Diurnal Grass Rats Research Articles

SAD rats: Effects of short photoperiod and carbohydrate consumption on sleep, liver steatosis, and the gut microbiome in diurnal grass rats

ABSTRACT Seasonal affective disorder (SAD) is a recurrent depression triggered by exposure to short photoperiods, with a subset of patients reporting hypersomnia, increased appetite, and carbohydrate craving. Dysfunction of the microbiota – gut – brain axis is frequently associated with depressive disorders, but its role in SAD is unknown. Nile grass rats (Arvicanthis niloticus) are potentially useful for exploring the pathophysiology of SAD, as they are diurnal and have been found to exhibit anhedonia and affective-like behavior in response to short photoperiods. Further, given grass rats have been found to spontaneously develop metabolic syndrome, they may be particularly susceptible to environmental triggers of metabolic dysbiosis. We conducted a 2 × 2 factorial design experiment to test the effects of short photoperiod (4 h:20 h Light:Dark (LD) vs. neutral 12:12 LD), access to a high concentration (8%) sucrose solution, and the interaction between the two, on activity, sleep, liver steatosis, and the gut microbiome of grass rats. We found that animals on short photoperiods maintained robust diel rhythms and similar subjective day lengths as controls in neutral photoperiods but showed disrupted activity and sleep patterns (i.e. a return to sleep after an initial bout of activity that occurs ~ 13 h before lights off). We found no evidence that photoperiod influenced sucrose consumption. By the end of the experiment, some grass rats were overweight and exhibited signs of non-alcoholic fatty liver disease (NAFLD) with micro- and macro-steatosis. However, neither photoperiod nor access to sucrose solution significantly affected the degree of liver steatosis. The gut microbiome of grass rats varied substantially among individuals, but most variation was attributable to parental effects and the microbiome was unaffected by photoperiod or access to sucrose. Our study indicates short photoperiod leads to disrupted activity and sleep in grass rats but does not impact sucrose consumption or exacerbate metabolic dysbiosis and NAFLD.

S-Cone Photoreceptors Regulate Daily Rhythms and Light-Induced Arousal/Wakefulness in Diurnal Grass Rats (Arvicanthis niloticus).

Beyond visual perception, light has non-image-forming effects mediated by melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). The present study first used multielectrode array recordings to show that in a diurnal rodent, Nile grass rats (Arvicanthis niloticus), ipRGCs generate rod/cone-driven and melanopsin-based photoresponses that stably encode irradiance. Subsequently, two ipRGC-mediated non-image-forming effects, namely entrainment of daily rhythms and light-induced arousal, were examined. Animals were first housed under a 12:12 h light/dark cycle (lights-on at 0600 h) with the light phase generated by a low-irradiance fluorescent light (F12), a daylight spectrum (D65) stimulating all photoreceptors, or a narrowband 480 nm spectrum (480) that maximized melanopsin stimulation and minimized S-cone stimulation (λmax 360 nm) compared to D65. Daily rhythms of locomotor activities showed onset and offset closer to lights-on and lights-off, respectively, in D65 and 480 than in F12, and higher day/night activity ratio under D65 versus 480 and F12, suggesting the importance of S-cone stimulation. To assess light-induced arousal, 3-h light exposures using 4 spectra that stimulated melanopsin equally but S-cones differentially were superimposed on F12 background lighting: D65, 480, 480 + 365 (narrowband 365 nm), and D65 - 365. Compared to the F12-only condition, all four pulses increased in-cage activity and promoted wakefulness, with 480 + 365 having the greatest and longest-lasting wakefulness-promoting effects, again indicating the importance of stimulating S-cones as well as melanopsin. These findings provide insights into the temporal dynamics of photoreceptor contributions to non-image-forming photoresponses in a diurnal rodent that may help guide future studies of lighting environments and phototherapy protocols that promote human health and productivity.

