fMRI analysis of MCP-1 induced prefrontal cortex neuronal dysfunction in depressive cynomolgus monkeys [post]

2020 unpublished
Depression is a serious mental illness, which is one of the main causes of disability at present. The cause and location of depression are still unclear. The purpose of this study is to establish a stable and reliable model of non-human primate depression, and further confirm the significance of neuritis in the pathogenesis of depression by combining in vivo and in vitro experiments. Methods We simulated the environment of human depression and established a cynomolgus monkeys depression model
more » ... depression model by pro-depressive prodedure (PDP). The model was evaluated by behavioral test and neurotransmitter detection, and the important functional changes of brain area were detected by Functional magnetic resonance imaging (fMRI). Abnormal inflammatory factors in serum and cerebrospinal fluid (CSF) were determined by multi factor kit. In addition, the mechanism was further verified by stereotactic injection of inflammatory factor antagonists into mouse prefrontal cortex(PFC) and cell experiments. Results Here we found that a 12-week exposure to PDP can effectively induce the depressive behaviors of cynomolgus monkeys. PDP increases the time of depressive-like and anxious-like behaviors and decreases locomotor and exploratory behaviors, which were maintained after a 4-week recovery period. PDP lowers the serum serotonin (5-HT), brainderived neurotrophic factor (BDNF) level at the end of the procedure. FMRI can reflect the state of brain function noninvasively based on the level of blood oxygen. The results demonstrate that fALFF signaling is downregulated in PFC. The downregulation of BDNF and NeuN(Neuronal nuclei antigen) in PFC are observed in depressive monkeys. At the same time, it was found that contents of the monocyte chemoattractant protein-1 (MCP-1) in serum, CSF and PFC are increased in cynomolgus monkeys receiving PDP treatment. Furthermore, we found that MCP-1 receptor antagonist (CCR2-RA-[R]) can significantly reduce the susceptibility of depression in mice and increase the expression of BDNF in serum and PFC of depressed mice and blocked the downregulation of MCP-1 on the expression of BDNF in SHSY-5Y cells. Conclusions In conclusion, PDP induces cynomolgus monkeys depression by secreting MCP-1 to impair the neurotrophic function of 5-HT in PFC. PDP is a satisfying method to establish inducible depressive model in cynomolgus monkeys. 4 Major depressive disorder (MDD) is one of the most common and most burdensome mental disorders worldwide. The 12-month and lifetime prevalence of major depressive disorder in US adults were 10.4% and 20.6%, respectively 1 . MDD generated great disability for its high severity and a long illness duration in a substantial part of patients. It thus ranked in the top five leading causes of years lived with disability in 2016 globally 2, 3 . Animal models are indispensable tools for preclinical research and drug screening in mood disorders 4 . Rats has traditionally been the species of choice in researching the pathogenesis of depressive-like behaviors. An explosion in the use of genetically modified mice switches most researchers to model depression and anxiety in mice 5 . However, solid evidence from twin studies suggested that the influence of genetic factors on MDD is around 30-40% 6 . Importantly, no specific gene was identified that authentically associated with the risk of depression 7 . Further, these rodent models have always been vilified for the "emotions are fictional causes to which we attribute animal behavior" 8 . Primatologist suggests that there is a striking continuum between humans and non-human primates when they are suffering from crippling depression 9 . The emotional similarities between the human and non-human primates far outweighs the differences as a dependent chimpanzee might starves to death when he encountered the death of his mother 8, 9 . So, non-human primates are ideal animal tools to under 'grief' and 'depression' in a closely related species. The brain structures involved in limbic regulation of emotion, such as the hippocampus and amygdala, are evolutionarily conserved from mouse to man 10 . However, the brain volume of a man is 2,700 times greater than that of a mouse. The tremendous difference suggests that the behavioral and physiological response to a stress in mice only represents a tiny fraction of the humankind. Cynomolgus monkey, which is behaviorally similar to human depression, was introduced in our research. The use of the near akin to human might deepen our understanding stress induced-social behaviors under the given social context and the biological background in the evolution history 5 .The spontaneous low-frequency fluctuations (LFF) in fMRI at rest were highly synchronous among the Thanks for
doi:10.21203/rs.2.19796/v1 fatcat:tp6emmkwm5gxddzjwi65vurnzi