Age-Related Decline in Brain Function is Related to an Infiltration of T Cells

Post by Flora Moujaes

What's the science?

The deterioration of tissues in the body, including brain tissue, is a hallmark of aging. But what are the mechanisms underlying this deterioration? Answering this question could help develop treatments for preventing aging. The brain contains neural stem cells that are responsible for the formation of new neurons in the brain. This process, known as neurogenesis, decreases with age. We still don’t fully understand why old age leads to a decrease in neurogenesis. The intrinsic properties of young and old neural stem cells are the same, therefore the reduced functioning of neural stem cells in older brains may be due to changes in their environment rather than the cells themselves. Neural stem cells can be located in a specialized microenvironment in the brain called a niche, which includes a number of other molecules and cells that support the stem cells’ ability to function. This week in Nature, Dulken and colleagues investigate how aging affects the neural stem cell niche in mice, and show for the first time that there is an infiltration of T-cells (immune cells not normally found in the brain) in the neural stem cell niche of older mice.

How did they do it?

First, to examine whether changes in the environment of neural stem cells are related to the reduction in neurogenesis in older mammals, the authors examined gene expression in individual cells found in the neural stem cell niche of the mouse brain. They compared three 3-month-old and three 28-month old mice, analysing the activation levels of the genes in nearly 15,000 cells. The researchers focused on cells in a specific region known as the subventricular zone, one of two places where neurogenesis has been found to occur in the adult mammalian brain. They used single-cell RNA sequencing to analyse the transcriptomes of each cell. The transcriptome or messenger RNA is essentially DNA in action: it is a set of molecules copied from DNA sequences that tell the cell how to behave.

Second, to explore the hypothesis that the T cells decrease the proliferation of neural stem cells, the researchers also examined what happened when (i) they enabled T cells to enter the brains of young mice and (ii) they cultured neural stem cells from young mice in vitro (i.e. in a petri dish) either in the presence or absence of T cells.

Finally, in order to determine whether their findings were generalizable from mice to humans, they also conducted an experiment on post-mortem human brain tissue, testing for the presence of T cells.

What did they find?

The authors identified eleven different cell types in the neural stem cell niche of the adult mouse brain and found that as expected, there were major differences in transcription between the young and old mice, as well as a 75% reduction in the number of neural stem cells. However, they also identified a large number of T cells (immune cells not usually found in the brain) in older mice. Furthermore, these T cells were located in close proximity to the neural stem cells. The T cells also differed from those usually found in blood, as the T cells in the brains of older mice secreted high levels of the molecule interferon-γ. Neural stem cells have receptors for a signalling interferon-γ, which discourages them from performing their normal function, and the researchers suggest that this is likely to be the main reason why neural stem cells may fail to replicate at the same rate in aged brains.

The authors enabled T cells to enter the brains of young mice and cultured neural stem cells from these young mice in vitro in the presence or absence of T-cells. In both cases, the presence of T cells resulted in a reduction in neurogenesis. Furthermore, they found that introducing an antibody to interferon-γ was able to restore this neurogenesis.

Finally, to determine whether these results could be generalized to humans, the authors examined post-mortem human brain tissue for the presence of T cells. T cells were present in the lining of the lateral ventricles and were more abundant in people aged 79-93 compared to people aged 20-44. This suggests that a similar mechanism could suppress neurogenesis in mice and humans.

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What's the impact?

This is the first study to show that T-cells infiltrate the brain of older mice and that their expression of interferon-γ may explain decreased neurogenesis in aging brains. The authors note that T cells in the aging brain appear to have proliferated through clonal expansion: an immune response to an antigen or harmful molecule wherein cells reproduce rapidly in order to protect the body. Another possibility is that T cells are merely able to enter the brain due to age-related disruptions in the blood-brain barrier. Overall these results may help us to better understand why brain function deteriorates with age, and opens new possibilities for finding treatments to ameliorate brain deterioration.

Dulken et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature (2019). Access the original scientific publication here.


ATP-Sensitive Potassium Channels Trigger Migraine Attacks

Post by Shireen Parimoo

What's the science?

Migraines are persistent, throbbing headaches that can last for days and lead to nausea, light sensitivity, and dizziness, among other symptoms. Migraines often occur in response to triggers like stress and physical activity, but despite being quite common in the population, it is not clear what causes them. There is evidence to suggest that inappropriate activation of certain cell membrane receptors in blood vessels might lead to a migraine attack, as drugs that target these receptors are effective in treating migraines in the short-term. Interestingly, one of the downstream effects of activating these receptors is the opening of ATP-sensitive potassium (KATP) channels, which are also activated by molecules that trigger migraines. However, the role of KATP channels in migraines has not yet been established. This week in Brain, Al-Karagholi and colleagues used pharmacological intervention to investigate the effect of opening KATP channels on migraines and arterial blood flow.

How did they do it?

