The Earth has rotated on its axis for billions of years, creating daily environmental rhythms of light and dark. These predictable daily light-dark cycles facilitated evolution of circadian rhythms in most organisms. Circadian rhythms are adaptive biological cycles that occur naturally over 24 h to promote activity-rest patterns and general well-being (Blume et al., 2019). Entrainment of these cycles depends upon certain environmental cues, the strongest of which is light. Rhythms in light exposure have been dampened and shifted in modern life, with reduced exposure to sunlight and increased artificial light at night (Lunn et al., 2017). Exposure to dim light at night (dLAN) is associated with health issues such as metabolic disruptions, oxidative stress, and immune system dysregulation (Fonken and Nelson, 2011, Fonken and Nelson, 2014). Circadian dysrhythmias are common in intensive care units (ICU) of hospitals, due to nighttime disruptions, inadequate exposure to daytime light, and constant exposure to low levels of light at night (Oldham et al., 2016). dLAN has detrimental effects on pathology and recovery in preclinical models. In mice, exposure to dLAN after stroke exacerbates negative outcomes and increased lesion size, which may have important implications for care of critically ill patients recovering in the ICU (Weil et al., 2020).

Spinal cord injury (SCI) affects approximately 300,000 people in the U.S. (Lasfargues et al., 1995). SCI elicits a hyperreactive response of immune cells, driving toxic neuroinflammation immediately following injury. Glial cells such as microglia, astrocytes, oligodendrocytes, oligodendrocyte progenitors, and blood-derived immune cells, play distinct roles in the SCI-elicited immune response. Although there are some positive effects of inflammation following SCI, extensive infiltration and overactivation of immune cells are major drivers of secondary damage after SCI. Cascading inflammation causes extensive cell death, deficits in locomotor activity, and chronic neuropathic pain (Gaudet and Fonken, 2018). In addition, individuals with SCI are predisposed to experiencing mood disorders like anxiety and depression (Lim et al., 2017). These behaviors may also be driven by inflammation (van West and Maes, 1999; Suarez et al., 2003). Given that the acute post-SCI inflammatory response likely exacerbates damage, strategies that quench early inflammatory reactions could benefit neuroprotection, recovery, and mood after SCI.

One potential neuroprotective pathway involves the link between circadian rhythms and inflammation. All known immune cells, including microglia and macrophages, contain intrinsic biological clocks, driving the regulation of immune responses (Keller et al., 2009; Nakazato et al., 2011). Indeed, “time-of-day” regulates microglia inflammatory reactivity; e.g., in rats, injection of lipopolysaccharide during the inactive phase induces more robust neuroinflammation compared injection during the active phase (Fonken et al., 2015). Circadian disruption also has detrimental effects in inflammatory diseases such as cancer, heart disease, and metabolic syndrome (Vyas et al., 2012; D'Ettorre et al., 2019). However, less is known about how circadian disruption affects neuroprotection and recovery after SCI.

Previous work explored the effects of dLAN on protein and gene expression to reveal disruption in core clock components (Fonken et al., 2013a). Swiss Webster mice exposed to ∼5 lx dLAN showed attenuated rhythmic expression of Bmal1, Per1, Per2, Cry1, and Cry2 mRNA relative to mice held on LD cycles. Additionally, dLAN reduced protein expression of both PER1 and PER2 in the SCN, revealing the effects of dLAN on gene- and tissue-specific changes in expression levels for various circadian clock genes. Exposure to dLAN increased microglial cytokine expression and sickness behavior following LPS administration (Fonken et al., 2013b), implying a possible effect of dLAN on inflammatory responses similar to that of SCI. Recent studies using C57BL/6 J mice established that 5 lx dLAN can disrupt sleep patterns in young and aged mice(Panagiotou and Deboer, 2020), but had minimal behavior effect in a C57BL/6 J derivative strain, B6.129S6-Per2tm1Jt/J (Cleary-Gaffney and Coogan, 2018). Further, C57BL/6 J mice exposed to 15 lx dLAN during development had increased hippocampal inflammatory gene expression accompanied by anxiety and depressive-like symptoms in adulthood(Chen et al., 2021a). These studies suggest that this strain—commonly used for transgenic manipulation—is susceptible to circadian disruption via dLAN but may require higher levels of light exposure than other strains.

Here, we predicted that exposure to dLAN after SCI may amplify SCI-elicited immune responses within the injured spinal cord, thereby exacerbating secondary damage to the lesion site and worsening recovery after SCI. To test this hypothesis, mice were divided into SCI and Sham groups. SCI mice were subjected to T9 laminectomy and moderate (65 kDyn) contusion SCI; sham animals received T9 laminectomy only. Sham and SCI mice were subsequently housed under typical light-dark conditions (LD) or newly housed in dLAN for the remainder of the study. Animals from all four experimental groups were examined over a period of 35 days post-operative (dpo). To reveal the extent that aberrant light at night shifted biology and behavior after SCI, we assessed the effects of dLAN on locomotor recovery, neuropathic pain-like behaviors, anxiety- and depressive- like behaviors, and neuroprotection.