Effects of Varying Durations of CUMS Exposure on Anxiety, Depression-Like Behavior, Learning and Memory in Perimenopausal Rats: Associated with the Apoptosis of Medial Prefrontal Cortex Neurons

Abstract

Perimenopausal is an important physiological period during which many women experience depression, anxiety and mild cognitive impairment. However, the correlation between perimenopausal anxiety, depression, and cognitive function is not well understood. In our previous studies, we found that the model of perimenopausal depression could be established at different times, but the cognitive function of these rats were different. In this study, we investigated the different effects of varying durations of Chronic unpredictable mild stress (CUMS) exposure on anxiety, depression-like behavior, learning and memory in perimenopausal rats (using sucrose water preference experiment, forced swimming test, open field test, Morris water maze test). Neuron structure and neuronal apoptosis were determined in the medial prefrontal cortex (mPFC) (using Nissl staining, TUNEL staining, and immunofluorescence staining). Our data showed that 3wCUMS could induce depression-like behavior in perimenopausal rats, while 3wCUMS did not induce anxiety-like behavior, and even promoted learning and memory capacity. However, 8wCUMS not only induced obvious anxiety and depressive-like behavior in perimenopausal rats, but also caused significant damage to their learning and memory capacity. Pathologically, staining observations confirmed that 8wCUMS inhibited neuronal loss and alleviated the abnormal reduction of the Nissl body in the mPFC. In parallel, 8wCUMS promoted neuronal apoptosis and elevated the protein expression levels of Bcl-2 while reducing those of Bax, Caspase-3. Therefore allowing us to come to a conclusion that 8wCUMS may cause learning and memory impairment by increasing neuronal apoptosis in the mPFC.

Note:
Funding declaration: This study was supported by the National Natural Science Foundation of China (NO. 82174248, 82274409), Natural Science Foundation of Fujian Province (NO. 2024J01132, 22023J01868, 2022J01362), National College Students Innovation and Entrepreneurship Training Program (NO. 202410393010, 202310393012), and the Research Initiation Grants of Fujian University of Traditional Chinese Medicine (NO. XJC2022012).

Conflict of Interests: The authors declare that they have no conflict of interest.

Ethical Approval: All experimental procedures have been reviewed and approved by the Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine (batch number: FJTCM 3w2022023), and were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (National Research Council, 1996).

Keywords: Perimenopausal period, Chronic unpredictable mild stress, medial prefrontal cortex, apoptosis, Cognitive impairment