Science | "Pain" What you "pain" is also the same as "fear"-how do mice feel each other's pain or fear?

Written | Edited by Qi | Empathy (Empathy, attention and sympathy-the difference between Sympathy, empathy is more to experience the experience with the other party) is an important part of social communication, mainly related to the experience of others Sensory and emotional state.

Although it has long been regarded as a unique human ability, it has been confirmed to exist in a series of species, usually manifested in emotional contagion, social transfer pain, observational fear, and pro-social behavior types, such as comfort and help, etc.
[ 1-4].

The anterior cingulate cortex (ACC) is a major node in the neural circuit that mediates empathy.
In humans and rodents, ACC affects direct and observed pain and socially metastatic pain.
The reaction is particularly important [5,6].

ACC is believed to be associated with brain regions including the thalamus, insula, amygdala and nucleus accumbens (nucleus accumbens, NAc) that regulate emotions and motivational states [7-9].
However, these specific ACC circuit components are in common The role of emotion-related behaviors is unclear.On January 7, Robert C.
Malenka's research group from Stanford University in the United States published an article titled "Anterior cingulate inputs to nucleus accumbens control the social transfer of pain and analgesia" in Science.
In this research , The author observed through a mouse model that the anterior cingulate cortex (ACC) and its projections to the nucleus accumbens (NAc) selectively participate in the social transfer of pain and analgesia, while fear of social transfer Metastasis depends on the projection of ACC to the basolateral amygdala (basolateral amygdala).

In general, the connection between ACC and different brain regions mediates different forms of empathy.
A deep understanding of evolutionarily conserved empathy mechanisms will help accelerate the development of new therapies for empathy-related defects associated with neuropsychiatric diseases.
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In experimental animals that have experienced pain, the presence of the same pain substance can regulate the expression of pain behavior and cause hyperalgesia in "bystander (BY)" mice that have not received any pain-inducing stimuli.
This phenomenon is called "social transfer of pain".

First, the author allowed BY mice to interact with mice in the same cage (CFA mice) experiencing inflammatory hyperalgesia for 1 hour, and then BY mice showed the same hyperalgesia as CFA mice (see Figure 1 below) .

So, what is the brain area responsible for regulating the social transfer of pain? The author used reporter mice generated by crossing FosCreERT2 (TRAP2) mice with Ai14-tdTomato strains to identify the types of neurons activated during the interaction, and found that the brain regions of BY mice related to empathy and motivation previously reported Such as ACC and NAc, as well as areas related to pain transmission, such as the thalamus, central amygdala, and midbrain peri-aqueduct gray matter are activated.

Therefore, the authors hypothesized that ACC neurons may form synaptic connections with NAc neurons to mediate the social transfer of pain.

Figure 1.
Schematic diagram of the experimental design of the social transfer effect of pain.
For this, the author injected AAV-CaMKIIa-YFP into ACC to confirm that ACC pyramidal neurons send projections to NAc, and at the same time, apply a single sheet in TRAP2-BY and -CFA mice.
Synaptic rabies virus tracing method confirms that there is a direct synaptic connection between ACC neurons and activated NAc neurons.

So is the ACC→NAc circuit necessary for the social transfer of pain? To this end, the author tested the necessity of ACC itself by injecting AAVs expressing inhibitory rhodopsin (NpHR) and placing an optical fiber directly above the ACC.

The authors found that activating NpHR during the interaction between BY and CFA mice can reduce the hyperalgesia of BY mice, but it cannot reduce the hyperalgesia of CFA mice.

Immediately afterwards, the author bilaterally injected AAVs expressing NpHR or YFP into ACC, and placed the optical fiber above NAc to detect the necessity of ACC→NAc projection.

Similar to the effect of inhibiting ACC, inhibiting the projection of ACC→NAc during the 1-hour interaction strongly impairs the social transmission of pain in mice.
On the contrary, if the light-sensitive channel protein ChR2 is expressed in ACC and ACC is activated during the interaction →NAc projection will cause the duration of hyperalgesia in mice to be significantly prolonged.

The role of empathy is not limited to the social transfer of pain.
In order to test the universality of the ACC→NAc circuit in the regulation of empathic behavior, the author further tested its role in observational fear.

The author asked the BY mice to observe the repeated electric shocks of the test mice.
During the short observation period, the BY mice showed a significant increase in "freezing-like behavior", and after 24 hours, the mice were reproduced in the electric shock observation scenario.
, Inhibiting the ACC→NAc loop does not reduce its freezing-like behavior, while the ACC→BLA loop has been proved to be related to it.

Finally, the author wants to know if pain can be transferred, can analgesia also be transferred? To test this possibility, the author again injected CFA to induce pain in all mice, and then injected a quarter of the mice with analgesic doses of morphine, and paired them to complete the 1-hour interaction process.

Unexpectedly, mice paired with the morphine treatment group showed significant pain relief.
When optogenetic suppression of ACC neurons using NpHR was used, it also prevented the social transfer effect of analgesia.

In general, the results of this study prove that mice can quickly and reliably accept the sensory and emotional states from their partners, and confirm the importance of the social environment to the experience of pain and the improvement of the neural circuits that mediate specific empathic responses.
In-depth understanding will greatly facilitate the development of appropriate interventions (empathy responses) for various neuropsychiatric diseases.

In the same journal, two professors Alexandra S.
Klein and Nadine Gogolla from the Max Planck Institute for Neurobiology in Germany commented on this wonderful study.

They believe that although the anterior cingulate gyrus cortex has been shown to play a role in empathizing with different sensory and emotional states, including pain, aversion, or fear, the neural mechanisms that cause different empathic behaviors are still unexplained.
mystery of.

Smith et al.
not only proved that the social transfer of pain depends on the ACC→NAc pathway, but the social transmission of fear involves another independent pathway: ACC→BLA.
More importantly, they also found a positive emotional state, namely Freeing from pain can also be achieved through social transmission, and a deeper understanding of the neural mechanism of social transmission in analgesia will be of great significance to human pain management.

Of course, this research also raises an interesting question, that is, does the ACC→BLA projection not only participate in the social transfer of fear, but also participate in the process of "freedom from fear" similar to ACC→NAc? In (red) The number of cases in the United States (blue) is currently one of the most recognized theories about the neural mechanism of empathy is the "perception-action model (PAM)".

Both hyperalgesia and analgesia in this study affected "bystander" mice, suggesting that the mice may have actually experienced systemic internal state changes.

In fact, studies in monkeys and rodents have proved the existence of "mirror neurons" in ACC.
These neurons are single nerve cells.
When an individual observes a sensory experience or motor behavior, Or when you experience and perform the same conditions yourself, this neuron will be activated.
Then it is important to study whether it is the activity of mirror neurons or other neuronal mechanisms to explain the social regulation of pain. Original link https://doi.
org/10.
1126/science.
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