Effects of light therapy on sleep/wakefulness, daily rhythms, and the central orexin system in a diurnal rodent model of seasonal affective disorder

BackgroundBright light therapy (BLT) is the first-line treatment for seasonal affective disorder. However, the neural mechanisms underlying BLT are unclear. To begin filling this gap, the present study examined the impact of BLT on sleep/wakefulness, daily rhythms, and the wakefulness-promoting orexin/hypocretin system in a diurnal rodent, Nile grass rats (Arvicanthis niloticus). MethodsMale and female grass rats were housed under a 12:12 h light/dark cycle with dim light (50 lx) during the day. The experimental group received daily 1-h early morning BLT (full-spectrum white light, 10,000 lx), while the control group received narrowband red light for 4 weeks. Sleep/wakefulness and in-cage locomotor activity were monitored, followed by examination of hypothalamic prepro-orexin and orexin receptors OX1R and OX2R expression in corticolimbic brain regions. ResultsThe BLT group had higher wakefulness during light treatment, better nighttime sleep quality, and improved daily rhythm entrainment compared to controls. The impact of BLT on the orexin system was sex- and brain region-specific, with males showing higher OX1R and OX2R in the CA1, while females showed higher prepro-orexin but lower OX1R and OX2R in the BLA, compared to same-sex controls. LimitationsThe present study focused on the orexin system in a limited number of brain regions at a single time point. Sex wasn't a statistical factor, as male and female cohorts were run independently. ConclusionsThe diurnal grass rats show similar behavioral responses to BLT as humans, thus could be a good model for further elucidating the neural mechanisms underlying the therapeutic effects of BLT.

Action potential firing rhythms in the suprachiasmatic nucleus of the diurnal grass rat, Arvicanthis niloticus

In mammals, daily physiological activities are regulated by a central circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). Recently, an increasing number of studies have used diurnal grass rats to analyze neuronal mechanisms regulating diurnal behavior. However, spontaneous action potential firing rhythms in SCN neurons have not been demonstrated clearly in diurnal grass rats. Therefore, the present study examined extracellular single-unit recordings from SCN neurons in acute hypothalamic slices of Arvicanthis niloticus (Nile grass rats). The results of this study found that circadian firing rhythms with the highest frequency occurred at dusk (6.4 Hz at zeitgeber time (ZT)10–12), while the secondary peak occurred at dawn (5.6 Hz at ZT0-2), and the lowest frequency took place in the middle of the night (3.6 Hz at ZT14-16). Locomotor activity recordings from a separate group of animals demonstrated that the Nile grass rats of the laboratory colony used in this study displayed diurnal behaviors that coincided with large crepuscular peaks under 12:12 h light–dark cycles and bimodal rhythms under constant dim red light. Thus, a positive correlation between SCN firing frequencies and locomotor activity levels was observed in the Nile grass rats. Previously, behavioral coupling of action potential firings in SCN neurons has been suggested by in vivo recordings while the present study demonstrates that the sustenance of bimodal firing rhythms in grass rat SCN neurons can last at least one day in vitro.

Impact of daytime light intensity on the central orexin (hypocretin) system of a diurnal rodent (Arvicanthis niloticus).

The neuropeptide orexin/hypocretin is implicated in sleep and arousal, energy expenditure, reward, affective state and cognition. Our previous work using diurnal Nile grass rats (Arvicanthis niloticus) found that orexin mediates the effects of environmental light, particularly daytime light intensity, on affective and cognitive behaviours. The present study further investigated how daytime light intensity affects the central orexin system in male and female grass rats. Subjects were housed for 4weeks in 12:12hr dim light:dark (50 lux, dimLD) or in 12:12hr bright light:dark cycle (1000 lux, brightLD). Day/night fluctuations in some orexin measures were also assessed. Despite similar hypothalamic prepro-orexin mRNA expression across all conditions, there were significantly more orexin-immunoreactive neurons, larger somata, greater optical density or higher orexin A content at night (ZT14) than during the day (ZT2), and/or in animals housed in brightLD compared to dimLD. Grass rats in brightLD also had higher cisternal CSF levels of orexin A. Furthermore, orexin receptor OX1R and OX2R proteins in the medial prefrontal cortex were higher in brightLD than dimLD males, but lower in brightLD than dimLD females. In the CA1 and dorsal raphe nucleus, females had higher OX1R than males without any significant effects of light condition, and OX2R levels were unaffected by sex or light. These results reveal that daytime light intensity alters the central orexin system of both male and female diurnal grass rats, sometimes sex-specifically, and provides insight into the mechanisms underlying how daytime light intensity impacts orexin-regulated functions.

