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.

“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.

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

Toddlers Learn Better When Experiences are Predictable

What's the science?

There are many benefits to predictable learning. For example, when something is predictable there is time to build expectations and better understand when those expectations have been violated. In toddlers, there is mixed evidence for the benefits of both predictable and unpredictable learning. It is still unclear which method of learning is ideal for toddlers during development. Recently in Current Biology, Benitez and colleagues test whether toddlers learn words better in predictable versus unpredictable situations.

How did they do it?

Toddlers were presented with a series of boxes that would open in a sequence to reveal a series of objects. The timing and location of box opening was predictable (always clockwise), however, the object to be revealed was unknown. This sequence exposure experiment was repeated 5 times. Then, a second labelling experiment was performed, where boxes would open either in the predictable sequence or in an unpredictable (i.e. an unexpected box would open that was different from the previously learned sequence) pattern to reveal an image paired with a recorded voice announcing what the object was. The authors used an eye tracking system to track how the toddlers attended to the objects and to rule out potential confounding effects of visual attention. They then tested, in a learning phase, whether the toddlers retained object-label pairs better for predictable vs. unpredictable events. They tested this using a “looking-while-listening” method where the object-label pair was presented and they were to look to the correct object.

What did they find?

Reaction times were greater for unpredictable events than predictable events in both the object revealing and labelling experiments suggesting that toddlers were tracking the sequence of events. They also demonstrated anticipatory looks towards a box where an object was about to be revealed meaning the toddlers developed expectations about the sequence of events. Toddlers were found to look at the correct object-label pair for a greater proportion of time than the incorrect object for the predictable events compared to the unpredictable events. Toddlers were also more accurate at looking to the object-label pair during predictable events.

What's the impact?

This is the first study to show that predictable events support word learning in toddlers. We now know that toddlers may learn better when new information is presented in a predictable way. Understanding how children learn during development is important for understanding developmental outcomes.

Benitez et al., Predictable events enhance word learning in toddlers. Current Biology (2018). Access the original scientific publication here.

Oxytocin Affects Social Sharing and Brain Activity in Women

What's the science?

Social interaction and relationships are rewarding; however, attachment anxiety can reduce rewarding effects of social interaction. Oxytocin is a neuropeptide released from the hypothalamus, known to facilitate social bonding and reduce anxiety. It is unknown how oxytocin may affect the experience of social interaction and anxiety differently in men and women. Furthermore, it isn’t known how brain activity may be altered in the presence of oxytocin in men and women. This week in NeuroImage, Ma and colleagues test the sex-differential effects of oxytocin on social sharing and associated brain activity.

How did they do it?

128 pairs of same-sex friends were randomized into two groups and given a placebo (as a control) or a dose of intranasal oxytocin (as a treatment; group allocation was blinded). Before the experiment participants filled in a) a friendship scale to ensure a high quality of friendship and b) questionnaires that controlled for mood and personality differences between the test groups. Attachment style was assessed using the Adult Attachment Scale. After administration of the placebo or oxytocin, the friends participated in a social sharing experiment where they shared emotional experiences with either their good friend or a stranger (same sex). The pairs performed the same task, and one person was in the MRI scanner (task-based functional MRI scan) while the other person was in an experimental room close by.

They were instructed that they would view an image either alone, with their friend or with a stranger. Then participants were shown images of people, landscapes or animals that were either neutral, positive or negative. After each picture they were asked to rate how positive or negative the image made them feel and how strong their feeling was. They were also asked to report on thoughts related to sharing with their friends after the sharing experiment. The fMRI data was acquired to measure effects on brain activity and functional connectivity and differences between men and women.

What did they find?

Oxytocin increased the positive experience of sharing, particularly for positive emotional content, in female but not male participants. Effects were most pronounced when sharing with female friends but not with strangers. For males, there was no effect of oxytocin on sharing between friends, however, it did increase positive emotion in the stranger > alone condition (i.e. viewing an image with a stranger vs. viewing it alone). Oxytocin generally increased thoughts of sharing with friends when undergoing the sharing with a friend condition. On the neural level the effects of oxytocin in females were accompanied by reduced activity in the amygdala and insula as well as decreased interplay between them, whereas the opposite pattern was observed in males. Moreover, oxytocin reduced the strength of the correlation between attachment anxiety and amygdala activity in females during social sharing with a friend, indicating that the effects of oxytocin may vary with attachment style.

What's the impact?

This is the first study to demonstrate effects of oxytocin on social sharing and which effects differ between men and women. We now know that oxytocin increases the positive experience of sharing with a friend in females but not in males and that brain activity during sharing is differentially affected in females vs. males. Furthermore, the effects of oxytocin on brain activity may differ depending on attachment anxiety. Future research should consider sex-differences when studying the behavioral and brain effects of oxytocin on anxiety, stress and social attachment. For the proposed therapeutic administration of oxytocin in disorders such as autism, sex-differences in responses may need particularly to be taken into account.

Ma et al., Sex- and context-dependent effects of oxytocin on social sharing. NeuroImage (2018). Access the original scientific publication here.