How Diet Can Impact Memory Function

Post by Rebecca Glisson

The takeaway

Diets that include excessive amounts of fat or sugar can impair our memory. Receptors in the hippocampus, an area of the brain that plays a key role in memory, can become overactive with a high-fat and sugar diet, and blocking these receptors can improve memory.

What's the science?

More and more often, scientists are uncovering how our diet is linked to brain function. For example, the endocannabinoid system of the brain, which includes type-1 cannabinoid receptors (CB1Rs), is known to be overactive in people with too much fat or sugar in their diets. This week in Current Biology, Ducourneau and colleagues investigated how a poor diet can lead to memory dysfunction via the endocannabinoid system.

How did they do it?

The authors wanted to study how diet impacts memory, particularly in adolescents, a critical period for the development of memory function. They gave juvenile male mice either a diet with high-fat and high-sugar or a normal diet, then had them perform an object recognition test to evaluate their memory. The test consisted of presenting a mouse with an object, then a delay of either 3 hours to test short-term memory or 24 hours to test long-term memory, then presenting the mouse with the same object and a new object. If the mouse remembered the original object, then they spent more time exploring the new object. Mice were then injected with a CB1R receptor antagonist, which blocks the activity of this receptor, and then tested again for their memory performance.

What did they find?

Mice with high-fat and sugar diets did worse on the 24-hour long-term object recognition test than control mice. Short-term memory performance, however, was not affected by diet, as measured via a test administered only 3 hours post-exposure. This suggests that poor diets have more of an impact on long-term memory function than short-term memory. When mice on the high-sugar, high-fat diet were injected with the CB1R activity blocker, they performed better on their memory test. This suggests that CB1R is responsible for memory issues when impacted by poor diets.

What's the impact?

This study is the first to show that diets high in sugar and fat lead to long-term memory impairment via the endocannabinoid system. Further, this memory impairment can be reversed by blocking cannabinoid receptors. A poor diet is especially harmful for memory development in adolescence.

Access the original scientific publication here.

Step Count Could Lower Risk of Cognitive Decline

Post by Anastasia Sares

The takeaway

A 14-year-long study on the changes in cognition of older adults showed that for those at higher risk for cognitive decline (higher Aβ), a moderate level of activity (5,000+ steps) was associated with less cognitive decline. For these people, physical activity was linked to levels of the protein called tau in the brain, and this accounted for most of the changes in cognition.

What's the science?

Alzheimer’s disease and other dementias are an area of intense medical interest, especially now that people are living longer. There have been many studies establishing an association where greater exercise is linked to decreased cognitive decline (previous BrainPost on the subject here); however, these studies are just that—associations. There are a few elements that scientists can improve to better understand this link.

First of all, many studies are cross-sectional. That is, the data are gathered at a single point in time. So, while a cross-sectional study may sample people across different ages, they do not follow the same participants over time to see how their health evolves based on different factors. In contrast to this are longitudinal studies, which do follow participants over time, but these are relatively rare since they are more time and resource-intensive.

Second, variables like “exercise” and “memory” are often measured via a questionnaire, since this is more convenient. However, this can be problematic if respondents do not answer reliably, which is a concern when studying people with potential cognitive decline. More objective methods of measuring these variables exist: step counters are very common and can gather objective data about daily activity levels.

This week in Nature Medicine, Yau and colleagues reported the results of a longitudinal study (part of the Harvard Aging Brain Study or HABS), which included activity measured with step counters, cognitive testing, and brain imaging. They show the relationship between moderate physical activity and preserved cognitive function, along with a potential mediating mechanism in the brain.

How did they do it?

The study included 296 people from the HABS study who were cognitively unimpaired when they first signed up for the research. Participants were asked to wear a pedometer for a week near the beginning of their participation to measure their step counts. In addition, the authors selected participants who had undergone at least two rounds of cognitive testing (PACC5) as well as PET imaging at the time of the study.

PET (Positron Emission Tomography) is a neuroimaging technique used to identify different molecules in the brain with the help of a tiny amount of radioactive tracers. The researchers used PET imaging to measure levels of Aβ and tau, two proteins known to be involved in Alzheimer’s pathology. People with naturally high levels of Aβ are more at risk for cognitive decline, and the accumulation of tau proteins in the brain may be one part of that process of decline. The authors suspected that higher physical activity might be related to less accumulation of tau in the brain, which would in turn be associated with better cognition, but only for people with high Aβ (which puts them at higher risk). This kind of relationship is called a mediation.

What did they find?

