Dr. Smith and his colleagues in the lab work on dendrites, tree-like structures that make connections with other cells to gather information for neurons. Their work shows evidence that the tree-like branches of dendrite, which were previously thought of as simple wires transmitting information, actually process information themselves in mammalian visual cortex in vivo.

“Imagine examining an electrical circuit under a microscope and finding that what you thought were wires are actually transistors,” said Dr. Smith.

In order to successfully examine the dendrites, which are two microns in diameter, less than 1/3 the width of a red blood cell, Dr. Smith custom built a laser-based, two-photon microscope. This custom microscope makes it possible to obtain recordings of electrical activity directly from dendrites.

“It is very rare to find a scientist who is well-trained in physics, optics and neuroscience,” said Carol Otey, PhD, chair of the department of cell biology and physiology, “and that is a powerful combination.”

The Klingenstein Fund supports researchers early in their careers who are engaged in basic or clinical research that may lead to a better understanding of neurological and psychiatric disorders. The award will provide $150,000 over a three-year period. The researchers will be able to carry out further experiments to investigate the nature of processing that dendrites perform.

“The award from the Klingenstein Fund is transformative. It will enable us to take on more ambitious experiments,” said Dr. Smith.

Media contact: Les Lang, (919) 966-9366, llang@med.unc.edu

Monday, April 8, 2013

CHAPEL HILL, N.C. – A study from the University of North Carolina School of Medicine offers new insights into how the nervous system processes hot and cold temperatures. The research led by neuroscientist Mark J. Zylka, PhD, associate professor of cell biology and physiology, found an interaction between the neural circuits that detect hot and cold stimuli: cold perception is enhanced when nerve circuitry for heat is inactivated.

“This discovery has implications for how we perceive hot and cold temperatures and for why people with certain forms of chronic pain, such as neuropathic pain, or pain arising as  direct consequence of a nervous system injury or disease, experience heightened responses to cold temperatures,” says Zylka, a member of the UNC Neuroscience Center.

The study also has implications for why a promising new class of pain relief drugs known as TRPV1 antagonists (they block a neuron receptor protein) cause many patients to shiver and “feel cold” prior to the onset of hyperthermia, an abnormally elevated body temperature. Enhanced cold followed by hyperthermia is a major side effect that has limited the use of these drugs in patients with chronic pain associated with multiple sclerosis, cancer, and osteoarthritis.

Zylka’s research sheds new light on how the neural circuits that regulate temperature sensation bring about these responses, and could suggest ways of reducing such side-effects associated with TRPV1 antagonists and related drugs.

The research was selected by the journal Neuron as cover story for the April 10, 2013 print edition and was available in the April 4, 2013 advanced online edition.

This new study used cutting edge cell ablation technology to delete the nerve circuit that encodes heat and some forms of itch while preserving the circuitry that sense cold temperatures. This manipulation results in animals  that were practically “blind” to heat, meaning they could no longer detect hot temperatures, Zylka explains. “Just like removing heat from a room makes us feel cold (such as with an air conditioner), removing the circuit that animals use to sense heat made them hypersensitive to cold. Physiological studies indicated that these distinct circuits regulate one another in the spinal cord.”

TRPV1 is a receptor for heat and is found in the primary sensory nerve circuit that Zylka studied. TRPV1 antagonists make patients temporarily blind to heat, which Zylka speculates is analogous to what happened when his lab deleted the animals’ circuit that detects heat: cold hypersensitivity.

Zylka emphasizes that future studies will be needed to confirm that TRPV1 antagonists affect cold responses in a manner similar to what his lab found with nerve circuit deletion.

The study was conducted in the Zylka lab by postdoctoral scientists Eric S. McCoy, Sarah E. Street, and Jihong Zheng and by research associates Bonnie Taylor-Blake and Alaine Pribisco. Funding for the research came from the Searle Scholars Program, The Klingenstein Foundation, The Rita Allen Foundation, the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Child Health and Human Development (NICHD).

