Astrocytes: The Unsung Heroes of the Brain

Post by Trisha Vaidyanathan

What are astrocytes?

Astrocytes are star-shaped cells that are found throughout the brain and contain thousands of very fine branches. Astrocytes are the largest type of a neural cell called “glia”, which is the Latin word for “glue,” because scientists originally thought they simply existed to hold the brain together. However, the field of astrocyte biology has exploded in recent years, and while many mysteries remain, it is now well-appreciated that astrocytes serve many critical functions in the brain. 

Astrocytes are an essential component of the synapse

Canonically, the neuronal synapse includes two players: the pre-synaptic neuron and the post-synaptic neuron. However, we now know that there is a third player — the astrocyte — resulting in what is called the “tripartite synapse”. Most neuronal synapses are enveloped by an astrocyte branch. By “hugging” the neuronal synapse, astrocytes can both monitor what is happening via different receptors and directly manipulate the synapse. Astrocytes can manipulate synapses in several ways, including altering ion and neurotransmitter concentrations via transporters or by releasing their own signaling molecules. Indeed, astrocytes are necessary for synapse formation, maintenance, elimination, and plasticity.

Astrocytes provide energy to the brain

Neurons require a massive amount of energy in the brain, and astrocytes take on the job of supplying that energy. Astrocytes contact blood vessels through special branches called “end-feet” where they help form the blood brain barrier, regulate blood flow, and, importantly, take in glucose from the blood. Astrocytes either store glucose as glycogen, or convert it into lactate. Lactate is then shuttled directly into hungry neurons, where it is rapidly converted into ATP, the energy currency of the cell. Astrocytes dynamically regulate glucose uptake, storage, and lactate shuttling to match the energy demands of the brain and regulate neuronal activity.

Astrocytes respond to injury and disease

A large body of evidence has demonstrated that astrocytes are able to react in the presence of disease or injury. When astrocytes become “reactive” they change their shape, gene expression, and function. Reactive astrocytes have been found in response to most types of brain insults, including traumatic brain injury, viral infections, stroke, epilepsy, neurodegenerative diseases, autoimmune disorders, cancer, and psychiatric diseases.

There is no single definition of a “reactive astrocyte” and the response varies with the type of disease/injury and severity. Interestingly, in some instances, the reactive state can be beneficial, while in other instances it can exacerbate the disease or injury. There is still much to understand about astrocyte reactivity and what drives the astrocyte to either help or hurt.

Astrocytes control circuits and behavior

Astrocytes have thousands of fine branches that allow them to communicate with many cells at once. A single astrocyte can simultaneously contact up to 100,000 synapses in the mouse brain and two million in the human brain. As such, they are uniquely suited to regulate larger neuronal circuits. The recent development of new tools has allowed scientists to identify a critical role for astrocytes in controlling many different circuits and behaviors. Astrocytes have been shown to play a pivotal role in behaviors like memory, learning, sleep, feeding, emotional regulation, motor behavior, and decision making. Precisely how astrocytes regulate these complex circuits and behaviors remains to be understood, but it’s becoming increasingly clear that astrocytes are critical to the bigger picture of the brain and behavior.

What don’t we know about astrocytes?

Relative to neurons, our understanding of astrocytes lags far behind. However, newer tools are allowing astrocyte biologists to begin exploring some basic questions about these long-ignored cells. New microscopes and genetically encoded sensors are providing insight into how astrocytes signal to the rest of the brain using calcium. New molecular tools are revealing unique features of human astrocytes that may be critical to their role in disease and injury. Lastly, new evidence suggests astrocytes may not be just a single class of cell, but instead may have specialized functions, much like different neuron subtypes.

While there is still a lot we don’t know about the fundamental functions of these cells, new advances are being made rapidly and it is becoming increasingly clear that astrocytes are essential to brain function.

