Inflammation increases the development of depression behaviors in male rats after spinal cord injury

Abstract

Following spinal cord injury, 18–26% of patients are diagnosed with depressive disorders, compared to 8–12% in the general population. As increased inflammation strongly correlates with depression in both animal and human studies, we hypothesized that the immune activation inherent to SCI could increase depression-like behavior. Thus, we proposed that reducing immune activation with minocycline, a microglial inhibitor, would decrease depression-like behavior following injury. Male Sprague-Dawley rats were given minocycline in their drinking water for 14 days following a moderate, mid-thoracic (T12) spinal contusion. An array of depression-like behaviors (social activity, sucrose preference, forced swim, open field activity) were examined prior to injury as well as on days 9–10, 19–20, and 29–30 post-injury. Peripheral cytokine levels were analyzed in serum collected prior to injury and 10 days post-injury. Hierarchical cluster analysis divided subjects into two groups based on behavior: depressed and not-depressed. Depressed subjects displayed lower levels of open field activity and social interaction relative to their not-depressed counterparts. Depressed subjects also showed significantly greater expression of pro-inflammatory cytokines both before and after injury and displayed lower levels of hippocampal neurogenesis than not-depressed subjects. Intriguingly, subjects who later showed depressive behaviors had higher baseline levels of the pro-inflammatory cytokine IL-6, which persisted throughout the duration of the experiment. Minocycline, however, did not affect serum cytokine levels and did not block the development of depression; equal numbers of minocycline versus vehicle-treated subjects appeared in both phenotypic groups. Despite this, these data overall suggest that molecular correlates of inflammation prior to injury could predict the development of depression after a physical stressor.

The Potential Role of Inflammation in Modulating Endogenous Hippocampal Neurogenesis After Spinal Cord Injury

“…The size of the hippocampus of humans with schizophrenia are reduced (Steen et al, 2006) with a reduction in the number of Ki67 + cells, although no changes in the number of NeuN + were noted (Reif et al, 2006;Allen et al, 2016). Rats with depression had decreased number of DCX + cells in the suprapyramidal blade of the dentate gyrus (Brakel et al, 2021). Increasing hippocampal neurogenesis through genetic manipulation was able to rescue mice from depressive like behaviors induced by chronic corticosterone administration (Hill et al, 2015).…”

“…Unfortunately, people living with SCI are much more likely to commit suicide with reports in England showing a 5-fold increase in per capita suicide rates (Savic et al, 2018). Furthermore, 28% of rats with T12 contusion SCI suffered from depression (Brakel et al, 2019) which was associated with increased serum levels of interleukin (IL)-6 and IL-1α before and IL-6 and tumor necrosis factor (TNF)-α after injury (Brakel et al, 2021). These findings imply predisposition to depression even before injury occurs if systemic increases in inflammation induces depression (Lee and Giuliani, 2019).…”

Osteopenia in a Mouse Model of Spinal Cord Injury: Effects of Age, Sex and Motor Function

“…In the current study, the mice recovered plantar-weight supported stepping, but the SCI might still affect the amount of locomotion that they engage in. For example, both rodents and humans have an increased incidence of depression after SCI [ 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ], which could reduce motivation to move in the home cage. Rather than locomotor function per se, focusing on activities that place high compressive loads on the bone or increasing the duration of physical activity may be important for re-establishing bone formation after SCI.…”

Breaking Mental Barriers Promotes Recovery After Spinal Cord Injury

“…A nationwide population-based cohort study has also found that SCI individuals, in particular those <50 years old, have a high risk of anxiety or depression post-discharge (Lim et al, 2017 ). On the cellular level, elevated levels of pro-inflammatory cytokines associated with depression- and anxiety-like behavior are present following spinal contusion injury in rats (Maldonado-Bouchard et al, 2016 ; Brakel et al, 2021 ). Experimentally, depression-like behavior in contused rats can be reversed with antidepressants (Luedtke et al, 2014 ).…”