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Introducing a new conceptual framework for astrocyte function

In Nature Neuroscience, Thomas Papouin and colleagues describe the role of astrocytes in “contextual guidance.”

Thomas Papouin
Thomas Papouin, PhD

As the field of astrocyte biology has exploded in recent years, neuroscientists have described myriad characteristics and behaviors of these non-neuronal cells, from reacting to the presence of food or water in a resource-limited environment to regulating the flow of blood in the brain. Once believed to be mere structural scaffolding in the brain, astrocytes are now appreciated for the many ways they control brain activity and behavior. In an effort to unite these findings into a unified concept of astrocyte function, Thomas Papouin, PhD, Assistant Professor of Neuroscience at Washington University, and his colleagues introduced the notion of “contextual guidance.” They published their commentary in Nature Neuroscience on October 19.

Dr. Papouin explains the theory of contextual guidance:

What is the purpose of this paper?

Our goal was simple yet ambitious: to provide a cohesive framework to the expending field of astrocyte biology. Over the last decade, astrocyte research, especially in relation to neuron-astrocyte interactions, has grown exponentially, taking on new scales of investigations, developing new tools, erupting with groundbreaking discoveries and ideas, and capturing the attention of many. But, with that sudden (and welcome) surge of interest, the lack of unified framework and common direction within the field has become increasingly apparent and grown more problematic. To give you an example, we know that astrocytes interact tightly with blood vessels, and we know that they also control synaptic function – but no models of astrocyte function are capable of articulating these two facets harmoniously. In fact, even the fundamental question, “what do astrocytes really do in the brain?” still remains completely unanswered, even within our community.

In this paper, we formalized a conceptual framework for astrocyte biology that is both minimalist and unifying. It seamlessly weaves together knowledge of astrocytes across decades of investigations, existing perspectives and emerging ideas. In doing so, we were able to establish simple truths on the all-encompassing role of astrocytes in brain circuits. This, in turn, allows bold new predictions and a reassessment of recent advancements through an entirely novel lens.

What is contextual guidance?

Contextual guidance posits that astrocytes modulate neural activity and functional connectivity within circuits in a state-dependent fashion. Simply put, astrocytes ensure that neural circuits and their outputs are tuned to the ongoing context. The context can be an internal state (like the metabolic status) or an external state (like an olfactory stimulus) that has relevance to the function of the circuit under consideration. After all, astrocytes are the ultimate regulator of the physical and biochemical properties of the brain’s interstitial space. This includes, for instance, their ability to regulate synaptic strength or to modulate potassium levels.

This framework allows a plethora of novel predictions and perspectives with which to tackle longstanding conundrums, such as whether there is an astrocyte “code” that transforms specific inputs into precise outputs, and how input-output fidelity/specificity might be achieved by astrocytes.

Thomas Papouin, PhD

However, the challenge has always been to understand whether this is simply homeostatic or whether this translates into a functional framework. In other words, are astrocytic outputs mobilized to maintain balance after neuronal activity or do they configure neural circuitry on demand? A wealth of new data now fuels the latter notion and astrocyte outputs, be it the regulation of blood flow, the supply of lactate, or the release of synapse-bound transmitters, appear mostly tuned to signals like hormones, neuromodulators, sensory saliencies or brain states. A parsimonious and useful view, therefore, is that astrocytes act as a local decoder of contextual signals to alter the local circuitry in an adaptive fashion.

How did you arrive at this idea of contextual guidance? Was there a particular discovery that sparked this concept?

I have been thinking about this idea for a long time now, in one form or another. At one point during my PhD, I became convinced that astrocytes might be better suited to respond to hormones and “slow stuff”, as I remember saying, that shape neural activity in response to the environment. Back then, however, the dogma was that astrocytes are primarily tuned to instantaneous synaptic activity or neuronal firing, and I did not think that made too much sense. My hunch eventually morphed into a quest to understand what drives astrocytes and whether astrocytes’ outputs on neural circuits follow a homeostatic logic or an instructive one.

A critical turning point for the field came with the discovery that astrocytes are not silent bystanders but display an expansive Christmas tree-like pattern of intricate intracellular calcium signals (see for instance PUBMED ID 25894291). These signals, it turns out, are remarkably sensitive to a wide array of neuroactive molecules, particularly neuromodulators, hormones, and other “slow stuff”.

For the first time, this allowed us to start picturing the role of astrocytes as sensors of context and modifiers of circuit configuration, which matches many of their other characteristics. However, one does not make a “theory” out of a single discovery so we waited until more evidence corroborated this view. Today, the evidence has simply become overwhelming. As for the name “Contextual Guidance,” the credit entirely goes to my wife but that is a different story.