References +

Chung, Won-Suk, Nicola J. Allen, and Cagla Eroglu. "Astrocytes control synapse formation, function, and elimination." Cold Spring Harbor perspectives in biology 7.9 (2015): a020370. DOI: 10.1101/cshperspect.a020370

Hasel, Philip, and Shane A. Liddelow. "Astrocytes." Current Biology 31.7 (2021): R326-R327. DOI: https://doi.org/10.1016/j.cub.2021.01.056

Kofuji, Paulo, and Alfonso Araque. "Astrocytes and behavior." Annual review of neuroscience 44 (2021): 49-67.DOI: https://doi.org/10.1146/annurev-neuro-101920-112225

Lawal, Oluwadamilola, Francesco Paolo Ulloa Severino, and Cagla Eroglu. "The role of astrocyte structural plasticity in regulating neural circuit function and behavior." Glia 70.8 (2022): 1467-1483. DOI: https://doi.org/10.1002/glia.24191

Magistretti, P., Allaman, I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci 19, 235–249 (2018). DOI: https://doi.org/10.1038/nrn.2018.19

Sofroniew, Michael V., and Harry V. Vinters. "Astrocytes: biology and pathology." Acta neuropathologica 119 (2010): 7-35. DOI: https://doi.org/10.1007/s00401-009-0619-8

How the Awake and Sleeping Brain Tags Relevant Information for Memory

Post by Meredith McCarty

The takeaway

This research provides evidence for a mechanism by which relevant information is selected or tagged for memory consolidation in the hippocampus, a region of the brain critical for memory. 

What's the science?

An essential feature of brain function is selecting relevant information to be stored in long-term memory. However, the neural mechanism by which this is accomplished has yet to be fully understood. The authors hypothesized that hippocampal neurons are involved in selecting, or “tagging”, relevant information for subsequent memory storage. This week in Science, Yang and colleagues identify a potential neural mechanism explaining how relevant information is selected for memory formation. 

How did they do it?

To study this mechanism, the authors had mice perform a spatial memory task. In this task, a water reward was delivered at the left or right arm of a figure 8-shaped maze (the location of this reward alternated on each trial). The mice had to navigate through this maze and choose the correct arm (left or right) to receive the water reward (the mice were water-restricted before beginning the task). Following this memory task, mice were placed in their familiar home cage and their neural data was recorded during periods of sleep. 

During the task and sleep periods, the authors recorded the spiking activity of single neurons via electrodes located in the hippocampus, measuring changes in spiking activity and identifying occurrences of sharp wave ripples (SPW-Rs). SPW-Rs are thought to be an essential feature of “offline” brain processing, during which populations of hippocampal neurons exhibit synchronized rapid firing, communicating compressed information to connected brain regions. To understand the relationship between neural activity and key decision and memory points in the task, the authors used neural decoding and analysis techniques, linking the mice’s real-time position in the maze on a given trial with the neural spiking and SPW-R recordings. 

What did they find?

First, the authors found a correlation between the mouse’s position in the maze and CA1 population spiking activity and were able to successfully decode the recent locations of the mice in the maze from the population spiking activity. When considering the activity of single neurons in isolation (which exhibit representational drift, meaning dynamic variability in activity across trials despite stable behavioral responses), the decoding accuracy deteriorated. This suggests that locations and events during the trial are represented at the population level — made up of variable activity of individual neurons — as opposed to the individual level. 

Next, when analyzing neural activity during the time after the mouse successfully navigated the maze and received a reward, the authors noted the emergence of SPW-R events on numerous trials. They were able to successfully decode task information from the content of these ripple events. These SPW-Rs were preceded by a decrease in theta activity, signifying the transition out of an active behavioral state. These findings suggest that SPW-Rs, theta power, and rewarding stimuli are related to memory replay and tagging events in the hippocampus.

When comparing awake and asleep neural activity, they found the occurrence of SPW-Rs during the awake task period to be a significant predictor of subsequent SPW-Rs during sleep. This suggests that the information tagged during awake SPW-Rs is subsequently replayed during sleep, furthering the process of memory consolidation.

What's the impact?

Based on these results, the authors propose a neurophysiological framework by which experiences are tagged for further memory consolidation in the hippocampus. The proposed mechanisms underlying this process are a decrease in theta power preceding the tagging of relevant information via SPW-Rs, and the subsequent repetitions of SPW-Rs during sleep that allow the replay of these events necessary for memory consolidation. 

This work has implications for both experimental and clinical work, to better understand how memories are formed, and how this process is disrupted in individuals with debilitating memory impairments.  

