Study shows different brain cells process positive, negative experiences

May 27, 2016 by Andrew Myers, Stanford University Medical Center
Study shows different brain cells process positive, negative experiences
This 3-D CLARITY image shows neural connections from the prefrontal cortex across an entire transparent mouse brain. Credit: Li Ye and Karl Deisseroth

Combining two cutting-edge techniques reveals that neurons in the prefrontal cortex are built to respond to reward or aversion, a finding with implications for treating mental illness and addictions.

The plays a mysterious yet central role in the mammalian brain. It has been linked to mood regulation, and different cells in the prefrontal cortex seem to respond to positive and negative experiences. How the prefrontal cortex governs these opposing processes of reward or aversion, however, has been largely unknown.

In a new paper published online May 26 in Cell, researchers at Stanford, led by Karl Deisseroth, have united two transformational research techniques to show how the prefrontal circuits that process positive and negative experiences are distinctly and fundamentally different from one another, both in how they function and in how they are wired to other parts of the brain.

"These cells are built differently," said Deisseroth, MD, PhD, professor of bioengineering and of psychiatry and behavioral sciences. "They didn't start the same and then change their nature with recent experience. They appear wired specifically to communicate positive or ."

This has deep implications for both our understanding of how reward and aversion work, but also for the potential development of drugs or other therapies to treat drug addiction and mental illnesses tied to reward and aversion.

The full dream

The paper fully combines, for the first time, two novel research techniques developed by Deisseroth: optogenetics and CLARITY.

Optogenetics is a technique for genetically modifying cells—neurons, in this case—in living animals so that their function can be turned on and off with light. CLARITY is a remarkable feat of chemical engineering in which the fatty, opaque tissues that constitute an intact, non-living brain are removed, leaving behind a transparent physical structure with all of its parts and wiring exactly in place.

"Unifying optogenetics and CLARITY enables us to discover how behavior arises from whole-brain circuit activity patterns without losing sight of individual neurons," said Deisseroth, who holds the D.H. Chen Professorship. "We can obtain the fine detail and the big picture at the same time."

Previously it has not been possible, for example, to determine whether the neurons in the prefrontal cortex that are active during distinct experiences are physically different kinds of cells or whether they simply receive different information. This distinction matters a great deal when thinking about the basic processing in this part of the brain, as well as when considering possible therapies targeted to cell type.

Prior techniques allowed researchers to either listen in on the activity of a group of neurons using electrodes or to image brain activity. But these techniques can't report how these cells are connected across an individual subject's brain as researchers track cell activity during behavior.

Now, by uniting optogenetics and CLARITY, Deisseroth's team has shown how to study both the function and the wiring of neurons simultaneously, thus hitting a crucial target for the National Institutes of Health's BRAIN Initiative.

"This is a first look at these cells in detail while retaining the link to activity during behavior," Deisseroth said. "It's like getting to know the various components of a computer circuit, but also digging deeper into what their individual properties are, how they are wired together and how they are used in the circuit. Ultimately, it helps you understand how it all works."

Achieving CLARITY

The first facet of the research involved CLARITY. It allowed the researchers to trace specific pathways and "label" specific molecular structures within the brains of the subjects, which in this case were mice. The researchers gave the mice positive or negative stimuli. Only the neurons that had been strongly active during the experience became labeled—along with their outgoing connections—allowing effective tracing of the distinct circuits through the brain.

Using optogenetics, the researchers controlled specific neurons, within the living animals that had been active during positive or negative experiences. The team was able to then evaluate how those particular affect behavioral outcomes.

Those mice had been optogenetically modified so that the cells becoming light-sensitive were only those that were most active during the positive or negative experience provided. For instance, the team was able to turn on only the positive-experience-associated cells to observe behavior in the mice. In effect, they were able to fool the mice into thinking they were experiencing a positive-valence stimulus, such as chocolate or cocaine, in order to observe how behavior changed.

By pairing the techniques in the same experiment, Deisseroth's team was able to determine not only that the molecular signature of the positive cells was different from those of the negative cells—both cocaine and chocolate associated with cells producing a particular molecular marker called NPAS4—but also that the positive and negative were wired to distant places in the brain in fundamentally differing ways.

