Calca, encoding the neuropeptide calcitonin gene-related peptide (CGRP), is involved in multiple biological functions. The Calca-expressing neurons in the parabrachial nucleus (PBN) play a crucial role in relaying aversive sensory information. They are associated with processes like nociplasticity, a poorly understood form of pain mediated by central nervous system plasticity, and may also be involved in taste-guided behaviors [1,2,5].

In KO mouse models, CALCA-/-mice showed increased cartilage degeneration, subchondral bone loss, and elevated osteoclast numbers in a post-traumatic osteoarthritis (ptOA) model compared to αCGRP-/-and WT mice. Osteophyte formation was reduced in CALCA-/-and αCGRP-/-mice, while reduced synovitis was seen only in CALCA-/-mice, suggesting different roles of CALCA-encoded peptides in ptOA [4]. In addition, preventing PBN Calca neurons from releasing neurotransmitters demonstrated that activation of Calca neurons is necessary for chronic pain manifestation, and direct stimulation showed they are sufficient to drive nociplasticity [1,2]. Chemogenetic inhibition of Calca neurons during CS1-CS2 pairing in a second-order conditioning paradigm in mice attenuated the conditioning, indicating their role in forming second-order memories [3].

In conclusion, Calca is essential for functions related to pain, taste, and memory formation. Gene knockout mouse models have revealed its significance in diseases such as ptOA, providing insights into potential therapeutic targets for these conditions.

References:

1. Condon, Logan F, Yu, Ying, Park, Sekun, Nelson, Tyler S, Palmiter, Richard D. 2024. Parabrachial Calca neurons drive nociplasticity. In Cell reports, 43, 114057. doi:10.1016/j.celrep.2024.114057. https://pubmed.ncbi.nlm.nih.gov/38583149/

2. Condon, Logan F, Yu, Ying, Park, Sekun, Nelson, Tyler S, Palmiter, Richard D. 2023. Parabrachial Calca neurons drive nociplasticity. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.10.26.564223. https://pubmed.ncbi.nlm.nih.gov/37961621/

3. Park, Sekun, Zhu, Anqi, Cao, Feng, Palmiter, Richard D. 2024. Parabrachial Calca neurons mediate second-order conditioning. In Nature communications, 15, 9721. doi:10.1038/s41467-024-53977-w. https://pubmed.ncbi.nlm.nih.gov/39521770/

4. Jiang, Shan, Xie, Weixin, Knapstein, Paul Richard, Baranowsky, Anke, Keller, Johannes. 2024. Transcript-dependent effects of the CALCA gene on the progression of post-traumatic osteoarthritis in mice. In Communications biology, 7, 223. doi:10.1038/s42003-024-05889-0. https://pubmed.ncbi.nlm.nih.gov/38396204/

5. Lemon, Christian H, Li, Jinrong, Ali, Md Sams Sazzad, Zumpano, Kyle T, Roberts, Catori J. 2025. Parabrachial Calca neurons influence aversive and appetitive taste function. In bioRxiv : the preprint server for biology, , . doi:10.1101/2025.02.28.640892. https://pubmed.ncbi.nlm.nih.gov/40093097/