How does this reshape our view of astrocytes?

I think the answer will depend on who you ask. This paper offers a viewpoint that could be seen as radically novel in the broader context of neuroscience. Often, non-specialists regard astrocytes as mere housekeeping cells with no significant function, primarily due to outdated textbook statements made by non–astrocyte-literate neuroscientists. In truth, this perspective has not been supported by any scientific papers for the past three or four decades, but that misconception has persisted by lack of a more broadly acceptable theory.

Here, we place astrocytes at the forefront of neural circuit function and adaptability, a view that is both backed with cellular-level mechanisms and behaviorally consequential. This elevates astrocytes from a perceived ‘housekeeper’ status to that of a circuit effector. From there, the predictions we make are only a small leap further. Considering the complete ubiquity of astrocytes, if validated, these predictions would fuel an overhaul of our perception of the cellular foundations of brain function. This would move the needle resolutely towards a genuine neuron-glia theory of brain computation and outputs, which, after all, has been hiding in plain sight all along.

For astrocyte aficionados, the view we describe may seem logical because it articulates, with few elemental principles, many moving parts that, until now, were challenging to piece together.

Are there aspects of astrocyte function that aren’t explained by contextual guidance, or gaps in the concept you’d like to fill?

We did not do a very good job at exploring the developmental or pathological ramifications of the concept, to be honest. This is simply because we do not have the expertise and did not have the space. It’ll be interesting to see if colleagues in the field who study, for instance, the role of astrocytes in synaptogenesis or in spinal cord injury, find the framework useful and can build upon it.

What is your lab pursuing in the field of astrocyte biology and how does it reflect contextual guidance?

Our lab’s research is closely inspired by the principles of contextual guidance. It helps us generate hypotheses and predictions. For example, one avenue of our research aims at investigating the extent to which astrocytes are involved in the circuit-level effects of neuromodulators that have been documented for a hundred years. Another aspect is centered on understanding the contribution of astrocytes to pro-cognitive functions facilitated by cholinergic neuromodulation. This work delves into the specifics of how astrocytes participate in cognitive processes and sheds light on their broader functional relevance to behavior.

We are also trying to refine some dimensions of astrocyte calcium signaling. Additionally, if astrocytes serve as a functional conduit for environmental cues to influence circuits, they may also be a gateway for the adverse effects of environmental toxins, and new research in our lab is aimed at elucidating how endocrine disruptors impact astrocytes in this context.

For the first time, this allowed us to start picturing the role of astrocytes as sensors of context and modifiers of circuit configuration, which matches many of their other characteristics.

Thomas Papouin, PhD

One key takeaway from the contextual guidance framework is the need to conduct in vivo studies that are behaviorally relevant and reflective of real-world conditions. But the limitations of traditional mouse models in exploring brain function in complex and dynamic environments has led us to consider transitioning some of our research into primate models. With a generous grant from the DoD, we are conducting pilot studies with collaborators at Washington University and Emory to explore this possibility.

Finally, one of the most immediate and impactful implications of the contextual guidance framework is that it provides a simple yet powerful means to model astrocyte function within artificial neural networks. Through collaborative work with my coauthor Dr. ShiNung Ching, we have already obtained stunning evidence of the transformative potential this holds for machine learning and artificial intelligence, some of which we included in the paper.

How do you anticipate having this unified conceptual framework around astrocyte function will affect the field?

Firstly, I hope that this framework will not only resonate within the astrocyte community but beyond. It provides a credible foundation to bridge the gap between astrocyte biology and the broader field of neuroscience, irrespective of model organism, circuit, or scale. In other words, we hope it will rally some of the neuron-traditionalists out there!

Secondly, the framework opens up opportunities to integrate other non-neuronal cells into the picture. For example, it offers new insights into how microglia and astrocytes might collaborate to influence neural circuits in a context-dependent manner.

Lastly, within the field itself, this framework allows a plethora of novel predictions and perspectives with which to tackle longstanding conundrums, such as whether there is an astrocyte “code” that transforms specific inputs into precise outputs, and how input-output fidelity/specificity might be achieved by astrocytes. It gives a potential function to the tiling of astrocytes throughout the brain in non-overlapping domains, a hallmark preserved in all species. It points at urgent questions such as resolving the role of astrocytes in the effects of hormones and neuromodulators on circuits and behavior. It also begs the question of a possible astrocytic memory of context-specific circuit configuration. Lastly, it opens up opportunities to test the relevance of astrocytes in artificial neural circuits used to model or emulate brain computation. These are some of the many inquiries that might not have arisen before.