Light rescues circadian behavior and brain dopamine abnormalities in diurnal rodents exposed to a winter-like photoperiod.

Seasonal affective disorder (SAD), beyond mood changes, is characterized by alterations in daily rhythms of behavior and physiology. The pathophysiological conditions of SAD involve changes in day length and its first-line treatment is bright light therapy. Animal models using nocturnal rodents have been studied to elucidate the neurobiological mechanisms of depression, but might be ill suited to study the therapeutic effects of light in SAD since they exhibit light-aversive responses. Here Arvicanthis ansorgei, a diurnal rodent, was used to determine behavioral, molecular and brain dopamine changes in response to exposure to a winter-like photoperiod consisting of a light-dark cycle with 8 h of light, under diminished light intensity, and 16 h of darkness. Furthermore, we evaluated whether timed-daily bright light exposure has an effect on behavior and brain physiology of winter-like exposed animals. Arvicanthis under a winter-like condition showed alterations in the synchronization of the locomotor activity rhythm to the light-dark cycle. Moreover, alterations in day-night activity of dopaminergic neurotransmission were revealed in the nucleus accumbens and the dorsal striatum, and in the day-night clock gene expression in the suprachiasmatic nucleus. Interestingly, whereas dopamine disturbances were reversed in animals exposed to daily light at early or late day, altered phase of the daily rhythm of locomotion was reverted only in animals exposed to light at the late day. Moreover, Per2 gene expression in the SCN was also affected by light exposure at late day in winter-like exposed animals. These findings suggest that light induces effects on behavior by mechanisms that rely on both circadian and rhythm-independent pathways influencing the dopaminergic circuitry. This last point might be crucial for understanding the mechanisms of non-pharmacological treatment in SAD.

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 12:12 h dim light:dark (DLD) or 8:16 h 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 12:12 h 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.

Abnormal hypothalamic response to light in seasonal affective disorder.

BACKGROUND: Vulnerability to the reduction in natural light associated with fall/winter is generally accepted as the main trigger of seasonal affective disorder (SAD), whereas light therapy is a treatment of choice of the disorder. However, the relationship between exposure to light and mood regulation remains unclear. As compared with green light, blue light was shown to acutely modulate emotion brain processing in healthy individuals. Here, we investigated the impact of light on emotion brain processing in patients with SAD and healthy control subjects and its relationship with retinal light sensitivity. METHODS: Fourteen symptomatic untreated patients with SAD (34.5 ± 8.2 years; 9 women) and 16 healthy control subjects (32.3 ± 7.7 years; 11 women) performed an auditory emotional task in functional magnetic resonance imaging during the fall/winter season, while being exposed to alternating blue and green monochromatic light. Scotopic and photopic retinal light sensitivities were then evaluated with electroretinography. RESULTS: Blue light enhanced responses to auditory emotional stimuli in the posterior hypothalamus in patients with SAD, whereas green light decreased these responses. These effects of blue and green light were not observed in healthy control subjects, despite similar retinal sensitivity in SAD and control subjects. CONCLUSIONS: These results point to the posterior hypothalamus as the neurobiological substrate involved in specific aspects of SAD, including a distinctive response to light and altered emotional responses.

Impact of blue vs red light on retinal response of patients with seasonal affective disorder and healthy controls.

OBJECTIVES: Seasonal affective disorder (SAD) is characterized by a mood lowering in autumn and/or winter followed by spontaneous remission in spring or summer. Bright light (BL) is recognized as the treatment of choice for individuals affected with this disease. It was speculated that BL acts on photosensitive retinal ganglion cells, particularly sensitive to blue light, which led to the emergence of apparatus enriched with blue light. However, blue light is more at risk to cause retinal damage. In addition, we reported using electroretinography (ERG) that a 60 min exposure of BL could reduce rod sensitivity. The goal of the present study was to verify if this decreased in sensitivity could be a consequence of the blue light portion present in the white light therapy lamps. We also wanted to assess the effect of monochromatic blue light vs red light in both healthy controls and patients with SAD. METHOD: 10 healthy subjects and 10 patients with SAD were exposed in a random order for 60 min to two different light colors (red or blue) separated by an interval of at least 1 day. Cone and rod ERG luminance-response function was assessed after light exposure. RESULTS: A two-way ANOVA indicates that blue light decreases the maximal ERG response (Vmax) in both groups in photopic (p<0.05) and scotopic conditions (p<0.01). CONCLUSION: The main finding of this experiment is that blue light reduces photoreceptor responses after only a single administration. This brings important concerns with regard to blue-enriched light therapy lamps used to treat SAD symptoms and other disorders.

Evidence of a biological effect of light therapy on the retina of patients with seasonal affective disorder.

BACKGROUND: Retinal sensitivity anomalies have been reported in patients affected by seasonal affective disorder (SAD). We used the electroretinogram (ERG) to assess seasonal change in retinal function in patients with SAD and healthy participants, as well as in patients following 4 weeks of light therapy. METHODS: ERG assessments were obtained in 22 SAD patients (2 men, 20 women, mean age 31 +/- 9 years) in the fall/winter season before and after 2 and 4 weeks of light therapy and in summertime. Matched healthy participants (2 men, 14 women; mean age 29 +/- 8 years) were evaluated once in the fall/winter and once in summer. The 29-item Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder version was administered. Standard ERG parameters were derived from the photopic and scotopic luminance response functions. Salivary melatonin concentration during ERG was assessed in both groups but during fall/winter assessments only. RESULTS: A significantly lower cone ERG maximal amplitude and lower rod sensitivity was found in SAD patients before light therapy compared with healthy participants. Following 4 weeks of light therapy, a normalization of cone and rod ERG function occurred. ERG parameters in the summer and melatonin concentrations in fall/winter were not significantly different between groups. CONCLUSIONS: Depressed patients with SAD demonstrate ERG changes in the winter compared with healthy comparison subjects with lower rod retinal sensitivity and lower cone maximal amplitude. These changes normalized following 4 weeks of light therapy and during the summer, suggesting that ERG changes are state markers for SAD.

Monoaminergic function in the pathogenesis of seasonal affective disorder.

Seasonal affective disorder/winter type (SAD) is characterized by recurrent depressive episodes during autumn and winter alternating with non-depressive episodes during spring and summer. Light therapy with full-spectrum, bright white light has been shown to be effective for this condition. Several hypotheses have been discussed in the literature about the pathogenesis of SAD. The most prominent includes disturbances in central monoaminergic transmission. Evidence can be inferred from studies showing a seasonal rhythm of central and peripheral serotonergic functioning which may be a predisposing factor for SAD. Some of the symptoms of SAD are believed to represent an attempt to overcome a putative deficit in brain serotonergic transmission. Moreover, 5-HT receptor challenge studies suggest altered activity at or downstream to central 5-HT receptors. Monoamine depletion studies support hypotheses about serotonergic and catecholaminergic dysfunctions in SAD and suggest that light therapy may well compensate for this underlying deficit. Further, albeit indirect, support for the importance of monoaminergic mechanisms in SAD and its involvement in the mechanism of the action of light therapy comes from studies showing antidepressant efficacy of serotonergic and noradrenergic antidepressants in the treatment of SAD. Altogether, disturbances in brain monoaminergic transmission seem to play a key role in the pathogenesis of SAD; monoaminergic systems may also play an important role in the mechanisms of the action of light therapy.