What if there was a way to help the human brain to allow us to battle addiction, ward off stress and anxiety and even prevent depression?
That is the monumental task being undertaken by a former Scotland County R-I graduate as part of a neuroscience research team at Washington University in St. Louis.
Kyle Parker, an instructor at the university, also serves on the research faculty in the Department of Anesthesiology at Washington University as part of Jordan McCall’s lab at the Center for Clinical Pharmacology, a collaborative group including the Department of Anesthesiology and St. Louis College of Pharmacy.
Parker is a 2004??? graduate of Scotland County R-I High School. He is the son of James and Christine Parker of Memphis.
Recently Parker’s work A Paranigral VTA Nociceptin Circuit that Constrains Motivation for Reward was featured in Cell, a leading publication in the science world.
The research has been featured in numerous other publications including “The Science Behind Giving Up” in ScienceDaily.
Parker was a Postdoctoral Research Associate in Michael Bruchas’s lab where this study was conducted.
“I started on this project when I came to Dr. Bruchas’s lab in July of 2015,” said Parker. “My work published in Cell was looking at the nociceptin opioid peptide, its receptor, and their function in reward-seeking behaviors.”
Parker was lead researcher on the project with the co-first authors graduate student Christian Pedersen post doctoral candidate Adrian Gomez contributing equally to the completion of the manuscript.
“My main role in the project was to lead this team of researchers, with the guidance of Dr. Bruchas, to try to understand how the nociceptin system affects reward behavior and the brain circuitry that this involves.”
The National Institutes of Health explains that the brain, our communications center, conatins billions of nerve cells called neurons that connect to each other in circuits. Each neuron has receptors on its surface. The neurons send and receive messages using molecules called neurotransmitters, which actually attach to the receptor, unlocking a response.
Parker explained that his research targeted the nociceptin opioid peptide (NOP) receptor, which is in the family of opioid receptors that include the mu-opioid peptide receptor (the receptor that opiates like morphine and heroin bind to).
“This family of receptors help coordinate a lot of different behaviors from food consumption to pain to general affect (emotion) depending on their location in the brain,” he explained.
The project was following up on previous research that had revealed a brain area called the ventral tegmental area (VTA) expresses the nociceptin opioid peptide (NOP) receptor in dopamine neurons and activating this receptor would inhibit these neurons and prevent them from releasing dopamine.
Dopamine is a neurotransmitter most often associated with emotional responses, but also known to impact movement, attention and learning.
“These VTA neurons are a main source of dopamine in the brain that help coordinate motivated behaviors, reward, and learning, which are all parts of drug addiction,” said Parker.
The main focus of Parker’s study was to find the areas of the brain that had the nociceptin neurons that connected to these dopamine neurons to ultimately inhibit them.
To do this, the researchers studies transgenic mice that express fluorescent genes in the cells that make nociceptin.
“We were able to find many areas in the brain that express nociceptin and more specifically, were able to locate VTA-projecting neurons through viral retrograde tracing experiments. The most prominent area we found was actually already in the VTA, just a little bit below and behind the VTA in a region called the paranigral nucleus of the VTA (pnVTA). Here we saw a group of cells that projected onto the dopamine cells, so we used different genetic techniques to manipulate and record the activity of the cells during reward-seeking behavior.”
As part of the study, an operant conditioning paradigm was used, as the mice learned how to put their nose through a small hole to get a reward, a dose of sugar water, from a dispenser. Later in the study, after the mice had learned how to easily earn the reward, the dispenser was changed to require three nose pokes to release the reward. Finally, a progressive ratio test was implemented, that required a progressively increased number of nose pokes to release the sugar water.
“What happens is that mice will eventually stop responding because the reward isn’t worth the cost anymore,” said Parker. “We call this the breakpoint. This typically happens after about 8 rewards where the effort required is much higher, around 20 nosepokes.”
During this process, the scientists were monitoring the subjects brains, and particularly the VTA neurons.
“What we found was that when animals are getting close to their breakpoint, we see the pnVTA nociceptin neurons become more active,” said Parker. “In fact, they are most active during the very last nose poke. We also found that if we manipulate the activity of these neurons, we can affect how hard the animals are willing to work for the reward. When we blocked the activity or killed these neurons in the mice, we see that the animals will work much harder for the reward. If we stimulate the activity of these neurons, the animals will give up much sooner.”
The research also experimented with manipulating the expression of the receptor.
“We were able to genetically take out the receptor only in the dopamine neurons and found that mice missing this receptor would reach very high breakpoints,” said Parker. “This was likely due to dopamine neurons not being inhibited by nociceptin so more dopamine is release and the animals continue seeking the reward.”
Based on the experimental results, the group concluded that nociceptin circuitry in the VTA is necessary for normal reward seeking behavior. If there is loss to the circuitry function, excessive reward seeking will result, but in cases of over activity, subjects will be less motivated.
“These neurons may be critical to understanding reward seeking behaviors observed in drug addiction,” said Parker. “This is where the research has its implications for human disease. New therapeutics are being tested to see if nociceptin receptor-based drugs can affect motivation for drugs of abuse, but the NOP receptor is also promising target for the treatment of depression and anxiety.”
The results have made the news across many science outlets, but Parker believes it may just be the tip of the iceberg.
“The nociceptin system is likely also involved in other components of affective behaviors, including anxiety-like behaviors and responses to stress,” he said. “The next steps are to seek out the neurocircuitry that drives the activity of these pnVTA nociceptin neurons. This is currently part of my research interests as well as Dr. Bruchas’s lab, but I’m also interested in other nociceptin neuron populations affect stress and anxiety behaviors, especially those involved in drug/alcohol withdrawal and binge-eating behaviors.’
Parker currently is involved in lab work investigating the role of excitatory VTA glutamate neurons that project to the locus coeruleus, an area of the brain with neurons that make and release norepinephrine.
“This area responds to stressful stimuli and increases vigilance and arousal,” he said. “We’re interested how the excitability of these neurons change after chronic stressful environments and whether these changes can cause depressive and anxiety-like symptoms in mice.”
Prior to joining the team at Washington University, Parker was a Postdoctoral Researcher at the University of Minnesota in Minneapolis where he moved after earning his PhD in Neuroscience at the University of Missouri – Columbia in 2013.
“My research interests have spanned through several studies in neuroscience including feeding, reward, exercise, and learning behaviors,” he said. “Most of these studies have involved looking at the function of opioid peptides and their receptors and the role they have in affective behaviors like motivation, feeding, and addiction behaviors.”
His PhD research focused on investigating how the brain communicates information about eating palatable food when not hungry.
The work was part of a published paper through the University of Missouri MU Bond Life Science Center highlighting the researchers’ work as unlocking the mechanisms in the brain that separate food consumption from cravings.