Superior Colliculus Lesions Lead to Disrupted Responses to Light in Diurnal Grass Rats (Arvicanthis niloticus).

The circadian system regulates daily rhythms of physiology and behavior. Although extraordinary advances have been made to elucidate the brain mechanisms underlying the circadian system in nocturnal species, less is known in diurnal species. Recent studies have shown that retinorecipient brain areas such as the intergeniculate leaflet (IGL) and olivary pretectal nucleus (OPT) are critical for the display of normal patterns of daily activity in diurnal grass rats (Arvicanthis niloticus). Specifically, grass rats with IGL and OPT lesions respond to light in similar ways to intact nocturnal animals. Importantly, both the IGL and OPT project to one another in nocturnal species, and there is evidence that these 2 brain regions also project to the superior colliculus (SC). The SC receives direct retinal input, is involved in the triggering of rapid eye movement sleep in nocturnal rats, and is disproportionately large in the diurnal grass rat. The objective of the current study was to use diurnal grass rats to test the hypothesis that the SC is critical for the expression of diurnal behavior and physiology. We performed bilateral electrolytic lesions of the SC in female grass rats to examine behavioral patterns and acute responses to light. Most grass rats with SC lesions expressed significantly reduced activity in the presence of light. Exposing these grass rats to constant darkness reinstated activity levels during the subjective day, suggesting that light masks their ability to display a diurnal activity profile in 12:12 LD. Altogether, our data suggest that the SC is critical for maintaining normal responses to light in female grass rats.

Daytime Light Intensity Modulates Spatial Learning and Hippocampal Plasticity in Female Nile Grass Rats (Arvicanthis niloticus)

Light has pervasive effects on the physiology and behavior of mammals. Several human studies have shown that light modulates cognitive functions; however, the mechanisms responsible for the effects of light remain unclear. Our previous work using diurnal male Nile grass rats (Arvicanthis niloticus) revealed that reduced illuminance during the day leads to impairments in hippocampal-dependent spatial learning/memory, reduced CA1 dendritic spine density, and attenuated hippocampal brain-derived neurotrophic factor (BDNF) expression in males. The present study examined the impact of ambient light intensity on hippocampal functions in female grass rats and explored sex differences in behavioral and hippocampal responses. Female grass rats were housed in either a 12:12-hr bright light–dark (brLD, 1000 lx) or dim light–dark (dimLD, 50 lx) cycle for four weeks. The dimLD group showed impaired spatial memory in the Morris water maze task and reduced CA1 apical dendritic spine density, similar to prior observations in males. However, the behavioral deficits seen in females were more severe than those seen in males, with dimLD females showing no evidence of long-term retention over the 24-hour periods between training sessions. In contrast to the attenuated hippocampal BDNF expression found in dimLD males, there was no significant difference in the expression of BDNF and of its receptor TrkB between females in brLD and dimLD. The results suggest that, as seen in male grass rats, reduced illuminance during the day impairs hippocampal-dependent spatial memory and hippocampal plasticity in female diurnal grass rats, but the underlying signaling pathways responsible for the effects of light restriction may differ between the sexes.

