Circadian rhythms

Depression brought to light

Exposure to abnormal light–dark cycles causes depression-like behaviour and learning deficits in mice. The defects seem to occur independently of disturbances to sleep and other processes regulated by the biological clock. See Letter p.594

Changes in environmental light can alter mood and adversely affect cognitive function1. Nonetheless, the identity of the neuronal circuitry involved in light-mediated regulation of mood and cognition, and how it functions, are poorly understood. A prevailing hypothesis is that, because alterations in light disrupt circadian rhythms (processes that are controlled by our in-built 24-hour 'biological clock'), including sleep, they then indirectly alter mood and impair learning. On page 594 of this issue, LeGates et al.2 explore the link between the effects of light on the circadian system and dysfunctional mood regulation, and begin to delineate the underlying neural circuitry. They provide convincing evidence that abnormal light exposure can directly affect mood and learningFootnote 1.

LeGates and colleagues exposed mice to 3.5 hours of light followed by 3.5 hours of dark (T7 light cycle), instead of the normal 12-hour light and 12-hour dark cycle. They then examined the effects of this abnormal light cycle on depression-like behaviour, and on learning and memory. The T7 cycle did not alter the total amount of sleep the mice had, suggesting that any physiological effects were independent of sleep deprivation. Moreover, it did not cause significant disruption to circadian rhythms; that is, the biological clocks, which regulate physiological activities in relation to circadian environmental cycles, remained intact and in phase with one another.

Nevertheless, mice experiencing the T7 cycle showed increased depression-related behaviour, along with increased levels of the hormone corticosterone, a potential link to depression. The mice were also impaired in some forms of learning and memory, as indicated by alterations in the extent of long-term potentiation (LTP) — an increase in the strength of synaptic connections between neurons that correlates with learning and memory — in the brain's hippocampus region. However, long-term synaptic depression (a decrease in strength) was unaffected, suggesting that light-induced changes are specific to synaptic strengthening.

Physiological functions such as sleep and metabolism are tightly regulated by circadian rhythms that are entrained by ambient light exposure3. Light is classically detected by photon-sensitive neurons — rods and cones in the retina of the eye — which relay information to retinal ganglion cells (RGCs) that, in turn, project to higher brain regions for image formation. However, a population of intrinsically photosensitive RGCs (ipRGCs), which express the photopigment melanopsin and are distinct both from other RGCs and from rods and cones, mediate non-image-forming processes in response to light4,5. The light sensitivity of melanopsin matches that of non-image-forming, but light-dependent, physiological processes that are regulated in a circadian manner, including locomotion and the pupillary light reflex6,7.

To examine whether the traits seen with the T7 light cycle were due to direct effects of light — independent of image-forming processes — LeGates and colleagues exposed mice that lacked ipRGCs to this light cycle. The ipRGC-deficient animals did not show alterations in depression-like behaviour, learning or LTP. The authors therefore conclude that light acting on ipRGCs directly contributes to mood regulation and learning.

These findings support the use of the T7-light-cycle paradigm as an animal model of depression, and particularly for evaluating antidepressant treatments. Existing paradigms tend to rely on the behavioural-despair model, which assesses how quickly an animal 'gives up' in an inhospitable situation and evaluates antidepressants by whether they can improve performance. Diversification of behavioural paradigms may help to uncover clinically applicable drug targets that could not be identified by these traditional approaches, and which may lead to more reliable and faster-acting antidepressants.

The study raises intriguing questions regarding the mechanisms and specific neuronal targets of ipRGCs in mediating the effects of light on the regulation of mood and cognitive function. For instance, it suggests that not only activation of ipRGCs but also changes in the long-term pattern of ipRGC exposure to light lead to synaptic plasticity (modification of the strength of neuronal synapses, which may underlie changes in behaviour). It remains unclear whether this effect is caused by changes in the synaptic strengths of ipRGCs themselves or by regulation of their downstream neuronal targets. LTP deficits seen in hippocampal synapses point to more general changes in plasticity, beyond the immediate synaptic projections of ipRGCs. The direct targets of ipRGC projections8 (including, but not limited to, the suprachiasmatic nucleus, the intergeniculate leaflet and the olivary pretectal nucleus) that mediate these synaptic abnormalities should be identified.

Interestingly, LeGates et al. report that long-term treatment with the antidepressant drugs fluoxetine and desipramine reverses some of the behavioural effects of the T7 cycle, as well as the associated LTP deficit. This indicates that the same neuronal-circuit elements, and possibly neurotrophic factors (which mediate neuronal growth), that, according to traditional models, mediate depressive-like behaviour, are involved in the depressive response to abnormal light exposure.

However, sensitivity to long-term antidepressant administration is a hallmark of behavioural paradigms that depend on chronic stress induction, such as social defeat9 (in which an animal repeatedly loses confrontations with another animal of the same species). Consequently, it should be further explored whether some of the more general synaptic plasticity reported by LeGates et al. is associated with stress due to exposure to the T7 cycle. It would also be of interest to test whether depressive-like behaviours respond to faster-acting antidepressants such as ketamine, which alleviate symptoms within hours10. Response to ketamine administration would help to determine whether these light-induced abnormal behaviours are as reversible in the short term as are depressive-like traits elicited during behavioural despair.

“This investigation provides a detailed road map by which to pursue understanding of the impact of light on mood and cognitive function.”

LeGates and co-workers' thorough investigation provides a detailed road map by which to pursue understanding of the impact of light on mood and cognitive function. Dissecting the direct effect of ipRGC synaptic projections on mood and cognition will not only elucidate a rather enigmatic neuromodulatory pathway, but may also provide new neuronal targets for treatments for mood and cognitive disorders.

Notes

  1. 1.

    *This article and the paper under discussion2 were published online on 14 November 2012.

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Correspondence to Lisa M. Monteggia.

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Monteggia, L., Kavalali, E. Depression brought to light. Nature 491, 537–538 (2012). https://doi.org/10.1038/nature11752

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