Study highlights connections between addictive drugs and brain function
in mice

Date:
January 18, 2022
Source:
DOE/Argonne National Laboratory
Summary:
Researchers used high-resolution technologies to see how dopamine
circuitry in mice is affected by addictive drugs. The results
answered older structural questions, while raising new ones about
plasticity and recovery in the brain.



FULL STORY ========================================================================== Researchers use advanced technology and mice to study dopamine neuron structure, addiction and the brain's ability to recover.


==========================================================================
A late 1980s commercial meant to combat drug addiction used a pair
of frying eggs as a metaphor for the effects of drugs on the human
brain. While researchers have long understood that there is a connection between drug abuse and adverse changes in the brain, it is only now that
they can study, in fine detail, alterations that actually occur.

Using state-of-the-art technology, researchers from the University
of Chicago and the U.S. Department of Energy's (DOE) Argonne National Laboratory detailed, for the first time, 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, which are Involved in multiple functions, from
voluntary movement to behavior. The results turned the page on older
questions regarding how dopamine is transmitted, while opening a new
chapter on others. Through continued work, the researchers hope to
understand how certain types of addictions work and, perhaps, develop
targeted treatments.

In a recent paper published in the journal eLife, the 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 clearly identify the process
by which dopamine is transmitted across neurons, as they don't make conventional physical connections, where signals are transferred across synapses.



========================================================================== "Evidence suggests that these neurons dump dopamine into extracellular
space, activating nearby neurons that possess dopamine sensing receptors,"
says Gregg Wildenberg, a lead investigator on the project. "But
connectomics has had little to say about these kinds of circuits because
they don't make typical connections, so we wanted to step into this area
to see how it actually worked." 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,
like cocaine? Obtaining that level of detail required the employment of Argonne's large volume, three-dimensional serial electron microscope. A high-powered microscope capable of visualizing the smallest details of
the brain, it allowed for a more intimate look at the dopamine neurons
from a selection of both cocaine sensitized mice and control animals.

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

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



==========================================================================
This process creates a 3D volume that allows researchers to identify
and trace different anatomical features of the dopamine neurons, which,
until recently, had proven something of a challenge.

"The leap of faith in this project was that we would actually be able
to detect anatomical changes that might be happening at any point in
the brain," said Narayanan "Bobby" Kasthuri, a co-investigator on the
project. "Could we take this microscopic slice of brain and find anything that's quantitatively different? That is also part of the reason why
we chose cocaine, because we thought whatever is happening is probably happening systemically throughout the brain." The results determined
that, indeed, dopamine neurons don't make physical connections, except
in some rare cases. And the latter may suggest that dopamine neurons
are not identical; that a different subclass may exist that is inclined
toward making more physical connections.

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

Some of these swellings, they found, were devoid of any vesicles, leading
some critics to charge that they could not be defined as proper release
sites. These empty varicosities, they say, likely indicate that there may
be other molecular components, in addition to the presence of vesicles,
that define dopamine release sites.

"We suggest that it's possible that these empty varicosities have
all the molecular machinery to release dopamine, but it may be that
dopamine vesicles are being shuttled actively throughout the axon and
we just happened to catch a snapshot in time where some are empty,"
said Wildenberg.

The cocaine portion of the study yielded two major changes, both of which
focus on axons, the ultrathin cables that project from neurons. Like
trees, axons sprout tendrils that branch away toward other axons to
deliver signals. After exposing the mice to cocaine, the team found an
increase in that branching.

In a totally unexpected result, they also found that about half of
the axons they studied formed huge swellings, or bulbs, at various
locations along the axon. The nearest correlation to these bulbs appears
in developing animals, at junctions where neurons meet muscle. In some
cases, an axon retracts, or is pruned, and then swells up into a large
bulblike structure.

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

"Now we know that there is an anatomical basis to drugs of exposure,"
noted Kasthuri. "These animals received one or two shots of cocaine and already, after two to three days, we saw widespread anatomical changes.

"It's not like some molecules are changing here or there," he added. "The circuit is rearranging much earlier and with much less exposure to
the drug than anybody would have thought." While the study has helped elucidate questions of form, function and dynamics in the dopamine system,
it also presents important new questions related to repeated exposure
and addiction, as well as treatment and recovery.

Primarily, can the brain overcome the structural rearrangements introduced
by addictive drugs, based upon its plasticity in other areas? Results
from this research and accessibility to powerful tools of discovery hold
the key to answering these types of questions in the future.

Research presented in this article was published in the Dec. 29, 2021,
issue of eLifeunder the title, "Cell type specific labeling and partial connectomes of dopaminergic circuits reveal non-synaptic communication
and large-scale axonal remodeling after exposure to cocaine." Authors
include: Wildenberg, Kasthuri and A.M. Sorokina, University of Chicago
and Argonne National Laboratory; J.L. Koranda, A. Monical, C. Heer, M.E.

Sheffield, X. Zhuang and DS McGehee, University of Chicago.

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

special promotion Explore the latest scientific research on sleep and
dreams in this free online course from New Scientist -- Sign_up_now_>>> academy.newscientist.com/courses/science-of-sleep-and-dreams ========================================================================== Story Source: Materials provided
by DOE/Argonne_National_Laboratory. Original written by John
Spizzirri. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Gregg Wildenberg, Anastasia Sorokina, Jessica Koranda, Alexis
Monical,
Chad Heer, Mark Sheffield, Xiaoxi Zhuang, Daniel McGehee, Bobby
Kasthuri.

Partial connectomes of labeled dopaminergic circuits reveal
non-synaptic communication and axonal remodeling after exposure
to cocaine. eLife, 2021; 10 DOI: 10.7554/eLife.71981 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220118144314.htm

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