 

Wednesday, March 20, 2013

CHAPEL HILL, N.C. – New research from the University of North Carolina School of Medicine for the first time explains exactly how two brain regions interact to promote emotionally motivated behaviors associated with anxiety and reward.

The findings could lead to new mental health therapies for disorders such as addiction, anxiety, and depression. A report of the research was published online by the journal, Nature, on March 20, 2013.

Located deep in the brain’s temporal lobe are tightly packed clusters of brain cells in the almond shaped amygdala that are important for processing memory and emotion. When animals or people are in stressful situations, neurons in an extended portion of the amygdala called the bed nucleus of the stria terminalis, or BNST, become hyperactive.

But, almost paradoxically, neurons in the BNST, which modulate fear and anxiety, reach into a portion of the midbrain that’s involved in behavioral responses to reward, the ventral tegmental area, or VTA.

“For many years it’s been known that dopamine neurons in the VTA are involved in reward processing and motivation. For example, they’re activated during exposure to drugs of abuse and naturally rewarding experiences,” says study senior author Garret Stuber, PhD, assistant professor in the departments of Psychiatry and Cell Biology and Physiology, and the UNC Neuroscience Center.  “On the one hand, you have this area of the brain – the BNST – that’s associated with aversion and anxiety, but it’s in direct communication with a brain reward center. We wanted to figure out exactly how these two brain regions interact to promote different types of behavioral responses related to anxiety and reward.”

In the past, researchers have tried to get a glimpse into the inner workings of the brain using electrical stimulation or drugs, but those techniques couldn’t quickly and specifically change only one type of cell or one type of connection. But optogenetics, a technique that emerged about seven years ago, can.

In the technique, scientists transfer light-sensitive proteins called “opsins” – derived from algae or bacteria that need light to grow – into the mammalian brain cells they wish to study. Then they shine laser beams onto the genetically manipulated brain cells, either exciting or blocking their activity with millisecond precision.

First, Stuber and colleagues used optogenetics for “photo-tagging,” to optically identify different types of neurons in vivo. This enabled them to identify a neuron in the BNST that’s projecting into the VTA. “So we know the neuron is directly interfacing with a reward-related brain region,” Stuber says.

They then exposed animals (mice) to a mild aversive stimulus, a carefully controlled but anxiety-provoking foot shock delivered repeatedly and unpredictably.  The BNST neurons projecting into the VTA showed changes in their firing rate, “But some cells would increase their activity and other would suppress their firing,” Stuber says, adding that it suggested there are functionally distinct populations of neurons within the BNST that are projecting to the VTA, thus highlighting the complexity of this neural circuit.

Stuber and his team then repeated the experiment, but this time optically identified BNST neurons that project to the VTA as either excitatory or inhibitory cells, by integrating the approach they developed with the use of transgenic animals that allows for precise targeting of distinct neuronal cell types. The glutamate (excitatory) neurons were the cell population that increased their activity in response to the foot shocks.  And the GABAergic (inhibitory) cells showed activity suppression during foot shock.

Finally, the researchers found that stimulating either of these brain cell pathways had opposing behavioral consequences. The glutamate neurons provoked an aversive, avoidance behavioral response and promoted anxiety-like behavior in the mice. In contrast, when Stuber’s team activated the GABAergic pathway projections from the BNST into the VTA, the animals showed reward-associated behaviors and less anxiety. They preferred that stimulation and would spend more time in the area of the cage where they had received it.

“If you activated the GABA cells, they showed less anxiety. And when we exposed them to foot shock and at the same time activated this GABAergic pathway, it actually reduced the anxiety-associated behavioral consequences of that otherwise “aversive” stimulation,” Stuber says.

“Because these cells are functionally and genetically distinct from each other, our findings also point to new potential targets for therapeutic interventions in neuropsychiatric disorders associated with alterations in motivated states such as addiction.