Inflammatory Effects of Trem1 are Associated with Risk of Developing Alzheimer’s Disease

Post by Shireen Parimoo

The takeaway 

Trem1 is a receptor protein found in macrophages – a type of white blood cell – that increases in older age and has pro-inflammatory effects. Deletion of Trem1 reduces inflammation by increasing mitochondrial metabolism and rescues cognitive deficits associated with aging and Alzheimer’s disease, such as memory loss. 

What's the science?

Myeloid cells like microglia and macrophages are critical for optimal brain and immune functioning. Alzheimer’s disease (AD) is characterized by pathology including the accumulation of amyloid protein and neurofibrillary tangles. Research has identified many families of genes that are associated with an increased risk of developing Alzheimer’s disease (AD). In aging mice, a receptor expressed on myeloid cells-1 (Trem1)  has pro-inflammatory effects that lead to higher rates of cognitive decline and greater amyloid accumulation. However, the exact role of Trem1 in AD is presently unclear. This week in Nature Neuroscience, Wilson and colleagues investigated the cellular mechanisms by which Trem1 regulates myeloid cell functioning and its effects on memory in typical aging and AD.

How did they do it?

The authors performed a series of experiments on several mouse models. The first included old and young wildtype mice and mice with deletion of both Trem1 alleles (Trem1-/-), which allowed them to identify the baseline effects of Trem1 deletion on myeloid cell functioning. Here, flow cytometry was used to look at Trem1 expression in myeloid cells of wildtype and mice with deleted Trem1 alleles. Next, inflammatory markers in plasma, peripheral macrophages, and the brain were quantified and compared to performance on spatial and object recognition memory tasks. The authors then used RNA sequencing to compare the differences in microglial and macrophage gene expression between the groups. Finally, as energy metabolism is important for regulating inflammatory responses, they investigated the effects of Trem1 deletion on macrophage metabolism by characterizing the expression of mitochondrial genes in the mouse models.

The second group consisted of mouse models of AD (i) without Trem1 deletion, (ii) with deletion of a single Trem1 allele, and (iii) with deletion of both Trem1 alleles. These AD mouse models enabled the authors to determine how Trem1 deletion affects the cellular responses of microglia and macrophages to amyloid burden and its effect on memory. As before, they measured Trem1 expression, inflammatory responses, memory performance, and mitochondrial metabolism. Finally, to determine whether Trem1 is implicated in human AD, the authors used human frontal cortex tissue from controls and patients with AD to quantify Trem1 levels and to examine the relationship between Trem1 and disease severity. 

What did they find?

Older wildtype mice had elevated Trem1 expression when compared to younger wildtype mice, as well as higher levels of inflammatory markers in plasma. Mice with Trem1 deletion, however, showed similar levels of plasma and brain inflammatory proteins as the younger mice. Anti-inflammatory markers in macrophages were lower in older than younger mice while pro-inflammatory markers showed the opposite pattern. Within the older group, mice with the deletion of both Trem1 alleles had higher anti-inflammatory and lower pro-inflammatory markers, better spatial and object memory performance, and different gene expression profiles of proteins associated with mitochondrial metabolism and inflammatory regulation in peripheral macrophages compared to the wildtype mice. Together, these results suggest that in typical aging, Trem1 expression negatively affects memory through pro-inflammatory mechanisms while Trem1 deficiency has neuroprotective effects.

Trem1 expression was higher in post-mortem brains of humans who had AD than those who didn’t, and elevated levels of Trem1 were associated with more advanced stages of AD. In mouse models of AD, mice with and without Trem1 deficiency had similar amyloid burden as well as similar levels of Trem1 in microglia. Compared to AD mice with both Trem1 alleles deleted, the deletion of only a single Trem1 allele rescued memory performance. Trem1 deletion in AD was also associated with lower inflammatory markers in the blood, indicating that the increased presence of Trem1 in aging has adverse effects on cognition due to increased inflammatory responses in AD, irrespective of amyloid burden. 

What's the impact?

This study is the first to demonstrate the role of Trem1 signaling in the risk of developing Alzheimer’s disease. The finding that Trem1 expression increases with age and promotes inflammation via metabolic pathways provides an avenue for future research to develop treatments targeting those specific pathways. 

Access the original scientific publication here.