P.3.a.007 - Disturbed DISC1 pathway interacts with adolescent cannabis exposure to produce impaired recognition memory restored by BDNF over-expression: a host-environment mouse model of severe mental illness

The same clock-genes, including Period (PER) 1 and 2, that show rhythmic expression in the suprachiasmatic nucleus (SCN) are also rhythmically expressed in other brain regions that serve as extra-SCN oscillators. Outside the hypothalamus, the phase of these extra-SCN oscillators appears to be reversed when diurnal and nocturnal mammals are compared. Based on mRNA data, PER1 protein is expected to peak in the late night in the paraventricular nucleus of the hypothalamus (PVN) of nocturnal laboratory rats, but comparable data are not available for a diurnal species. Here we use the diurnal grass rat (Arvicanthis niloticus) to describe rhythms of PER1 and 2 proteins in the PVN of animals that either show the species-typical day-active (DA) profile, or that adopt a night-active (NA) profile when given access to running wheels. For DA animals housed with or without wheels, significant rhythms of PER1 or PER2 protein expression featured peaks in the late morning; NA animals showed patterns similar to those expected from nocturnal laboratory rats. Since the PVN is part of the circuit that controls pineal rhythms, we also measured circulating levels of melatonin during the day and night in DA animals with and without wheels and in NA wheel runners. All three groups showed elevated levels of melatonin at night, with higher levels during both the day and night being associated with the levels of activity displayed by each group. The differential phase of rhythms in the clock-gene protein in the PVN of diurnal and nocturnal animals presents a possible mechanism for explaining species differences in the phase of autonomic rhythms controlled, in part, by the PVN. The present study suggests that the phase of the oscillator of the PVN does not determine that of the melatonin rhythm in diurnal and nocturnal species or in diurnal and nocturnal chronotypes within a species.

The contribution of the pineal gland on daily rhythms and masking in diurnal grass rats, Arvicanthis niloticus

Melatonin is a hormone rhythmically secreted at night by the pineal gland in vertebrates. In diurnal mammals, melatonin is present during the inactive phase of the rest/activity cycle, and in primates it directly facilitates sleep and decreases body temperature. However, the role of the pineal gland for the promotion of sleep at night has not yet been studied in non-primate diurnal mammalian species. Here, the authors directly examined the hypothesis that the pineal gland contributes to diurnality in Nile grass rats by decreasing activity and increasing sleep at night, and that this could occur via effects on circadian mechanisms or masking, or both. Removing the pineal gland had no effect on the hourly distribution of activity across a 12:12 light-dark (LD) cycle or on the patterns of sleep-like behavior at night. Masking effects of light at night on activity were also not significantly different in pinealectomized and control grass rats, as 1h pulses of light stimulated increases in activity of sham and pinealectomized animals to a similar extent. In addition, the circadian regulation of activity was unaffected by the surgical condition of the animals. Our results suggest that the pineal gland does not contribute to diurnality in the grass rat, thus highlighting the complexity of temporal niche transitions. The current data raise interesting questions about how and why genetic and neural mechanisms linking melatonin to sleep regulatory systems might vary among mammals that reached a diurnal niche via parallel and independent pathways.

Suprachiasmatic Nucleus and Subparaventricular Zone Lesions Disrupt Circadian Rhythmicity but Not Light-Induced Masking Behavior in Nile Grass Rats.

The ventral subparaventricular zone (vSPVZ) receives direct retinal input and influences the daily patterning of activity in rodents, making it a likely candidate for the mediation of acute behavioral responses to light (i.e., masking). We performed chemical lesions aimed at the vSPVZ of diurnal grass rats (Arvicanthis niloticus) using N-methyl-D,L-aspartic acid (NMA), a glutamate agonist. Following NMA lesions, we placed grass rats in various lighting conditions (e.g., 12:12 light-dark, constant dark, constant light); presented a series of light pulses at circadian times (CT) 6, 14, 18, and 22; and placed them in a 7-h ultradian cycle to assess behavioral masking. Extensive bilateral lesions of the vSPVZ disrupted the expression of circadian rhythms of activity and abolished the circadian modulation of masking responses to light, without affecting light-induced masking behavior per se. We also found that in diurnal grass rats, NMA was capable of destroying not only neurons of the vSPVZ but also those of the suprachiasmatic nucleus (SCN), even though excitotoxins have been ineffective at destroying cells within the SCN of nocturnal rodents. The vulnerability of the grass rat's SCN to NMA toxicity raises the possibility of a difference in density of receptors for glutamate between nocturnal and diurnal species. In cases in which damage extended to the SCN, masking responses to light were present and similar to those displayed by animals with damage restricted to the vSPVZ. Thus, extensive bilateral lesions of the SCN and vSPVZ disrupted the expression of circadian rhythms without affecting acute responses to light in a diurnal species. Our present and previous results suggest that retinorecipient brain areas other than the SCN or vSPVZ, such as the intergeniculate leaflet or olivary pretectal nucleus, may be responsible for the mediation of masking responses to light in the diurnal grass rat.

