Neuron: It hurts to look at?

Empathic behavior is ubiquitous in mammals, and its manifestations vary across species

Multiple brain regions are involved in empathic pain behavior: damage to the prefrontal cortex impairs the formation of empathic pain behavior; anterior cingulate cortex mirror neurons increase activity in empathic pain behavior; nucleus accumbens-anterior cingulate cortex neural loop The circuit is activated in empathic pain behavior, and inhibition of this circuit can relieve pain

On April 19, 2022, in the journal Neuron, the research team of Chen Tao from Fourth Military Medical University revealed the circuit and molecular mechanism of empathic pain behavior with cerebral hemisphere laterality

Figure 1: Bystander pain behavior flow

The researchers established a behavioral model of bystander pain: bystander mice and left common peroneal nerve ligation pain model mice were placed in a mouse cage separated by a plastic plate

Further virus tracing experiments found that excitatory neurons in the IC area can project anterogradely to the BLA, and the IC area can receive retrograde projections from the BLA area, which indicates that there is a direct anatomical connection projection from IC to BLA

Figure 2: Chemogenetics modulates IC→BLA neural circuits

Chronic activation of the IC→BLA neural circuit by chemogenetics showed transient pain responses in normal mice, while inhibition of this neural circuit in bystander mice alleviated pain behavior, suggesting that this neural circuit regulates empathic pain behavior

Through in vitro electrophysiological experiments, it was found that during empathic pain behavior, the excitatory postsynaptic currents of circuit neurons in bystander mice increased, the release of presynaptic glutamate increased, and pyramidal neurons in the IC projecting BLA brain regions and Excitatory inputs to interneurons are all increased

Figure 3: Virus Induces Apoptosis of Interergic Neurons

Further use of the virus strategy to specifically induce the pain response of bystander mice after pyramidal neurons in the BLA brain region is attenuated, while after inducing internergic neuron death (Fig.

In order to further find the molecular mechanism of synaptic regulation of pain empathy behavior, they found by RNA sequencing that the IC and BLA regions of bystander mice were enriched in the expression of genes related to synaptic transmission, among which synaptotagmin-2 (regulatory presynaptic vesicle transport and Exocytosis and regulation of vesicle release) and RIM3 (distributed in the postsynaptic region and involved in synaptic transmission) were enriched and up-regulated

Virus-specific reduction of synaptotagmin-2 or RIM3 expression on the IC→BLA loop significantly reduced presynaptic glutamate release and improved pain responses in bystander mice, indicating that presynaptic synaptotagmin-2 and postsynaptic The protein RIM3 regulates the IC→BLA loop synaptic transmission process of pain empathy behavior

The anterior cingulate cortex is a key brain region that regulates empathic behavior

Collectively, this paper sheds light on the neural circuits and synaptic modulation mechanisms of pain empathic behavior: enhanced glutamatergic synaptic transmission from the right insular cortex projecting to the right basolateral amygdala circuit, this enhanced Depends on the synaptic proteins synaptotagmin-2 and RIM3

Original source:

Ming-Ming Zhang, et al.