Orexinergic signaling mediates light-induced neuronal activation in the dorsal raphe nucleus
Introduction
Seasonal affective disorder (SAD) is a major depressive disorder that recurs in the fall and winter due to the reduction of natural daylight in the environment (Rosenthal et al., 1984). To correct for the light deficiency, light therapy has been utilized and is known to be one of the most effective treatment methods for SAD (Rosenthal et al., 1984). Light is the most salient cue for entraining circadian rhythms (Pittendrigh, 1993). Therefore, it has been hypothesized that light therapy improves mood by resetting the circadian rhythms that become desynchronized with the environment due to light deficiency (Lewy, 2009). In addition to the circadian system, deficits in central monoaminergic systems, particularly serotoninergic transmission, have also been implicated in the pathogenesis of SAD and selective serotonin (5-HT) reuptake inhibitors (SSRIs) can be effective in treating SAD (Ruhrmann et al., 1998). However, the underlying neural pathways through which light regulates mood are still for the most part uncharted territory (Levitan, 2007).
A major barrier to progress for research in this area is the lack of adequate animal models (Cryan and Slattery, 2007, Pollak et al., 2010). Those readily available to researchers such as nocturnal mice and rats are not optimal for exploring the effects of light in regulating mood in diurnal humans due to the substantial differences between the diurnal and nocturnal animals in their circadian physiology and direct responses to light (Smale et al., 2003, Challet, 2007). For instance, the daily fluctuations in hypothalamic 5-HT content are oppositely phased, with the peak level occurring during the day in diurnal species, and at night in nocturnal ones (Poncet et al., 1993, Cuesta et al., 2008). Moreover, light enhances activity and promotes wakefulness in diurnal species, but inhibits activity and induces sleep in nocturnal ones (Campbell and Dawson, 1990, Redlin, 2001). Therefore, a diurnal animal model is needed to elucidate the neural pathways mediating the effects of light on the circadian, arousal and monoaminergic systems, which could ultimately contribute to mood regulation.
In the present study, we utilized a diurnal rodent model, the Nile grass rats (Arvicanthis niloticus). These grass rats show diurnal patterns of general activity in the field and laboratory (McElhinny et al., 1997, Blanchong et al., 1999). When housed in winter-like lighting conditions, they show depression-like behaviors, supporting their potential for use as an animal model of SAD (Ashkenazy-Frolinger et al., 2010, Workman and Nelson, 2011, Yan, 2011). To explore the neural pathways mediating the effects of light on mood, an acute light pulse (LP) was administered in the early subjective day to grass rats housed in constant darkness (DD). This LP was intended to mimic the acute effect of light therapy, which is generally carried out during early daytime (Terman and Terman, 2005, Terman, 2007). Using c-Fos as a marker, the brain responses were examined, in three interconnected brain regions/cell populations that could potentially be involved in mediating the effects of light on mood regulation: the principal circadian clock in the suprachiasmatic nucleus (SCN) (Stephan and Zucker, 1972), the wakefulness-promoting orexin neurons (Sakurai, 2007), and the largest serotonergic nucleus within the dorsal raphe nucleus (DRN) (Wiklund et al., 1981). The results provide insights into the neural pathways mediating the effects of light in brain regions that are involved in mood regulation.
Section snippets
Animals and experimental groups
The grass rats (A. niloticus) were obtained from a laboratory colony established with animals from East Africa. Food (Prolab 2000 #5P06, PMI Nutrition LLC, MO, USA) and water were provided ad libitum. Adult male and female grass rats (n = 32) were kept in a 12:12-h light/dark cycle (LD, 300lux/1lux). The time of lights-on was defined as Zeitgeber time (ZT) 0, and the time of lights-off was defined as ZT12. To explore the neural pathways mediating the effects of light, the animals were exposed to
Time course of Fos-ir following light exposure during subjective day
Following the light exposure, the time course of neural activity was assessed in the SCN, PF-LHA and DRN (Fig. 1). In the SCN (Fig. 1A), no apparent changes in the number of Fos-ir nuclei were observed from the beginning through the end of the 120-min light exposure (one-way ANOVA, F3,19 = 0.26, p > 0.05). In the PF-LHA of the tuberal hypothalamus, the number of Fos-ir nuclei increased over time following the light exposure (Fig. 1B, one-way ANOVA, F3,19 = 7.03, p < 0.05). The significant increase was
Discussion
The results from the present study show that in diurnal grass rats, light exposure during subjective daytime increases neural activity in the PF-LHA and in the DRN as measured by Fos-ir. In the PF-LHA, increased Fos-ir was co-localized with orexinergic cells. Furthermore, blocking the orexinergic signaling using an OXR1 antagonist inhibits the light-induced neural activity in the DRN. The results suggest that in a diurnal brain, light induces excitatory responses in the 5-HTergic DRN through
Acknowledgements
W.A. performed the experiment, analyzed the data and wrote the manuscript. G.L. performed the experiment and analyzed the data. L.Y. designed the experiment and wrote the manuscript. All authors have approved the final draft of the manuscript. We thank Drs. Antonio A. Nunez and Laura Smale for helpful comments on the manuscript. We also thank Jennifer Kott for technical assistance. G.L. is supported by the Provost Undergraduate Research Initiative Awards from College of Social Science of MSU.
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