Physiology and behavior are synchronized to light-dark cycles via direct photic input from the retina to the suprachiasmatic nucleus (SCN) of the hypothalamus, which serves to synchronize biological rhythms to the external 24 h day. The timing, duration, and intensity of light serves as a potent zeitgeber (entraining cue). Therefore, inopportune exposure to light during the night has deleterious effects on physiology and behavior via disruption of circadian rhythms (Fonken and Nelson, 2014; Navara and Nelson, 2007). Emerging evidence highlights the myriad of adverse consequences associated with nighttime light and how disrupted circadian rhythms alter health outcomes and increase risk for disease. Indeed, even exposure to low level, dim light at night (dLAN) disrupts molecular clock rhythms (Fonken et al., 2013a). Importantly, dLAN has a wide range of effects on immune function, including impairing innate immune response (Bedrosian et al., 2011), disrupting daily rhythms of circulating immune cells (Okuliarova et al., 2021b), and inducing pro-inflammatory cytokines (i.e., increasing TNF (Bedrosian et al., 2013), IL-1β (Walker et al., 2020), and IL-6 (Bumgarner et al., 2020). Furthermore, the onset of these effects can be rapid; neuroimmune changes have been reported after as few as four nights of exposure to light in otherwise healthy mice (Bedrosian et al., 2013; Bumgarner et al., 2023, Bumgarner et al., 2020; Walker et al., 2020).

In the context of CNS disease states, including stroke, innate immune response and the initiation of inflammation play critical roles in pathophysiological progression of neuronal injury (Iadecola and Anrather, 2011). During acute ischemia, cerebral arteries become occluded from the formation of an embolism or thrombus, resulting in reduced blood flow to regions of the brain that may result in neuronal death. Notably, ischemic strokes are one of the leading causes of death and long-term disability worldwide (Feigin et al., 2021) and vessel recanalization is currently the only acute treatment. Thus, identifying and eliminating modifiable factors that promote excess neuronal damage during the acute recovery phase is crucial to achieving optimal outcomes. We propose that post-stroke dLAN exposure is a modifiable risk factor for poor outcome due to its rapid and substantial effects on the immune system. Indeed, inflammation is a crucial factor in stroke recovery; it has the potential to promote recovery via the clearance of debris and support of tissue repair, as well as the potential to exacerbate neuronal damage through creation of a neurotoxic microenvironment. The timing and nature of inflammation contributes to the evolution of secondary neuronal damage.

The overarching hypothesis for this study is that post-stroke dLAN exposure amplifies stroke damage and mortality by modifying the CNS immune response. In particular we focused on microglia because they are the predominant resident immune cells of the central nervous system, possess molecular circadian clocks that display robust rhythms (Fonken et al., 2015), and have been extensively studied in the context of stroke (Zhao et al., 2017). The mechanisms driving neuro-immune interactions with light at night in a disease state such as ischemic stroke, remains unspecified. Therefore, in the present study we investigated early infarct development and changes in microglia following post-stroke exposure to dLAN and determined the contribution of microglia to secondary neuronal damage following exposure to dark nights versus dLAN.