Conclusion
CCI-induced CHOP upregulation impairs dCA1 synaptic plasticity and neuronal activity, leading to chronic pain-related cognitive deficits.
Methods
The memory capability following CCI was assessed utilizing the Morris water maze (MWM) and fear conditioning test (FCT). Activation of the UPR was quantified by assessing levels of CHOP and key ER stress sensors. The terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay and the levels of cleaved caspase-3 were utilized to assess apoptosis level. Synaptic plasticity was assessed via a modified Golgi-Cox staining method, and long-term potentiation (LTP) measurements were taken. Neuronal activity was determined by immunofluorescence and fiber photometry. Knockdown of CHOP and alleviation of ER stress were selectively induced by LV-Ddit3-shRNAs and the chemical chaperone 4-phenylbutyric acid (4-PBA), respectively.
Results
Mice subjected to CCI displayed enduring pain and cognitive impairments evident on Days 21-28 post-surgery. Following CCI, changes in the dorsal CA1 (dCA1) manifested as ER dilation, upregulation of CHOP and upstream signaling molecules, reduced dendritic spine density, and PSD95 levels, and impaired LTP. Additionally, the co-localization of CaMKIIα/c-Fos and CaMKIIαdCA1-mediated calcium signaling was significantly reduced, while the activation of CaMKIIα was found to mitigate cognitive impairments in CCI mice. Selective knockdown of CHOP enhanced synaptic plasticity and CaMKIIα neuron activity, while 4-PBA treatment alleviated ER stress, synergistically improving cognitive deficits associated with chronic pain.