Participants with low Aβ levels experienced less cognitive decline than those with high Aβ levels, and physical activity did not have much of an effect. However, for those with high Aβ, there was a significant effect of physical activity, with participants who logged more than 5,000 steps seeing the best results. Mediation analyses showed that for these people, cognitive decline was fully mediated by tau accumulation: that is, physical activity was related to less tau accumulation, and less tau was related to less cognitive decline. The activity didn’t have any further relationship with cognitive decline after accounting for the relationship with tau. The effect of activity plateaued after 5,000 steps, suggesting this is a good target for older adults to start increasing their step count.

What's the impact?

This study strengthens our confidence in the ability of exercise to stave off cognitive decline. Increasing step count is one way for older adults to improve physical activity and lower their risk of cognitive decline with aging. To further validate the effectiveness of exercise to combat aging, we need randomized controlled trials where people are assigned randomly to different levels of exercise and see whether the effect holds.

Access the original scientific publication here.

Astrocyte Ensembles are Involved in Memory Stabilization and Recall

Post by Amanda Engstrom

The takeaway

Engrams are the physical traces of memory in the neurons of the brain. This study reveals that astrocytes play a more direct role than previously thought, forming lasting ensembles that reactivate during memory recall. These astrocytic ensembles, driven by noradrenergic signaling, act as a multiday trace that helps stabilize and preserve memories over time.

What's the science?

Memory formation and stabilization involve specific neuronal ensembles, or groups of interconnected neurons that work together. Chemical and physical changes in these neurons then form memory traces – called engrams – to be activated during learning and recall. Remembering something transiently destabilizes memories, but the mechanism that subsequently re-stabilizes the memory is not completely understood and cannot be explained by neuronal engrams alone. Astrocytes are highly abundant non-neuronal cells within the central nervous system (CNS) that interact both structurally and functionally with neurons and other glial cells. They are known to be developmentally diverse and adaptive to physiological and pathological changes; however, the role of astrocytes in forming or stabilizing experience-dependent memories is not clear. This week in Nature, Dewa and colleagues investigated astrocytes that respond to memory formation and recall in order to assess their contribution to memory stabilization.

How did they do it?

The authors developed a tool to identify behaviorally relevant astrocyte ensembles in an unbiased manner by generating mice that allow them to label astrocytes that have been activated (marked by an increase in Fos gene expression) during a specific time window. For their studies, the authors “tagged” astrocytes either during a fear conditioning protocol or 24 hours later in a fear memory recall session. They then compared astrocyte activation with neuronal engram activity in the same fear conditioning paradigm. Once the authors identified the astrocyte ensembles, they performed a pharmacological screening for molecules that can activate astrocyte Fos expression and validated these target molecules through circuit analysis, imaging, and single-cell transcriptomics. Next, the authors determined the transcriptional response to memory formation and recall at different timepoints. Finally, they perturbed the astrocyte ensemble by using a peptide inhibitor to silence the target signaling cascade, as well as enhanced the ensemble signaling by overexpressing downstream signaling targets. Then they tested the efficiency of fear conditioning and recall using the same behavioral fear paradigm.  

What did they find?

The density of activated (Fos+) astrocytes did not significantly increase immediately after fear conditioning. However, 24 hours later, during recall, there was a significant increase in the number of activated astrocytes across the entire brain, especially in the amygdala, compared to fear conditioning without recall. This is unique to astrocytes, as neurons are activated both during fear conditioning and recall. There was a significant regional correlation between neuronal and astrocyte activation at recall, suggesting that astrocyte ensembles are recruited in regions of active neuronal engrams. The authors identified noradrenaline (NA) as a strong inducer of Fos expression in astrocytes, and using fiber photometry, (an imaging technique to measure cellular activity) determined that during fear recall, NA signals are stronger and last longer than during fear conditioning.

The single-cell transcriptomics on astrocytes in the amygdala revealed that after fear conditioning, astrocytes upregulate adrenergic receptor genes (Adra1a and Adrb1), which increased in expression over 24 hours, indicating a “priming” state that develops over a day and then decreases over time. Disrupting the astrocyte ensemble disrupted memory stability and reduced the mouse’s response in the fear recall test. When the ensemble was enhanced through the overexpression of Adrb1 in astrocytes, the density of activated astrocytes increased, and improved memory retention and recall. Together, these results show that fear conditioning induces an astrocyte ensemble that is primed via NA signaling and persists for roughly one day. Upon recall, the astrocyte ensemble is activated and stabilizes the memory.

What's the impact?

This study is the first to show that astrocytes form their own experience-dependent ensembles that reactivate during memory recall and help stabilize memories over multiple days. This work expands the traditional neuron-centric view of memory consolidation and argues for the critical role of astrocytes in memory stabilization and recall.