Animals endure many physical and social stressors throughout their lifetime and have evolved crucial mechanisms to cope with these challenges. The brain is one of the primary organs involved in perceiving and adapting to various stressors. However, it remains unclear how neurons initially sense stress or which downstream signaling pathways drive behavioral responses. Addressing these questions enhances our understanding of neuronal mechanisms and provides new insights into stress-related disorders such as anxiety or depression.
The primary cilium is a microtube-based, non-motile, organelle emanating from the surface of most vertebrate cell types, including neurons in the brain. Although it is considered to be the special cellular antenna to sense environmental signals and transduce them intracellularly to regulate cellular behavior, little is known about the signaling mechanisms and physiological role of primary cilium in neocortical neurons.
On March 7, 2025, a study titled “Primary ciliary protein kinase A activity in the prefrontal cortex modulates stress in mice” was published online in Neuron by Prof. Song-Hai Shi’s group at Tsinghua University. This study, for the first time, reveals a crucial role of the primary cilia of prefrontal cortical excitatory neurons in modulating animal stress (Figure 1).
Figure 1. Prefrontal cortical neuron primary cilia modulate animal stress
In this study, the authors found that, in response to various animal stressors, primary cilia in the mouse prefrontal cortex (PFC) exhibit a consistent axonemal elongation. Selective removal of excitatory neuron primary cilia in the prefrontal, but not sensory, cortex leads to a reduction in animal stress sensing and response. Treatment with corticosterone, the major stress hormone, elicits an increase in primary ciliary cAMP level in PFC excitatory neurons and a decrease in neuronal excitability dependent on primary cilia. Suppression of primary ciliary protein kinase A (PKA) activity in PFC excitatory neurons reduces animal stress. These results suggest that excitatory neurons in the PFC are involved in sensing and regulating animal stress via primary ciliary cAMP/PKA signaling.
This study resolves the long-lasting mystery of the function and mechanism of neuron primary cilia in the neocortex. It provides new directions to the animal stress response and the stress-related disorders.
Dr. Song-Hai Shi and Dr. Hang Shi are the co-corresponding authors of this work. Postdoc fellow, Shuimu Tsinghua Scholar Jiajun Yang is the first author. Dr. Jun Chu and Dr. Liang Wang from Chinese Academy of Sciences are especially acknowledged for their support. This work was supported by STI2030-Major Projects (2021ZD0202300), National Natural Science Foundation of China (32021002), Beijing Outstanding Young Scientist Program (BJJWZYJH01 201910003012), Beijing Municipal Science & Technology Commission (Z211100003321001 and Z221100003422011), Chinese Institute for Brain Research (Beijing) and New Cornerstone Investigator Program.
Link to paper:
Editor: Li Han
