Researchers describe a novel underlying mechanism involved in PTSD and other anxiety disorders This study shows how stress blocks the release of an anti-anxiety neuropeptide in the brain, and it could pave the way for new therapeutic targets for PTSD.

lynn dobrunz 2017UAB neurobiologist Lynn Dobrunz, Ph.D.University of Alabama at Birmingham neurobiologist Lynn Dobrunz, Ph.D., has discovered a novel mechanism for how stress-induced anxiety — the type of experience that can produce post-traumatic stress disorder, or PTSD — affects circuit function in the hippocampus, the area of the brain where aversive memories are formed.

These studies by Dobrunz and colleagues fill an important gap in knowledge between the molecular, circuit and behavioral effects of the brain-signaling molecule called neuropeptide Y. Their findings, published in the Journal of Neuroscience, could pave the way for new therapeutic targets to increase neuropeptide Y release in the appropriate brain pathway for patients with anxiety disorders.

Increased levels of neuropeptide Y are well-known to produce anxiety-relieving effects. In contrast, the levels of neuropeptide Y are reduced in people with PTSD and other anxiety disorders. Until now, the mechanism of how changing levels of neuropeptide Y alters circuit function to reduce or increase anxiety behavior has not been known. Besides describing a mechanism for that, the UAB researchers also show that the stress of exposing mice to a predator scent — a compound found in the feces of foxes — prevents the release of neuropeptide Y, potentially enhancing anxiety.

PTSD is a public health challenge. It is marked by reactions to trauma or a life-threatening event that do not go away or even grow worse — reactions such as jumpiness, difficulty sleeping or upsetting memories. About 3.5 percent of the U.S. population has PTSD in a given year, and the rate for women is nearly three times higher than that for men, according to the U.S. Department of Veterans Affairs. The estimated prevalence of PTSD among Gulf War veterans and veterans of Iraq and Afghanistan exceeds 10 percent.

Major findings

In their research, Dobrunz and colleagues focused on the CA1 area of the hippocampus. CA1 is involved in learning and memory, and distinct sets of neurons there are able to release neuropeptide Y.

Two neural pathways activate CA1 — the Schaffer collateral, or SC, pathway and the temporoammonic, or TA, pathway. While both pathways are involved in fear learning, the TA pathway has been shown to be particularly sensitive to stress. Using a novel, physiologically based assay, the researchers were able to send a train of electrical pulses through these pathways to stimulate the release of endogenous neuropeptide Y from three subtypes of neurons in CA1.

PTSD is a public health challenge. It is marked by reactions to trauma or a life-threatening event that do not go away or even grow worse — reactions such as jumpiness, difficulty sleeping or upsetting memories. About 3.5 percent of the U.S. population has PTSD in a given year, and the rate for women is nearly three times higher than that for men.
This release caused a change in plasticity — specifically, a suppression of short-term facilitation — of TA synapses onto excitatory neurons in the CA1. The endogenous release also changed plasticity of SC synapses, but this required activation of both the SC and TA pathways.

Importantly, the researchers found that stressing mice with predator scent — a mouse model of PTSD — impaired the release of endogenous neuropeptide Y in the TA pathway and altered the function of the TA synapses. This impairment of neuropeptide Y release, Dobrunz and colleagues say, contributes to circuit dysfunction in the CA1 area of the hippocampus in response to stress.

From this study and what others know about the hippocampus, the UAB results suggest the following train of events: 1) The stress of smelling a predator scent impairs neuropeptide Y release. 2) This reduction in neuropeptide Y release enhances short-term plasticity of TA synapses. 3) The enhanced plasticity, in turn, boosts the strength of that pathway to drive more spiking of CA1 nerve cells. 4) Increased spiking alters the hippocampal output, a changed output that may increase the consolidation of fear learning.

“Our study,” the authors wrote, “is the first demonstration of the impact of endogenously released neuropeptide Y on SC and TA short-term plasticity in response to stimulation with a physiologically derived spike train. While no in vitro experiment completely duplicates in vivo conditions, these experiments bring us one step closer to the physiological situation and advance our understanding of how temporally complex activity regulates neuropeptide Y release from neuropeptide Y-positive interneurons.”

Furthermore, Dobrunz says, her novel assay could also be used to detect effects of endogenous neuropeptide Y release in other neurological and neuropsychiatric disorders where neuropeptide Y is implicated. These include epilepsy, depression and schizophrenia.

Besides Dobrunz, who is an associate professor of neurobiology, the authors of “Endogenously released neuropeptide Y suppresses hippocampal short-term facilitation and is impaired by stress-induced anxiety” are Qin Li and Aundrea F. Bartley, UAB Department of Neurobiology, Civitan International Research Center and the Evelyn F. McKnight Brain Institute.