Decreased daytime illumination leads to anxiety-like behaviors and HPA axis dysregulation in the diurnal grass rat (Arvicanthis niloticus)

The impact of ambient light on mood and anxiety is best exemplified in seasonal affective disorder, in which patients experience depression and anxiety in winter when there is less light in the environment. However, the brain mechanisms underlying light-dependent changes in affective state remain unclear. Our previous work revealed increased depression-like behaviors in the diurnal Nile grass rat (Arvicanthis niloticus) housed in a dim light–dark (dim-LD) cycle as compared to the controls housed in a bright light–dark (bright-LD) condition. As depression is often comorbid with anxiety and is associated with dysregulation of the body’s stress response system, the present study examined the anxiety-like behaviors as well as indicators of the hypothalamic-pituitary-adrenal (HPA) axis functioning in the grass rats. Animals housed in dim-LD showed increased anxiety-like behaviors compared to bright-LD controls, as revealed by fewer entries and less time spent at the center in the open field test and more marbles buried during the marble-burying test. Following the marble-burying test, dim-LD animals showed higher plasma corticosterone (CORT) levels and hippocampal Fos expression. Although the daily CORT rhythm was comparable between bright-LD and dim-LD groups, the day/night variation of corticotropin-releasing hormone mRNA expression in the paraventricular nucleus was diminished in dim-LD animals. In addition, glucocorticoid receptor and mineralocorticoid receptor mRNA expression were higher in the hippocampus of dim-LD animals. The results suggest that in diurnal species, reduced daytime illumination can lead to increased anxiety-like behaviors and altered HPA axis functioning, providing insights into the link between decreased environmental illumination and negative emotion.

Hypothalamic dopaminergic neurons in an animal model of seasonal affective disorder

Light has profound effects on mood regulation as exemplified in seasonal affective disorder (SAD) and the therapeutic benefits of light therapy. However, the underlying neural pathways through which light regulates mood are not well understood. Our previous work has developed the diurnal grass rat, Arvicanthis niloticus, as an animal model of SAD. Following housing conditions of either 12:12h dim light:dark (DLD) or 8:16h short photoperiod (SP), which mimic the lower light intensity or short day-length of winter, respectively, grass rats exhibit an increase in depression-like behavior compared to those housed in a 12:12h bright light:dark (BLD) condition. Furthermore, we have shown that the orexinergic system is involved in mediating the effects of light on mood and anxiety. To explore other potential neural substrates involved in the depressive phenotype, the present study examined hypothalamic dopaminergic (DA) and somatostatin (SST) neurons in the brains of grass rats housed in DLD, SP and BLD. Using immunostaining for tyrosine hydroxylase (TH) and SST, we found that the number of TH- and SST-ir cells in the hypothalamus was significantly lower in the DLD and SP groups compared to the BLD group. We also found that treating BLD animals with a selective orexin receptor 1 (OX1R) antagonist SB-334867 significantly reduced the number of hypothalamic TH-ir cells. The present study suggests that the hypothalamic DA neurons are sensitive to daytime light deficiency and are regulated by an orexinergic pathway. The results support the hypothesis that the orexinergic pathways mediate the effects of light on other neuronal systems that collectively contribute to light-dependent changes in the affective state.

