The ability of detecting harmful stimuli through biological testing is crucial for an individual's survival. Pain and itch, as essential components of the body's somatic sensations, aid in defending against external nociceptive stimuli and prevent tissue damage. Despite sharing similar neuroanatomical pathways and involvement in the development of related chronic diseases, pain and itch are fundamentally distinct. These two sensations elicit different neural perception and behavioral responses. However, how the respective information of pain and itch is encoded and processed in the brain to produce distinct sensations remains a scientific question that requires further research.
On May 23, 2023, Prof. Ji Hu from the School of Life Science and Technology of ShanghaiTech University and his collaborators jointly published a research article titled “Representation and Control of Pain and Itch by Distinct Prefrontal Neural Ensembles” in the scientific journal Neuron, exploring the distinct neural ensembles in the medial prefrontal cortex responsible for the separate representation of pain and itch information. It proposed that these two neural ensembles regulate pain or itch-related sensory and emotional behaviors by projecting downstream to specific areas with priority.
For the first time, researchers utilized single-cell precision in vivo microendoscopic Ca2+ imaging to investigate the distinct response patterns of neurons in the medial prefrontal cortex in response to pruriceptive or nociceptive information. By real-time and long-term monitoring of neural activity, they discovered that both stimuli could cause complex and diverse calcium signaling activity in excitatory neurons of the PL subregion. In-depth data analysis suggested that although pain- and itch-activated PL neurons were anatomically intermixed, they could be distinguished from each other in their response properties to pruriceptive or nociceptive information, indicating that separate groups of neurons in the PL region encode and process pain and itch modalities, respectively.
The research team further utilized targeted labeling and manipulation of active neuronal populations to elucidate the bidirectional regulation of acute pain and itch-related behaviors by specific ensembles of neurons labeled with acute pain or acute itch in mice. The results demonstrated that selective inhibition of chloroquine-activated PL neurons using chemical genetics significantly alleviated chloroquine-induced scratching behavior, but had no effect on acute pain-related behaviors induced by capsaicin (such as licking, flinching, and lifting the affected paw). In contrast, selective inhibition of capsaicin-activated PL neurons further enhanced capsaicin-induced pain, but had no significant effect on chloroquine-induced scratching. Additionally, specific activation of the itch-specific neuronal population positively regulated aversive emotions caused by pruritus, whereas activation of the pain-specific neuronal population inversely regulated pain-related emotions. These findings indicate that PL harbors two distinct neuronal populations that independently encode pain and itch and regulate pain- and itch-related behavioral outputs in opposite ways.
To further elucidate the heterogeneous characteristics of these two neuronal populations and explore the neural circuits underlying their regulation of pain and itch behaviors, the researchers constructed whole-brain input-output projection maps of the two neuronal ensembles activated by pain and itch in the PL region. The experimental results indicated significant differences in the inputs received by these two neuronal populations in some brain areas. Similarly, their output circuits also differed. For example, pain-activated PL neurons were found to dominate the dorsal medial thalamus, while itch-activated PL neurons were more likely to dominate the basolateral amygdala. Furthermore, the researchers demonstrate that the projection from PL to the dorsal medial thalamus negatively regulated pain behavior, while the projection from PL to the basolateral amygdala positively regulated pruritus-related sensory and emotional behaviors.
In conclusion, these findings reveal the separate representation of pain and itch by distinct neuronal populations in the PL region, and provide a comprehensive analysis of the heterogeneous characteristics of cortical neurons activated by pain and itch, including their anatomical location, functional properties, whole-brain connectivity, response patterns to pruriceptive or nociceptive information, and behavioral outputs. The existence of such heterogeneity at different levels lays the material foundation for the differential processing of pain and itch in the same area.
|
Figure: A schematic diagram of the neural mechanism for the classification and differential regulation of pain and itch by prefrontal cortical neuron ensembles.
The research findings of this article provide new knowledge towards the ultimate elucidation of the neural mechanisms underlying the classification and encoding of pain and itch, and how they lead to different sensory experiences. This creates a new theoretical framework for understanding somatosensory information processing in the brain, and provides new directions for the treatment of diseases related to pain or itching abnormalities.
Qian Pan, PhD student from the School of Life Science and Technology at ShanghaiTech University, Su-Shan Guo, PhD student from the School of Basic Medical Sciences at Shanghai Jiao Tong University, and Ming Chen, an associate researcher from the School of Life Science and Technology at ShanghaiTech University (now a researcher at the Brain Science Institute of Fudan University), are co-first authors of this article. Ji Hu, a researcher at the School of Life Science and Technology at ShanghaiTech University, Ming-Gang Liu, a researcher at the School of Basic Medical Sciences at Shanghai Jiao Tong University, and Professor Tian-Le Xu are co-corresponding authors and supervised the study.
Paper links: https://www.cell.com/neuron/fulltext/S0896-6273(23)00342-2