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.



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.
Program in Developmental Neurogenetics, Institute for the Developing Mind, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California 90027.
Allison T
AT
Knoll
Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20814.
Lindsay R
LR
Halladay
Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20814.
Andrew J
AJ
Holmes
Program in Developmental Neurogenetics, Institute for the Developing Mind, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California 90027, Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California 90089, and plevitt@med.usc.edu.
Pat
0000-0002-9717-1695
P
Levitt
D000704:Analysis of Variance; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D003214:Conditioning, Classical / Q000502:physiology*; D005239:Fear; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors / Q000235:genetics*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology; D040641:Quantitative Trait Loci / Q000235:genetics*
D002317:Cardiovascular Agents; C578666:Hcn1 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D011743:Pyrimidines; C082246:ICI D2788
HCN1; anxiety; associative learning; individual differences; quantitative trait gene; threat detection