Plastic oscillators and fixed rhythms: Changes in the phase of clock-gene rhythms in the PVN are not reflected in the phase of the melatonin rhythm of grass rats

The same clock-genes, including Period (PER) 1 and 2, that show rhythmic expression in the suprachiasmatic nucleus (SCN) are also rhythmically expressed in other brain regions that serve as extra-SCN oscillators. Outside the hypothalamus, the phase of these extra-SCN oscillators appears to be reversed when diurnal and nocturnal mammals are compared. Based on mRNA data, PER1 protein is expected to peak in the late night in the paraventricular nucleus of the hypothalamus (PVN) of nocturnal laboratory rats, but comparable data are not available for a diurnal species. Here we use the diurnal grass rat (Arvicanthis niloticus) to describe rhythms of PER1 and 2 proteins in the PVN of animals that either show the species-typical day-active (DA) profile, or that adopt a night-active (NA) profile when given access to running wheels. For DA animals housed with or without wheels, significant rhythms of PER1 or PER2 protein expression featured peaks in the late morning; NA animals showed patterns similar to those expected from nocturnal laboratory rats. Since the PVN is part of the circuit that controls pineal rhythms, we also measured circulating levels of melatonin during the day and night in DA animals with and without wheels and in NA wheel runners. All three groups showed elevated levels of melatonin at night, with higher levels during both the day and night being associated with the levels of activity displayed by each group. The differential phase of rhythms in the clock-gene protein in the PVN of diurnal and nocturnal animals presents a possible mechanism for explaining species differences in the phase of autonomic rhythms controlled, in part, by the PVN. The present study suggests that the phase of the oscillator of the PVN does not determine that of the melatonin rhythm in diurnal and nocturnal species or in diurnal and nocturnal chronotypes within a species.

Acute effects of light on the brain and behavior of diurnal Arvicanthis niloticus and nocturnal Mus musculus

Photic cues influence daily patterns of activity via two complementary mechanisms: (1) entraining the internal circadian clock and (2) directly increasing or decreasing activity, a phenomenon referred to as “masking”. The direction of this masking response is dependent on the temporal niche an organism occupies, as nocturnal animals often decrease activity when exposed to light, while the opposite response is more likely to be seen in diurnal animals. Little is known about the neural mechanisms underlying these differences. Here, we examined the masking effects of light on behavior and the activation of several brain regions by that light, in diurnal Arvicanthis niloticus (Nile grass rats) and nocturnal Mus musculus (mice). Each species displayed the expected behavioral response to a 1h pulse of light presented 2h after lights-off, with the diurnal grass rats and nocturnal mice increasing and decreasing their activity, respectively. In grass rats light induced an increase in cFOS in all retinorecipient areas examined, which included the suprachiasmatic nucleus (SCN), the ventral subparaventricular zone (vSPZ), intergeniculate leaflet (IGL), lateral habenula (LH), olivary pretectal nucleus (OPT) and the dorsal lateral geniculate (DLG). In mice, light led to an increase in cFOS in one of these regions (SCN), no change in others (vSPZ, IGL and LH) and a decrease in two (OPT and DLG). In addition, light increased cFOS expression in three arousal-related brain regions (the lateral hypothalamus, dorsal raphe, and locus coeruleus) and in one sleep-promoting region (the ventrolateral preoptic area) in grass rats. In mice, light had no effect on cFOS in these four regions. Taken together, these results highlight several brain regions whose responses to light suggest that they may play a role in masking, and that the possibility that they contribute to species-specific patterns of behavioral responses to light should be explored in future.

Circadian modulation of memory and plasticity gene products in a diurnal species

Cognition is modulated by circadian rhythms, in both nocturnal and diurnal species. Rhythms of clock gene expression occur in brain regions that are outside the master circadian oscillator of the suprachiasmatic nucleus and that control cognitive functions, perhaps by regulating the expression neural-plasticity genes such as brain derived neurotrophic factor (BDNF) and its high affinity receptor, tyrosine kinase B (TrkB). In the diurnal grass rat (Arvicanthis niloticus), the hippocampus shows rhythms of clock genes that are 180° out of phase with those of nocturnal rodents. Here, we examined the hypothesis that this reversal extends to the optimal phase for learning a hippocampal-dependent task and to the phase of hippocampal rhythms in BDNF/TrkB expression. We used the Morris water maze (MWM) to test for time of day differences in reference memory and monitored daily patterns of hippocampal BDNF/TrkB expression in grass rats. Grass rats showed superior long-term retention of the MWM, when the training and testing occurred during the day as compared to the night, at a time when nocturnal laboratory rats show superior retention; acquisition of the MWM was not affected by time of day. BDNF/TrkB expression was rhythmic in the hippocampus of grass rats, and the phase of the rhythms was reversed compared to that of nocturnal rodents. Our findings provide correlational evidence for the claim that the circadian regulation of cognition may involve rhythms of BDNF/TrkB expression in the hippocampus and that their phase may contribute to species differences in the optimal phase for learning.