This research was supported by National Institutes of Health Grant MH-108342 and a UAB Center for Clinical and Translational Sciences pilot award.
Save the Date Web Announcement 4

 

Congratulations to Drs. Pozzo-Miller and King who have received a Research Experience for Undergraduates award from the National Science Foundation. This award will allow the Department of Neurobiology to host 10 students from outside of UAB for 10 weeks of summer research training and professional development.  Students who are interested in pursuing PhD training after their BS/BA should apply for the March 1, 2017 deadline.  The application is online now at: http://www.uab.edu/medicine/neurobiology/education/undergraduate-summer-research





The Civitan International Research Center is announcing the availability of trainee travel awards to facilitate presentations at meetings, conferences or symposia related to research and/or clinical activities addressing neurodevelopmental disabilities. Individual awards of up to $1000 will apply toward conference registration fees, airfare, hotel and meals according to UAB travel policy.


Application deadlines will be April 1 and September 1, 2017. 

Applications should include the following in a single pdf file:
·  a description of the travel opportunity and relationship to the trainee program of study
·  a one-page CV from the trainee 
·  a letter of endorsement from the mentor clearly stating how the student will benefit from participation and also that no other support is available for this travel
·  travel budget details
·  copy of abstract – include letter of acceptance 

The mission of the CIRC is to improve the well-being and the quality of life of individuals and families affected by neurodevelopmental disabilities; to provide interdisciplinary clinical and research training in neurodevelopmental disabilities; to utilize this knowledge to develop and provide high quality exemplary services and programs; and to exchange information in a timely way with consumers, practitioners, scientists, and society.

Submission guidelines:
Title the subject matter: Travel Application "Last name"  
Submit to:
Vicki Hixon vhixon@uab.edu






The Scientist - January 2017 Edition - Exploring Life, Inspiring Innovation
www.The-scientist.com

SCIENTIST TO WATCH Assistant Professor, University of Alabama at Birmingham. Age: 35
BY CATHERINE OFFORD
Day
Jeremy Day: Reward  Researcher

As an undergraduate at Auburn University in the early 2000s, Jeremy Day was thinking of becoming an architect. But an opportunity to work on a research project investigating reward learning in rodents changed the course of his career. “It really hooked me,” he says. “It made me immediately wonder what mecha- nisms were underlying that behavior in the animal’s brain.”

It’s a question Day has pursued ever since. In 2004, he enrolled in a PhD program at the University of North Carolina at Chapel Hill and began studying neural reward signaling under the mentorship of neu- roscientist Regina Carelli. “He was a stellar student by all accounts,” Carelli recalls. “He was very clear on the type of work he wanted to do, even that early on in his career.” Focusing on the nucleus accum- bens, a brain region involved in associative learning, Day measured dopamine levels in rats undergoing stimulus-reward experiments. Although a rat’s brain released dopamine on receipt of a reward early in training, Day found that, as the rodent became accustomed to spe- cific cues predicting those rewards, this dopamine spike shifted to accompany the cues instead, indicating a changing role for the chemical during learning.1

Day completed his PhD in 2009, but realized that to better understand dopamine signaling and errors in the brain’s reward system that lead to addiction, he would need a broader skill set. “I had a strong background in systems neuroscience, but my training in molecular neuroscience was not as strong,” he explains. So he settled on “a field that I knew almost nothing about”—epigenetics—and joined David Sweatt’s lab at the University of Alabama at Birmingham (UAB) as a postdoc. For someone used to a field where “data come in as it’s happening,” Day says, “transitioning to a molecular lab where you might do an assay and you don’t get an answer for a week or two was a culture shock.”

Initially, Day investigated epigenetic modification in the nucleus accumbens. “The idea was that we’d block DNA methylation and see if we could also block learning,” he explains. But things didn’t go according to plan. “We worked on that for a couple of years and, basically, all the results from that experiment were negative.”

Instead of giving up, Day refocused. “He demonstrated a lot of perseverance,” recalls Sweatt. “It really took commitment and determination to stick with the project.” Leaving the nucleus accumbens, Day tried similar experiments in another site involved in dopaminergic pathways. “We found that if we blocked DNA methylation in that region, we could completely block an animal’s ability to learn about rewards,” Day says.2

In 2013, Day received a grant from the National Institute on Drug Abuse (NIDA) that helped him set up as an assistant professor at UAB the following year. He has continued collaborating with Sweatt—now at Vanderbilt University School of Medicine—who calls his former postdoc “a rising star in the discipline.” In 2016, they published evidence that extra-coding RNAs—noncoding RNAs whose sequences overlap with protein- coding regions—help regulate neuronal DNA methylation in an activity-dependent   manner.3

Now, Day is most excited about CRISPR-Cas9’s potential to explore epigenetics in the brain. “For the first time, we have the ability to look at the causal role for these modifications in gene regulation, neural function, and behavior,” he says. “It’s a really fun time to be in the field.” J

REFERENCES 1. J.J. Day et al., “Associative learning mediates dynamic shifts in dopamine signaling in the nucleus accumbens,” Nat Neurosci, 10:1020-28, 2007. (Cited  359 times) 2. J.J. Day et al., “DNA methylation regulates associative reward learning,” Nat Neurosci, 16:1445-52, 2013. (Cited 82 times) 3.  K.E. Savell et al., “Extra-coding RNAs regulate neuronal DNA methylation dynamics,” Nat Commun, 7:12091, 2016. (Cited 1 time)