Summary: Astrocytes, long considered passive support cells, are now shown to play a central role in controlling behavior by modulating neuronal activity through a slower biochemical signaling pathway.
In larval zebrafish, researchers discovered that astrocytes respond to norepinephrine by releasing ATP into the extracellular space. That ATP is enzymatically converted into adenosine, a neuromodulator that acts on neurons to suppress persistent swimming when the animal’s efforts prove futile. Unlike the millisecond-scale signaling of neurotransmitters between neurons, this astrocyte-driven purinergic pathway unfolds over seconds to minutes, enabling flexible behavioral adjustments.
Key Facts:
- Biochemical circuit: Activated astrocytes release ATP, which is degraded to adenosine that then modulates neuronal activity.
- Slower timescale: This neuromodulatory pathway operates over seconds to minutes, not the millisecond timing of synaptic transmission.
- Therapeutic potential: Astrocyte-mediated neuromodulation may offer new targets for psychiatric and neurological interventions.
Source: HHMI
Overview
Recent research from teams at Janelia and Harvard expands our understanding of how non-neuronal astroglial cells—astrocytes—contribute directly to behavior. Building on earlier work that linked radial astrocytes to a zebrafish “giving up” behavior, the new study deciphers the molecular steps by which astrocytes communicate with neurons to change behavioral state.
Neurons often rely on fast neurotransmitters to exchange information in millisecond windows, but neuromodulators tune the activity of neuronal populations over much longer intervals. The newly described astrocyte circuit provides a clear example: norepinephrine elevates calcium in astrocytes, triggering ATP release. Extracellular enzymes then convert ATP to adenosine, which acts on neuronal adenosine receptors to suppress continued swimming when the animal perceives its effort is not producing forward progress.
This work reframes astroglia as active effectors in neuromodulatory signaling rather than passive background cells. It also suggests that a full account of brain computation must combine classical neuronal circuit connectivity with slower biochemical computations performed by non-neuronal cells.
“Many people assume the computations that drive behavior arise primarily from patterns of neuronal connectivity,” says Alex Chen, a joint PhD student at Janelia and Harvard and lead author on the study. “Our results show biochemical and glial processes contribute essential information that integrates with neuronal wiring to shape behavior.”
Senior author Misha Ahrens emphasizes the clinical relevance: if neuromodulatory flow often travels through astrocytes, these cells and the enzymes that process extracellular ATP could be considered in strategies to treat psychiatric disorders.
Uncovering the conversation
The new study builds on earlier findings from 2019 showing radial astrocytes ramp up activity as a larval zebrafish realizes its swimming is futile. That earlier work demonstrated astroglial activity reached a threshold that preceded the animal’s decision to stop swimming, but the mechanism by which astrocytes signaled neurons remained unclear.
Using genetically encoded sensors and targeted manipulations, the researchers traced the bidirectional exchange: neurons release norepinephrine, which raises intracellular calcium in astrocytes. Elevated astrocyte calcium leads to ATP release into the extracellular space. Although ATP can act directly on neuronal purinergic receptors, blocking those receptors did not change behavior in this system, suggesting a secondary transformation occurs.
The team demonstrated that extracellular ATP is enzymatically broken down into adenosine, and that neuronal adenosine receptors mediate the behavioral suppression. Blocking neuronal adenosine receptors reduced the giving-up response, confirming adenosine as the effective neuromodulator in this pathway.
The researchers highlight that this indirect biochemical circuit—neuron to astrocyte to ATP to adenosine to neuron—permits modulation on slower timescales appropriate for decisions that unfold over seconds to minutes. Enzymes that process ATP in the extracellular space may therefore be key regulators of signal timing and represent potential therapeutic targets.
Complementary studies in other models reinforce the generality of this motif: work in mice shows norepinephrine-driven neuromodulation in the hippocampus can flow through astrocytes to affect neuronal communication, related pathways have been identified in flies, and recent mouse studies have linked similar mechanisms to depressive-like behaviors. Taken together, these results suggest an evolutionarily conserved astroglial purinergic signaling axis across species.
“The pathway appears conserved across flies, fish and mammals, which hints at an ancient circuit motif used by nervous systems to implement state changes,” Chen notes.
About this neuroscience research news
Author: Nanci Bompey
Source: HHMI
Contact: Nanci Bompey – HHMI
Image: The image is credited to Neuroscience News
Original Research: Closed access. “Norepinephrine changes behavioral state through astroglial purinergic signaling” by Alex Chen et al. Science
Abstract
Norepinephrine changes behavioral state through astroglial purinergic signaling
Both neurons and glia communicate through diffusible neuromodulators, but how neuron–glial interactions within such neuromodulatory networks shape circuit computation and behavior has been unclear.
In larval zebrafish, the neuromodulator norepinephrine drives an initial fast excitation followed by delayed inhibition of behavior and circuit activity during futility-induced state transitions. The researchers found that astroglial purinergic signaling implements the inhibitory arm of this motif: norepinephrine triggers astroglial release of ATP, extracellular conversion of ATP into adenosine, and behavioral suppression through activation of hindbrain neuronal adenosine receptors.
These findings assign a computational and behavioral role to an evolutionarily conserved astroglial purinergic signaling axis in norepinephrine-mediated state transitions and position astroglia as important effectors in neuromodulatory signaling.