Sixteen adults suffering from migraines participated in the study over two days. They were given 20ml of levcromakalim (LKM, a drug that opens KATP channels) on one day and a saline placebo on the other day. The study was a randomized, double-blind, crossover study, which means that the treatments were administered in a randomized manner, the participants and researchers did not know which treatment was being administered on a given day, and the participants took both LKM and the placebo over the course of the two days. The authors acquired baseline measures of migraine symptoms and physiological measures like blood pressure, heart rate, and electrocardiogram before treatment. After LKM and placebo injection, they monitored the physiological measures regularly for two hours in addition to blood flow velocity in the middle cerebral artery (in the brain), the diameter of the left superficial temporal artery (in the forehead) and radial artery (in the forearm), and the partial pressure of CO2 in the left radial artery. Participants also recorded the incidence and intensity of migraines and headaches for 12 hours after receiving treatment. To determine the effect of opening KATP channels on migraines, the authors compared these measures across the placebo and LKM conditions. 

What did they find?

All participants experienced migraines within hours of being treated with LKM, whereas only one person experienced a migraine after the placebo treatment. The migraines were focused on frontal and temporal areas on the head and were accompanied by nausea, sensitivity to light and sound, palpitations, flushing, and a warm sensation. Unlike migraines, the frequency of headaches did not differ significantly across the two treatment conditions, although the headaches were more intense after LKM injection than after placebo treatment. This suggests that the opening of KATP channels selectively induces migraine attacks. After LKM treatment, there was also an increase in heart rate, reduction in blood pressure, and an increase in the diameter of the superficial temporal artery. However, the change in blood flow velocity or radial artery diameter was not different across the two treatments. The superficial temporal artery supplies blood to the temples, which is one of the main areas where participants report experiencing pain during a migraine attack. Thus, the effect of LKM on the temporal artery further strengthens the role of KATP channels in inducing migraines.

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What's the impact?

This study is the first to establish a role of KATP channels in migraine attacks by using a pharmacological intervention to induce migraines. As KATP channels are found in various types of cells and tissues and serve many different functions, it is still unclear how and when these channels cause migraines. This opens the door for future research in identifying which KATP channels result in migraines, further characterizing the mechanistic pathway underlying migraine onset, and developing novel drugs to treat migraines. 

Al-Karagholi et al. Opening of ATP-sensitive potassium channels causes migraine attacks: a new target for the treatment of migraine. Brain (2019). Access the original scientific publication here.

Visual Attention is Associated with Spatially Specific Neural Activity

Post by Elisa Guma

What's the science?

The visual system is organized retinotopically, such that mapping of visual inputs from retina to neurons within the visual cortex is spatially organized. In humans, these maps are commonly identified using functional magnetic resonance imaging. However, the relationship of these between these maps and those identified in humans and animals electrophysiologically  requires further investigation. It is thought that visual attention is related to the strength of alpha band activity (which is measured electrophysiologically) in the cortex. This week in Human Brain Mapping Popov and colleagues investigated whether alpha-band activity changes are retinotopically distributed using magnetoencephalography (MEG), a technique used to measure magnetic fields produced by electric currents in the brain.

How did they do it?

Thirty healthy participants (15 males/15 females) underwent MEG scanning while performing a visual response inhibition task (similar to the Eriksen flanker task). Briefly, participants were asked to fixate their gaze on a central white square. Next, a spatial cue, either a barrel or bowtie, was presented to them at one of 16 locations. Following a short interval (2.5 seconds) in which participants had to maintain their fixation on the cue, a target shape appeared at the same location in which the spatial cue was presented. The targets were flanked by either the same shape (bowtie-bowtie), or the opposite shape (bowtie-barrel). The goal of the task was for participants to identify whether the target was a bowtie or a barrel. The authors used spatial location tuning functions to associate spatial location of alpha frequency brain activity to the spatial location of the visual cues. Finally, they mapped the activation patterns onto a probabilistic atlas of the human brain.

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What did they find?

The authors found that maintenance of the cue position when the cue was in a location in the left half of the visual field was associated with a decrease in alpha band power on the opposite (right) side, and an increase in alpha power on the same side (left side). Next, they observed an increase in response time and a decrease in accuracy when the targets were flanked by the opposite shape. This was reflected in patterns of alpha activity such that when participants were not distracted by flankers of the opposite shape, but rather saw the same object for target and flank, they were better able to maintain alpha activity in the spatial location of the target. Further, the slower the reaction time of the participants, the less focal the alpha-band activation. Finally, using a brain atlas the authors show that their maps of alpha activity map onto areas of the visual cortex in the brain in a retinotopic fashion: Changes in the location of the target stimuli in the visual field were reflected by spatial differences in the activation pattern in the visual cortex..

What's the impact?

This study found that alpha-band activity in a spatial attention task had spatial specificity and was affected by participants’ distractibility and response time. These findings demonstrate that the alpha-band activity is critical in allocation of the brain’s resources in directing spatial attention. A deeper understanding of the way in which neural activity underlies visual attention may help us understand the mechanisms underlying visual perception and attention.

Popov et al. Spatial specificity of alpha oscillations in the human visual field. Human Brain Mapping (2019). Access the original scientific publication here.