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The release of dopamine in the brain plays a key role in determining how we respond when we perceive a potential reward or benefit. But so far little has been understood about the mechanism behind this. A new collaborative paper from Prof Stephanie Cragg's Group and Prof Ed Mann published in Nature Communications has uncovered a dominant regulator of the dynamics of dopamine output.

Dopamine in the striatum of the brain is critical to the selection and learning of our motivated actions. Dopamine neurons input into a system called the basal ganglia which regulates our voluntary actions and helps us to respond particularly to something we perceive as having a benefit or rewarding property, and consequently carrying motivational value. Dopamine helps us select actions and learn from the associations we make between a stimulus, our action and its outcome, to change the way we might respond next time.

Notably, when some types of dopamine neurons are lost in Parkinson’s, this leads to problems moving. Other dopamine neurons are targeted by addictive drugs, which boost dopamine signals and lead to maladaptive levels of learning, leading to behavioural choices to seek drugs.

So far it is known that dopamine neurons form immensely and uniquely branched axons in the striatum. The release of dopamine in the striatum is dynamically gated moment-by-moment, a short-term plasticity, but the key controllers of this plasticity have not been well understood.

 

Dopamine neurons dynamically change their firing rate over a large range of frequencies to signal different events related to reward prediction, anticipation, prediction errors and perhaps movement, so it is important that we understand how dopamine axons convert this activity into dopamine output. The axons of dopamine neurons are not passive cables that faithfully convert neuronal activity into dopamine release, but rather they contain active mechanisms that will significantly impact on the kinds of signals that dopamine neurons ultimately convey in the form of dopamine release. - Professor Stephanie Cragg

However, it is relatively difficult to study the mechanisms operating in axons that govern transmitter output, and those that operate in DA axons are not well understood. A further difficulty arises because the axons of dopamine neurons are considered unusual because they form the most immensely branched axons reported anywhere in the brain. "Their tree-like axonal arbours are unmyelinated and vast, which raises unaddressed questions about whether action potentials can be propagated throughout this tree, as well as about bioenergetics demands on these neurons that might promote disease." (Prof Cragg).

A new paper from Professor Stephanie Cragg and her team, first authored by DPhil student Mark Condon and in collaboration with Associate Professor Ed Mannhas managed to uncover some surprising observations on this unusual neuronal network. Unlike for many other types of synapses in the brain, the team has found that the short-term plasticity in dopamine release is not very sensitive to calcium and initial release probability. Instead, it shows a form of release-insensitive depression. By detecting dopamine and imaging calcium in axons, results suggest that the critical mechanisms are those that shape the ability to depolarise or repolarise axons.

The team also unexpectedly found that the dopamine transporter (DAT), thought to be mainly involved in the re-uptake of dopamine after release, actually plays a major role through modifying axonal excitability. "The DAT seems to be a dominant regulator of the dynamics of dopamine output, and a major factor is the regulation of the excitability state of those curiously branched DA axons." (Prof Cragg).

This breakthrough piece of work demonstrates that axonal excitability plays a major role in shaping the dynamics of dopamine output from this arbour, whereas calcium and prior release, which normally play a large role in short-term plasticity in other synapses, are relatively minor players. "In addition, we make the novel finding that the dopamine uptake transporter, which covers the length of these axons, changes the activation state of the axons and sets up the rules of play. This transporter is far from being just a dopamine uptake pump!" (Prof Cragg).

These findings will encourage researchers to investigate the underlying mechanisms including ion channels. Newly emerging tools for imaging axons can test the findings' suggestion that the way action potentials propagate through the axonal arbour may be more limited than previously assumed. There are also implications for investigating how the process changes in disease states where dopamine transporters are dysregulated, such as in drug addictions and Parkinson's.

 

The full publication "Plasticity in striatal dopamine release is governedby release-independent depression and thedopamine transporter" is available to read in Nature Communications.

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