Given the strong linkage between the prefrontal cortex and various psychiatric illness, Deisseroth said this study opens the possibility in future studies to identify and target different cell types with diverse therapeutic approaches, including drugs or external stimulation techniques.

Deisseroth said the findings of this study, as with his other transformational work, are the result of a remarkable interdisciplinary effort. In this case, the team included Liqun Luo, PhD, a Stanford professor of biology whose lab developed a mouse line that was used for one of several different experience-dependent labeling strategies in the paper, and Jennifer McNab, PhD, a Stanford assistant professor of radiology who helped quantify the cellular pathways through the . The experimental work was led by postdoctoral researchers Li Ye and William Allen, and by Kimberly Thompson, a graduate student. All three were lead authors of the paper.

"The Stanford community is an incredible place for interdisciplinary research," Deisseroth said. "The right people are always just a short walk away. This study and its implications are a testament to the value of that environment."

Explore further: Optogenetics illuminates pathways of motivation through brain, study shows

Related Stories

Optogenetics illuminates pathways of motivation through brain, study shows

November 18, 2012
Whether you are an apple tree or an antelope, survival depends on using your energy efficiently. In a difficult or dangerous situation, the key question is whether exerting effort—sending out roots in search of nutrients ...

Optogenetics reveals new insights into circuits of the brain

April 20, 2016
To date, scientists have largely been in the dark with regard to how individual circuits operate in the highly branched networks of the brain. Mapping these networks is a complicated process, requiring precise measurement ...

Both sides now: Brain reward molecule helps learning to avoid unpleasant experience, too

February 29, 2016
The brain chemical dopamine regulates how mice learn to avoid a disagreeable encounter, according to new research from the Perelman School of Medicine at the University of Pennsylvania. "We know that dopamine reinforces 'rewarding' ...

Scientists uncover neural pathway responsible for opioid withdrawal

February 4, 2016
In addition to the desire to experience a "high," one of the obstacles drug addicts encounter is the difficulty of overcoming a myriad of harsh withdrawal symptoms including anxiety, depression, nausea, vomiting and diarrhea. ...

Stanford and MIT scientists win Perl-UNC Neuroscience prize

April 25, 2012
The University of North Carolina at Chapel Hill has awarded the 12th Perl-UNC Neuroscience prize to Karl Deisseroth, MD, PhD of Stanford University and Edward Boyden, PhD and Feng Zhang, PhD of the Massachusetts Institute ...

Scientists cast light on the brain's social cells

June 24, 2014
Picture yourself hovering over an alien city with billions of blinking lights of thousands of types, with the task of figuring out which ones are connected, which way the electricity flows and how that translates into nightlife. ...

Recommended for you

New neurons in the adult brain are involved in sensory learning

February 23, 2018
Although we have known for several years that the adult brain can produce new neurons, many questions about the properties conferred by these adult-born neurons were left unanswered. What advantages could they offer that ...

Neuroscientists discover a brain signal that indicates whether speech has been understood

February 22, 2018
Neuroscientists from Trinity College Dublin and the University of Rochester have identified a specific brain signal associated with the conversion of speech into understanding. The signal is present when the listener has ...

Study in mice suggests personalized stem cell treatment may offer relief for multiple sclerosis

February 22, 2018
Scientists have shown in mice that skin cells re-programmed into brain stem cells, transplanted into the central nervous system, help reduce inflammation and may be able to help repair damage caused by multiple sclerosis ...

Nolan film 'Memento' reveals how the brain remembers and interprets events from clues

February 22, 2018
Key repeating moments in the film give viewers the information they need to understand the storyline. The scenes cause identical reactions in the viewer's brain. The results deepen our understanding of how the brain functions, ...

Biomarker, clues to possible therapy found in novel childhood neurogenetic disease

February 22, 2018
Researchers studying a rare genetic disorder that causes severe, progressive neurological problems in childhood have discovered insights into biological mechanisms that drive the disease, along with early clues that an amino ...

A look at the space between mouse brain cells

February 22, 2018
Between the brain's neurons and glial cells is a critical but understudied structure that's been called neuroscience's final frontier: the extracellular space. With a new imaging paradigm, scientists can now see into and ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.