Intergeniculate leaflet lesions result in differential activation of brain regions following the presentation of photic stimuli in Nile grass rats

The intergeniculate leaflet (IGL) plays an important role in the entrainment of circadian rhythms and the mediation of acute behavioral responses to light (i.e., masking). Recently, we reported that IGL lesions in diurnal grass rats result in a reversal in masking responses to light as compared to controls. Here, we used Fos as a marker of neural activation to examine the mechanisms by which the IGL may influence this masking effect of light in grass rats. Specifically, we examined the patterns of Fos activation in retinorecipient areas and in brain regions that receive IGL inputs following 1-h light pulses given during the early night in IGL-lesioned and sham-operated grass rats. Three patterns emerged: (1) IGL lesions had no effect on the Fos response to light, (2) IGL lesions resulted in a reversal in Fos responses to light, and (3) IGL lesions resulted in a lack of a Fos response to light. Of specific interest were the suprachiasmatic nucleus (SCN) and the olivary pretectal nucleus (OPT), both of which are retinorecipient and connect reciprocally with the IGL. Light-induced Fos expression in the SCN was unaffected by IGL lesions, whereas the OPT exhibited a significant reduction in Fos expression following a light pulse in animals with IGL lesions. Altogether, our results suggest that the OPT, but not the SCN, exhibits a reversal in Fos responses to light following IGL lesions that reverse masking responses in diurnal grass rats. Our results suggest that interconnections between the IGL and downstream brain areas (e.g., OPT) may play a role in determining the direction of the behavioral response to light.

Attenuated orexinergic signaling underlies depression-like responses induced by daytime light deficiency

Light has profound effects on mood, as exemplified by seasonal affective disorder (SAD) and the beneficial effects of bright light therapy. However, the underlying neural pathways through which light regulates mood are not well understood. Our previous work has developed the diurnal grass rat, Arvicanthis niloticus, as an animal model of SAD (Leach et al., 2013a,b). By utilizing a 12:12-h dim light:dark (DLD) paradigm that simulates the lower light intensity of winter, we showed that the animals housed in DLD exhibited increased depression-like behaviors in the forced swim test (FST) and sweet solution preference (SSP) compared to animals housed in bright light during the day (BLD). The objective of the present study was to test the hypothesis that light affects mood by acting on the brain orexinergic system in the diurnal grass rat model of SAD. First, orexin A immunoreactivity (OXA-ir) was examined in DLD and BLD grass rats. Results revealed a reduction in the number of OXA-ir neurons in the hypothalamus and attenuated OXA-ir fiber density in the dorsal raphe nucleus of animals in the DLD compared to those in the BLD group. Then, the animals in BLD were treated systemically with SB-334867, a selective orexin 1 receptor (OX1R) antagonist, which led to a depressive phenotype characterized by increased immobility in the FST and a decrease in SSP compared to vehicle-treated controls. Results suggest that attenuated orexinergic signaling is associated with increased depression-like behaviors in grass rats, and support the hypothesis that the orexinergic system mediates the effects of light on mood.

