Effect of intraventricular injection of mitochondria on depressive-like behaviors, activity of indoleamine 2-3-dioxygenase pathway and mitochondrial function indices in the prefrontal cortex of depressed old male rats

Abstract

Aged people are more at risk of psychological disorders such as depression and anxiety, which are associated with reduced quality of life and disability. Mitochondrial dysfunction and abnormalities in the tryptophan-kynurenine (Kyn) pathway are associated with age-related mood disorders. This study aimed to investigate the effects of intraventricular injection of mitochondria on depression-like behaviors, the activity of the indoleamine 2-3 dioxygenase (IDO) pathway, and indicators of mitochondrial function in the prefrontal cortex of depressed old male rats. Materials and Methods: Twenty-eight old male rats (20-22 months) and 10 young (3 months) male Wistar rats were randomly divided into 4 groups including aged control rats (Aged), aged rats receiving mitochondria (Aged+ Mit), aged rats depression model (Aged+CMS), and aged rats depression model receiving mitochondrial (Aged+CMS+Mit). The animals in the third and fourth groups were subjected to chronic mild stress for 28 days to induce the depression model. Mitochondria were extracted from fresh brain tissue of 3-month-old young rats and injected intracerebroventricularly in the Aged+Mit and Aged+CMS+Mit groups after induction of the depression model. Two weeks after mitochondrial injection, forced swimming tests and sucrose tolerance test were performed to investigate depression-like behaviors, and the open field and elevated maze tests were performed to investigate anxiety-like behaviors. Finally, the prefrontal brain region was separated for molecular and histological investigations. The protein expressions of cytochrome c and IDO were measured by Western blot method. In addition, mitochondrial function indices including ATP and mitochondrial membrane potential (MMP), and the tryptophan-kynurenine pathway were measured in the PFC. The Cox-Golgi staining method was used to examine the length and number of dendritic spines in the PFC neurons. Results: Chronic stress induced depressive- and- anxiety-like behaviors in the stress-subjected aged animals. Nevertheless, mitochondrial injection reduced the symptoms of anxiety and depression in aged animals, which was associated with a decrease in protein expression and enzyme activity of IDO, a decrease in Kyn level, an increase in ATP level, an improvement in MMP, and a decrease in the release of cytochrome c in the PFC. Besides, the administration of mitochondria led to an increase in dendritic length and the number of dendritic spines in the PFC neurons of aged animals subjected to chronic stress.