Retina-Brain Projections Mediate Light-Dependent Changes in Mood and Cognition

Post by Shireen Parimoo

What's the science?

Light affects our biological circadian clock and sleep-wake patterns, and changes in our exposure to light or to the solar cycle (e.g. working night shifts, shorter days in the winter) can negatively impact our mood and cognition. In mammals, these effects are driven by intrinsically photosensitive retinal ganglion cells (ipRGCs) in the retina of the eye that project to various parts of the brain. For example, a sub-type of ipRGCs project to the suprachiasmatic nucleus (SCN) in the hypothalamus, which regulates our sleep-wake cycle based on light exposure. Similarly, removing ipRGCs eliminates the effect of light on mood and cognition, but it is unknown how this occurs in the brain. Specifically, which regions in the brain mediate these effects? This week in Cell, Fernandez and colleagues examined whether the SCN and the peri-habenular nucleus in the dorsal thalamus, both of which receive input from ipRGCs, mediate the effect of light on learning and mood in mice.

How did they do it?

To examine the role of the SCN, the authors measured the sleep patterns, locomotor activity, and gene expression in mice with intact ipRGC retinal projections (control mice) and mice that only had ipRGC projections to the SCN. These mice were either exposed to a 12-hour or a 3.5-hour alternating light-dark cycle for two weeks, after which changes in cognition and mood were evaluated. Cognitive performance was assessed with the Novel Object Recognition and the Morris water maze tasks, and mood was assessed using a sucrose preference task, the tail suspension test, and the forced swim test. To identify regions that perihabenular neurons project to, the authors used a cholera toxin ß-subunit (CTß) tracer. They also injected a retrograde viral vector into the target region and a vector carrying a fluorescent protein into the peri-habenular nucleus. This allowed them to identify the peri-habenular targets with more precision, as the peri-habenular nucleus projections would only fluoresce if they were infected by the retrograde vector from their targets. The authors then used designer receptors exclusively activated by designer drugs (DREADDs) to determine if peri-habenular neurons are involved in regulating light-dependent effects on mood and cognition. These DREADDs were chronically activated by clozapine-N-oxide (CNO), which was administered to the mice through their drinking water or through intraperitoneal injections (DREADD mice). Mood and cognitive performance of DREADD and control mice were assessed using the tasks described above. Mice underwent a learned helplessness paradigm, a forced swim test, and a social defeat paradigm in darkness to examine if the peri-habenular nucleus also regulates non-light-dependent changes in mood. Finally, the authors tested if the peri-habenular projections to the ventromedial prefrontal cortex (vmPFC) were sufficient to induce light-dependent changes in mood by selectively activating this circuit using DREADDs.

What did they find?

The SCN mediated light-dependent changes in cognitive processes, but not mood. The control mice and the SCN-only mice had similar sleep and locomotor activity patterns, demonstrating that ipRGC projections to the SCN regulate the sleep-wake cycle. The two groups of mice also did not differ in their cognitive performance, since both groups performed worse on the cognitive tasks after the 3.5 hour light-dark cycle than after the 24 hour light-dark cycle. No light-dependent effects on mood were observed in the SCN-only mice, compared to control mice that showed altered mood on the 3.5 hour light-dark cycle, as was previously published by LeGates et al. (2012, Nature). The peri-habenular nucleus of the thalamus, on the other hand, was involved in regulating light-dependent changes in mood, but not cognition. This is consistent with their finding that peri-habenular neurons project to mood-regulating regions such as the vmPFC and the nucleus accumbens.

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“DREADD mice” with chronically active perihabenular neurons spent more time immobile after the tail suspension test and the forced swim test and they showed less preference for sucrose than control mice (suggesting depression/loss of pleasure). These findings highlight the role of the peri-habenular nucleus in light-dependent mood alterations. In fact, specific activation of the perihabenular - vmPFC circuit was sufficient to induce these changes in mood. Inhibiting peri-habenular neurons did not lead to mood changes under the 3.5 hour light-dark cycle in animals whose ipRGC projections to the peri-habenular nucleus were intact. This result confirms that the peri-habenular nucleus is necessary for light-dependent mood effects to occur. Finally, the peri-habenular nucleus did not affect light-dependent changes in cognitive processes or non-light-dependent changes in mood.

What's the impact?

This is the first study to describe the independent pathways through which light-sensitive ipRGCs affect mood and cognition in mice. The authors showed that using input from ipRGCs, the SCN both acts as a circadian pacemaker and mediates the effect of light exposure on cognitive processes. Furthermore, they demonstrated that with input from a different population of ipRGCs, the peri-habenular nucleus regulates light-dependent changes in mood. These findings improve our understanding of the biological effects of light on mood and cognition.

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Fernandez et al., Light Affects Mood and Learning through Distinct Retina-Brain Pathways. Cell (2018). Access the original scientific publication here.