Depression-Like Responses Induced by Daytime Light Deficiency in the Diurnal Grass Rat (Arvicanthis niloticus)

Seasonal Affective Disorder (SAD) is one of the most common mood disorders with depressive symptoms recurring in winter when there is less sunlight. The fact that light is the most salient factor entraining circadian rhythms leads to the phase-shifting hypothesis, which suggests that the depressive episodes of SAD are caused by misalignments between the circadian rhythms and the habitual sleep times. However, how changes in environmental lighting conditions lead to the fluctuations in mood is largely unknown. The objective of this study is to develop an animal model for some of the features/symptoms of SAD using the diurnal grass rats Arvichantis niloticus and to explore the neural mechanisms underlying the light associated mood changes. Animals were housed in either a 12∶12 hr bright light∶dark (1000lux, BLD) or dim light∶dark (50lux, DLD) condition. The depression-like behaviors were assessed by sweet-taste Saccharin solution preference (SSP) and forced swimming test (FST). Animals in the DLD group showed higher levels of depression-like behaviors compared to those in BLD. The anxiety-like behaviors were assessed in open field and light/dark box test, however no significant differences were observed between the two groups. The involvement of the circadian system on depression-like behaviors was investigated as well. Analysis of locomotor activity revealed no major differences in daily rhythms that could possibly contribute to the depression-like behaviors. To explore the neural substrates associated with the depression-like behaviors, the brain tissues from these animals were analyzed using immunocytochemistry. Attenuated indices of 5-HT signaling were observed in DLD compared to the BLD group. The results lay the groundwork for establishing a novel animal model and a novel experimental paradigm for SAD. The results also provide insights into the neural mechanisms underlying light-dependent mood changes.

Responses of brain and behavior to changing day-length in the diurnal grass rat (Arvicanthis niloticus)

Seasonal affective disorder (SAD) is a major depressive disorder that recurs in the fall and winter when day-length gets short. It is well accepted that day-length is encoded by the principal circadian clock located in the suprachiasmatic nucleus (SCN), but very little is known about day-length encoding in diurnal mammals. The present study utilized the grass rat, Arvicanthis niloticus, to investigate how the circadian system responds to photoperiodic changes in a diurnal mammal that shows day-length-dependent mood changes. The animals were initially housed in equatorial day-length (12h, EP) followed by either long (16h, LP) or short (8h, SP) photoperiods. The LP animals showed an expansion of the peak phase of the PER1 and PER2 rhythm in the SCN as well as an extended behavioral active phase. In contrast, the SP animals did not show any compression of their active phase nor a change in the peak duration of PER1 or PER2 expression, compared to those in EP. The results suggest that the circadian system in the diurnal grass rats is less responsive when day-length gets short compared to when it gets longer. The depression-like behaviors were assessed using sweet solution preference (SSP) and forced swimming test (FST). Animals in the SP group showed decreased SSP and increased immobility time in FST as compared to the EP group, suggesting a depressive phenotype. The present study serves as the first step toward exploring the role that the circadian system plays in SAD using a diurnal rodent model.

Dim light at night increases depressive-like responses in male C3H/HeNHsd mice

Daily patterns of light exposure have become increasingly variable since the widespread adoption of electrical lighting during the 20th century. Seasonal fluctuations in light exposure, shift-work, and transmeridian travel are all associated with alterations in mood. These studies implicate fluctuations in environmental lighting in the development of depressive disorders. Here we argue that exposure to light at night (LAN) may be causally linked to depression. Male C3H/HeNHsd mice, which produce nocturnal melatonin, were housed in either a standard light/dark (LD) cycle or exposed to nightly dim (5lux) LAN (dLAN). After four weeks in lighting conditions mice underwent behavioral testing and hippocampal tissue was collected at the termination of the study for qPCR. Here were report that mice exposed to dLAN increase depressive-like responses in both a sucrose anhedonia and forced swim test. In contrast to findings in diurnal grass rats, dLAN mice perform comparably to mice housed under dark nights in a hippocampus-dependent learning and memory task. TNFα and IL1β gene expression do not differ between groups, demonstrating that changes in these pro-inflammatory cytokines do not mediate dLAN induced depressive-like responses in mice. BDNF expression is reduced in the hippocampus of mice exposed to dLAN. These results indicate that low levels of LAN can alter mood in mice. This study along with previous work implicates LAN as a potential factor contributing to depression. Further understanding of the mechanisms through which LAN contributes to changes in mood is important for characterizing and treating depressive disorders.