Study highlights links between addictive substances and brain function in mice – ScienceDaily


Researchers are using advanced technology and mice to study the structure of dopamine neurons, addiction and the brain’s ability to recover.

A late 1980s commercial intended to combat drug addiction used a pair of fried eggs as a metaphor for the effects of drugs on the human brain. While researchers have long understood the link between substance abuse and unwanted changes in the brain, it is only now that they can examine in detail the changes that actually occur.

Using cutting-edge technology, researchers from the University of Chicago and the US Department of Energy’s (DOE) Argonne National Laboratory have, for the first time, detailed specific changes that occur in the brains of mice exposed to cocaine.

The research provides new insights into the function of key dopamine neuron structures involved in multiple functions, from voluntary movement to behavior. The results turned the page on older questions about dopamine transmission while turning a new chapter on others. Through continued work, researchers hope to understand how certain types of addiction work and perhaps develop targeted treatments.

In a recent article published in the magazine eLifethe researchers describe how they are building on the burgeoning field of connectomics, the development of highly detailed and accurate 3D maps of every neuron in the brain and their connections.

For their part, the team set out to more precisely identify the process by which dopamine is transmitted across neurons, since they don’t make traditional physical connections where signals are transmitted across synapses.

“Evidence suggests that these neurons release dopamine into the extracellular space and activate nearby neurons that have dopamine receptors,” says Gregg Wildenberg, a principal investigator on the project. “But connectomics has little to say about these types of circuits because they don’t make typical connections, so we wanted to delve into that area to see how it actually works.”

Another motivation for the project was to understand dopamine’s involvement in addiction. What, if any, anatomical changes in dopamine circuits are caused by drugs of abuse such as cocaine?

Achieving this level of detail required the use of Argonne’s large-volume, three-dimensional serial electron microscope. A powerful microscope capable of visualizing the smallest details of the brain allowed a closer look at the dopamine neurons of a selection of cocaine-sensitized mice and control animals.

Using resources from the University of Chicago, the team collected approximately 2,000 40-nanometer-thick slices (1 mm = 1 million nm) of midbrain and forebrain dopamine-associated slices.

From these samples, the SEM generated a collection of 2D single images – a total of over 1.5 terabytes of data. These were digitally reassembled using the Cooley visualization cluster at the Argonne Leadership Computing Facility, a user facility of the DOE Office of Science.

This process creates a 3D volume that allows researchers to identify and track various anatomical features of dopamine neurons, which until recently had proved challenging.

“The leap of faith in this project was that we would actually be able to detect anatomical changes that could occur at any point in the brain,” said Narayanan “Bobby” Kasthuri, a co-researcher on the project. “Could we take this microscopic slice of the brain and find anything that’s quantitatively different? That’s also one of the reasons we chose cocaine, because we thought whatever was happening was probably happening systemically throughout the brain.”

The results revealed that dopamine neurons actually don’t make any physical connections, except in a few rare cases. And the latter might suggest that dopamine neurons are not identical; that there may be another subclass that tends to make more physical connections.

In general, they found that small swellings, or varicose veins — sites responsible for releasing dopamine — could be classified into four different types, based in part on size as well as the amount of neurotransmitter-carrying vesicles each varicose vein contained.

They found that some of these swellings were vesicle-free, leading some critics to claim that they could not be defined as proper release sites. These empty varicose veins, they say, likely indicate that there may be other molecular components that define dopamine release sites besides the presence of vesicles.

“We suspect it’s possible that these empty varices have all the molecular machinery to release dopamine, but it may be that dopamine vesicles are actively being transported down the axon and we happened to have a snapshot where some are empty ‘ said Wildenberg.

The cocaine portion of the study revealed two major changes, both centered on axons, the ultrathin cables that protrude from neurons. Like trees, axons sprout tendrils that branch out to other axons to deliver signals. After the mice were exposed to cocaine, the team noticed an increase in this branching.

In a completely unexpected finding, they also found that about half of the axons they examined formed huge swellings, or nodules, at various locations along the axon. The closest correlation to these nodules occurs in developing animals, at junctions where neurons meet muscle. In some cases, an axon retracts or is pruned and then swells into a large bulbous structure.

The team saw evidence of both sprouting and retracting, sometimes in the same axon. According to the researchers, the finding represents the first documentation of this behavior in the context of a disease model.

“Now we know that there is an anatomical basis for exposure to drugs,” Kasthuri noted. “These animals were given a shot or two of cocaine and within two to three days we saw extensive anatomical changes.

“It’s not like some molecules are changing here or there,” he added. “The circuit rearranges much sooner and with far less exposure to the drug than anyone would have thought.”

While the study helped elucidate questions about form, function, and dynamics in the dopamine system, it also raises important new questions related to repeat exposure and addiction, as well as treatment and recovery.

Above all, can the brain overcome the structural changes introduced by drugs based on its plasticity in other areas? The results of this research and access to powerful discovery tools are key to answering these types of questions in the future.

The research presented in this article was published in the December 29, 2021 issue eLife entitled “Cell-type specific labeling and partial connectomes of dopaminergic circuits reveal non-synaptic communication and large-scale axonal remodeling after cocaine exposure”.

Authors include: Wildenberg, Kasthuri and AM Sorokina, University of Chicago and Argonne National Laboratory; Koranda JL, Monical A, Heer C, Sheffield ME, Zhuang X and McGehee DS, University of Chicago.

Funding for this research was provided by a McKnight Foundation technical award, an NIH BRAIN Initiative grant, and an NSF NeuroNex grant.


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