the acquisition of socially transferred pain but not the expression of the mechanical sensitivity used to assay pain thresholds. A behavioral protocol revealed the rapid social transfer of analgesia, which also required activity in ACC-to-NAc inputs. By contrast, ACC-to-NAc input activity was not required for the social transfer of fear, which instead required activity in ACC projections to the basolateral amygdala (BLA).


We established that mice rapidly adopt the sensory-affective state of a social partner, regardless of the valance of the information (that is, pain, fear, or pain relief). We find that the ACC generates specific and appropriate empathic behavioral responses through distinct downstream targets. Specifically, ACC-to-NAc input activity is necessary for the social transfer of pain and analgesia but not the social transfer of fear, which instead requires ACC-to-BLA input activity. Elucidating circuit-specific mechanisms that mediate various forms of empathy in experimentally accessible animal models is necessary for generating hypotheses that can be evaluated in human subjects using noninvasive assays. More sophisticated understanding of evolutionarily conserved brain mechanisms of empathy will also expedite the development of new therapies for the empathy-related deficits associated with a broad range of neuropsychiatric disorders.

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

Complete Freund’s adjuvant (CFA)–induced pain is transferred from cagemates to bystanders after a 1-hour social interaction. Bystanders also exhibit pain relief after interacting with cagemates that are experiencing pain and morphine analgesia. The social transfer of pain and analgesia both require ACC-to-NAc projections, whereas the social transfer of fear requires ACC projections to the BLA. Data represent mean ± SEM; dashed line indicates mean baseline threshold for all groups; **P < 0.01 and ****P < 0.0001.


Empathy is an essential component of social communication that involves experiencing others’ sensory and emotional states. We observed that a brief social interaction with a mouse experiencing pain or morphine analgesia resulted in the transfer of these experiences to its 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 both pain and analgesia. By contrast, the ACC→NAc circuit was not necessary for the social transfer of fear, which instead depended on ACC projections to the basolateral amygdala. These findings reveal that the ACC, a brain area strongly implicated in human empathic responses, mediates distinct forms of empathy in mice by influencing different downstream targets.

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