Summary: Researchers have discovered a new genetic candidate for testing therapies that could affect fear learning in PTSD.
Source: Children’s Hospital of Los Angeles.
Researchers at The Saban Research Institute of Children’s Hospital Los Angeles have identified a new genetic candidate for testing therapies that might affect fear learning in people with PTSD or other conditions. Results of the study have been published in the Journal of Neuroscience.
Individuals with trauma and stress-related disorders can manifest symptoms of these conditions in a variety of ways. Genetic risk factors for these and other psychiatric disorders have been established but do not explain the diversity of symptoms seen in the clinic – why are some individuals affected more severely than others and why do some respond better than others to the same treatment?
“People often experience stress and anxiety symptoms, yet they don’t usually manifest to the degree that results in a clinical diagnosis,” says Allison T. Knoll, PhD, post-doctoral fellow at The Saban Research Institute of Children’s Hospital Los Angeles. “We felt that if we could understand differences in the severity of symptoms in a typical population, it might provide clues about clinical heterogeneity in patients.”
The strategy was simple. Instead of focusing on a single gene identified for a given condition, the team at CHLA tried a different approach to discover genes that may impact symptom severity. Using a population-based mouse model, they studied normal variation in how well the mice detected threats and fears. They used mice that are well-characterized for learning behavior, and also exhibit a wide range of “high” and “low” anxiety, modeling the range found in humans. The investigators tested to see how well the mice learned to detect threats, a form of fear learning that all humans and animals do. When this learning is exaggerated in children or adults, symptoms of PTSD and anxiety are expressed.
“By understanding the biological origins of individual behavioral differences – in this case a measure of anxiety – we can move beyond a single disorder diagnosis and treat the dimensions that produce a behavior spanning a multitude of diagnoses,” said Knoll.
Using genetic tools, the researchers found a number of candidate genes that might influence learning of fear, and ultimately narrowed down to a single gene, Hcn1. The researchers were able to further demonstrate the impact of the Hcn1 gene on fear learning by interfering with the function of this gene before the learning challenge. They found that the mice did not learn fear. Even when the researchers disrupted gene function after the mice learned the fear, the mice were unable to express it.
“We’re suggesting that instead of focusing only on the genes that are thought to cause a disorder – for example, PTSD or anxiety disorder – it is important to discover those genes that can have a profound effect on how severely an individual is impacted by their disorder,” said Pat Levitt, PhD, Principal Investigator of the study, and the Simms/Mann Chair in Developmental Neurogenetics at CHLA. Levitt is also provost professor of Pediatrics, Neuroscience, Psychiatry and Pharmacy at the Keck School of Medicine of USC.
About this PTSD research article
Additional contributors to the study include Lindsay R. Halladay and Andrew J. Holmes, both of the Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH.
Funding: Funding was provided in part by the CHLA Simms/Mann Chair in Developmental Neurogenetics and the National Institute of Health (R01 MH080759).
Source: Ellin Kavanaugh – Children’s Hospital of Los Angeles Image Source: This NeuroscienceNews.com image is in the public domain. Original Research:Abstract for “Quantitative Trait Loci and a Novel Genetic Candidate for Fear Learning” by Allison T. Knoll, Lindsay R. Halladay, Andrew J. Holmes, and Pat Levitt in Journal of Neuroscience. Published online June 8 2016 doi:10.1523/JNEUROSCI.0177-16.2016
Cite This NeuroscienceNews.com Article
[cbtabs][cbtab title=”MLA”]Children’s Hospital of Los Angeles. “A New Genetic Candidate For The Treatment of PTSD.” NeuroscienceNews. NeuroscienceNews, 20 June 2016. <https://neurosciencenews.com/ptsd-genetics-treatment-4518/>.[/cbtab][cbtab title=”APA”]Children’s Hospital of Los Angeles. (2016, June 20). A New Genetic Candidate For The Treatment of PTSD. NeuroscienceNew. Retrieved June 20, 2016 from https://neurosciencenews.com/ptsd-genetics-treatment-4518/[/cbtab][cbtab title=”Chicago”]Children’s Hospital of Los Angeles. “A New Genetic Candidate For The Treatment of PTSD.” https://neurosciencenews.com/ptsd-genetics-treatment-4518/ (accessed June 20, 2016).[/cbtab][/cbtabs]
Quantitative Trait Loci and a Novel Genetic Candidate for Fear Learning
Trauma- and stress-related disorders are clinically heterogeneous and associated with substantial genetic risk. Understanding the biological origins of heterogeneity of key intermediate phenotypes such as cognition and emotion can provide novel mechanistic insights into disorder pathogenesis. Performing quantitative genetics in animal models is a tractable strategy for examining both the genetic basis of intermediate phenotypes and functional testing of candidate quantitative traits genes (QTGs). Here, existing and newly collected data were used for collaborative genome-wide mapping of cued fear acquisition and expression in 65 mouse strains from the BXD genetic reference panel. For fear acquisition, we identified a significant locus on chromosome (Chr) 10 and eight suggestive loci on Chr 2, 4, 5, 11, 13, and 15. For fear expression, we identified one significant and another highly suggestive locus on Chr 13, as well as four suggestive loci on Chr 10, 11, and X. Across these loci, 60 putative QTGs were identified. The quantitative trait locus on distal Chr 13 contained a single, highly promising gene at the location of the peak likelihood ratio statistic score. The gene, hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1), regulates neuronal excitability. Validation experiments using behavioral pharmacology revealed that functional Hcn channels in the basolateral amygdala are necessary for conditioned fear acquisition and expression. Hcn1, together with the other candidate QTGs, thus provide new targets for neurobiological and treatment studies of fear learning and trauma- and stress-related disorders.
SIGNIFICANCE STATEMENT There is a knowledge gap in understanding the genetic contributions to behavioral heterogeneity in typical and atypical populations. Mouse genetic reference panels (GRPs) provide one approach for identifying genetic sources of variation. Here, we identified three loci for conditioned fear acquisition and expression in a mouse GRP. Each locus contained candidate quantitative trait genes (QTGs). One locus had a single QTG, Hcn1 (hyperpolarization-activated cyclic nucleotide-gated channel 1), which has been implicated in neuronal excitability and learning. This discovery was validated using behavioral pharmacology, revealing that Hcn channels in the basolateral amygdala are required for fear acquisition and expression. The study thus identifies novel candidate QTGs that may contribute to variation in emotional learning and highlight the utility of mouse GRPs for the identification of genes underlying complex traits.
“Quantitative Trait Loci and a Novel Genetic Candidate for Fear Learning” by Allison T. Knoll, Lindsay R. Halladay, Andrew J. Holmes, and Pat Levitt in Journal of Neuroscience. Published online June 8 2016 doi:10.1523/JNEUROSCI.0177-16.2016