Along with Stuber, UNC study co-authors from the department of psychiatry are Joshua H. Jennings, Dennis R. Sparta, Alice M. Stamatakis and Randall L. Ung.  Other co-authors on this study include Kristen E. Pleil  and Thomas L. Kash who are affiliated with  the department of pharmacology, and the Bowles Center for Alcohol Studies.

Support for the study comes from the National Institutes of Health, the Whitehall Foundation, and the Foundation of Hope.

Media contact: Tom Hughes, 919-966-6047, tahughes@unch.unc.edu

Monday, Nov. 12, 2012

CHAPEL HILL, N.C. – Last year a clinical trial of L-DOPA -- a mainstay of Parkinson’s disease therapy -- was launched for Angelman syndrome, a rare intellectual disorder that shares similar motor symptoms such as tremors and difficulty with balance. The clinical trial is based on a 10-year-old case report showing benefit with the drug, but few studies since have explored the neurological justification for using L-DOPA to treat parkinsonian features in Angelman syndrome.

New research from the University of North Carolina School of Medicine, conducted in animal models of the disorder,  now provides justification for this therapeutic approach. The study, published online ahead of print on Nov. 12 by the Journal of Clinical Investigation, suggests that L-DOPA could compensate for a loss of the neurochemical dopamine in the brain’s motor pathways and improve motor symptoms. However, it also indicates that the drug could add to an already increased amount of dopamine in the brain’s reward pathways and thus have unanticipated consequences on emotion and attention.

“The results were extremely surprising, because we don’t know of any other disorder where dopamine is affected one way in one brain pathway and the opposite way in another,” said Benjamin D. Philpot, PhD, associate professor of cell biology and physiology at UNC.

“If what we see in humans mirrors what we see in mice, then it does provide some optimism that L-DOPA might provide benefit for tremor,” said C.J. Malanga, MD, PhD, associate professor of neurology at UNC. “But it also raises caution that researchers might want to consider assessing other aspects of Angelman syndrome that might be affected by dopamine -- not just motor symptoms but also other neuropsychiatric features.”  Malanga and Philpot are senior authors of the study.

Angelman syndrome affects about every one out of every 15,000 people. Individuals with the disorder have minimal verbal communication – some never speak a single word – as well as seizures and motor problems. It is caused by defects in UBE3A, a gene involved in the development of the brain’s wiring. Much of what has been learned about this gene has come from a mouse model lacking UBE3A.

Philpot and Malanga decided to use these Angelman syndrome model mice to explore how dopamine is affected in Angelman syndrome. Dopamine is a well-known neurotransmitter, one of many chemicals responsible for transmitting signals between neurons in the brain. In their experiments, the researchers found that the behavioral deficits seen in the Angelman syndrome model were not due to the loss of dopamine-producing brain cells -- as in Parkinson’s disease -- or reduced production of the important neurochemical.

Rather, they found that it was associated with differences in release of the dopamine molecule from brain cells. Specifically, dopamine release was decreased in one brain pathway -- the motor or nigrostriatal pathway -- and increased in another -- the reward or mesolimbic pathway.  But instead of having a greater effect on reward, dopamine also appeared to be less effective at motivating behavior in these mice.   

“One of the interesting features of people with Angelman syndrome is that they generally have a very happy disposition and a lower threshold for humor. It is interesting that we found this effect in the reward pathway, because it could provide a biological basis for this happy disposition,” said Philpot.

Malanga cautions that this happy disposition, as well as the lack of communication skills, might make it hard for researchers to tell if their Angelman syndrome patients are experiencing negative consequences of an altered reward pathway, such as changes in mood or compulsive behaviors. Therefore, he recommends that clinical trials assess many different outcome measures to ensure that L-DOPA treatment does not lead to unanticipated outcomes.

The research was funded by the National Institutes of Health, the Simons Foundation, the Angelman Syndrome Foundation and Autism Speaks. Study co-authors from UNC were Thorfinn T. Riday; Elyse C. Dankoski; Michael C. Krouse; Eric W. Fish, PhD; Paul L. Walsh; Ji Eun Han; Clyde W. Hodge, PhD; and R. Mark Wightman, PhD.