Summary: A new study sheds light on how the brain changes as a result of chronic stress. Selective noradrenaline release rewires connectivity patterns between different brain regions. Activity in the amygdala and networks that process sensory stimuli increased.

Source: ETH Zurich

Researchers at ETH Zurich have shown for the first time that selective release of the neurotransmitter noradrenaline reconfigures communication between large-scale networks in the brain. Their findings provide insights into rapid neural processes that occur in the brain during stressful situations.

In moments of acute stress – for example, a life-threatening situation in road traffic – our brain has just a split second to react. It focuses attention on the most important environmental cues in order to make life-or-death decisions in fractions of a second. To accomplish this, efficient communication needs to be quickly established between various areas of the brain by forming so-called functional networks.

How the brain guides these rapid processes has been thus far unclear. Tests on humans suggested a major role for the neurotransmitter noradrenaline (also called norepinephrine), which the brain releases in large quantities during stressful situations. However, it is not possible to directly examine this theory in people, because noradrenaline release cannot be selectively manipulated.

Two ETH Zurich research teams, headed by Johannes Bohacek and Nicole Wenderoth, joined forces to crack this difficult problem. Animal tests allowed the researchers to prove for the first time that a release of noradrenaline was itself enough to connect various regions of the brain very quickly. In these tests, the scientists applied the latest genetic tricks to stimulate a tiny center in the mouse brain: the locus coeruleus, which supplies the entire brain with noradrenaline.

The ETH researchers performed real-time magnetic resonance imaging (MRI) scans of the anaesthetized animals’ brains while triggering noradrenaline release from the locus coeruleus.



Astonishing results

The scientists were astonished by the results: selective noradrenaline release re-wired the connectivity patterns between different brain regions in a way that was extremely similar to the changes observed in humans exposed to acute stress. Networks that process sensory stimuli, such as the visual and auditory center of the brain, exhibited the strongest increase in activity. A similar rise in activity was observed in the amygdala network, which is associated with states of anxiety.

Valerio Zerbi, first author of the published study and an expert on MRI techniques in mice, was astounded: “I couldn’t believe that we were seeing such strong effects.” In addition, the researchers were able to demonstrate that areas of the brain with a particularly strong response to the stress-like release of noradrenaline also have a high number of specific receptors for detecting it.

“Overall, our results show that modern imaging techniques in animal models can reveal correlations that allow us to understand fundamental brain functions in humans,” Bohacek says. The researchers hope to use similar analyses in humans to diagnose pathological hyperactivity of the noradrenaline system, which is associated with anxiety and panic disorders.

About this neuroscience research article

Source:

ETH Zurich

Media Contacts:

Johannes Bohacek – ETH Zurich

Image Source:

The image is in the public domain.

Original Research: Closed access

“Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation”. Johannes Bohacek et al.

Neuron. doi:10.1016/j.neuron.2019.05.034

Abstract

Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation

Highlights

• Chemo-connectomics combines chemogenetics (DREADDs) with resting-state fMRI

• Locus coeruleus (LC) activation rapidly increases brain-wide functional connectivity

• Connectivity changes correlate positively with adrenergic receptor distribution

• LC activation shifts large-scale network connectivity toward salience processing

Summary

The locus coeruleus (LC) supplies norepinephrine (NE) to the entire forebrain and regulates many fundamental brain functions. Studies in humans have suggested that strong LC activation might shift network connectivity to favor salience processing. To causally test this hypothesis, we use a mouse model to study the effect of LC stimulation on large-scale functional connectivity by combining chemogenetic activation of the LC with resting-state fMRI, an approach we term “chemo-connectomics.” We show that LC activation rapidly interrupts ongoing behavior and strongly increases brain-wide connectivity, with the most profound effects in the salience and amygdala networks. Functional connectivity changes strongly correlate with transcript levels of alpha-1 and beta-1 adrenergic receptors across the brain, and functional network connectivity correlates with NE turnover within select brain regions. We propose that these changes in large-scale network connectivity are critical for optimizing neural processing in the context of increased vigilance and threat detection.

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